A 43-year-old man presented to a community hospital with acute chest pain and shortness of breath and was diagnosed with anterior ST-elevation myocardial infarction. He was a smoker with a history of alcohol abuse, hypertension, and hyperlipidemia, and in the past he had undergone percutaneous coronary interventions to the right coronary artery and the first obtuse marginal artery.

Angiography showed total occlusion in the left anterior descending artery, 90% stenosis in the right coronary artery, and mild disease in the left circumflex artery. A drug-eluting stent was placed in the left anterior descending artery, resulting in good blood flow. 

However, his left ventricle continued to have severe dysfunction. An intra-aortic balloon pump was inserted. Afterward, computed tomography showed subsegmental pulmonary embolism with congestion. His mean arterial pressure was 60 mm Hg (normal 70–110), central venous pressure 12 mm Hg (3–8), pulmonary artery pressure 38/26 mm Hg (15–30/4–12), pulmonary capillary wedge pressure 24 mm Hg (2–15), and cardiac index 1.4 L/min (2.5–4).

The patient was started on dobutamine and norepinephrine and transferred to Cleveland Clinic on day 2. Over the next day, he had runs of ventricular tachycardia, for which he was given amiodarone and lidocaine. His urine output was low, and his serum creatinine was elevated at 1.65 mg/dL (baseline 1.2, normal 0.5–1.5). Liver function tests were also elevated, with aspartate aminotransferase at 115 U/L(14–40) and alanine aminotransferase at 187 U/L (10–54).

Poor oxygenation was evident: his arterial partial pressure of oxygen was 64 mm Hg (normal 75–100). He was intubated and given 100% oxygen with positive end-expiratory pressure of 12 cm H₂O.

Echocardiography showed a left ventricular ejection fraction of 15% (normal 55%–70%) and mild right ventricular dysfunction.

ECMO and then Impella placement

On his third hospital day, a venoarterial extracorporeal membrane oxygenation (ECMO) device was placed peripherally (Figure 1).

His hemodynamic variables stabilized, and he was weaned off dobutamine and norepinephrine. Results of liver function tests normalized, his urinary output increased, and his serum creatinine dropped to a normal 1.0 mg/dL. However, a chest radiograph showed pulmonary congestion, and echocardiography now showed severe left ventricular dysfunction.

On hospital day 5, the patient underwent surgical placement of an Impella 5.0 device (Abiomed, Danvers, MA) through the right axillary artery in an effort to improve his pulmonary edema. The ECMO device was removed. Placement of a venovenous ECMO device was deemed unnecessary when oxygenation improved with the Impella.

Three days after Impella placement, radiography showed improved edema with some remaining pleural effusion.

ACUTE CARDIOGENIC SHOCK

Cardiogenic shock remains a challenging clinical problem: patients with it are among the sickest in the hospital, and many of them die. ECMO was once the only therapy available and is still widely used. However, it is a 2-edged sword; complications such as bleeding, infection, and thrombosis are almost inevitable if it is used for long. Importantly, patients are usually kept intubated and bedridden.

In recent years, new devices have become available that are easier to place (some in the catheterization laboratory or even at the bedside) and allow safer bridging to recovery, transplant, or other therapies.

This case illustrates the natural history of cardiogenic shock and the preferred clinical approach: ie, ongoing evaluation that permits rapid response to evolving challenges.

In general, acute cardiogenic shock occurs within 24 to 48 hours after the initial insult, so even if a procedure succeeds, the patient may develop progressive hypotension and organ dysfunction. Reduced cardiac output causes a downward spiral with multiple systemic and inflammatory processes as well as increased nitric oxide synthesis, leading to progressive decline and eventual end-organ dysfunction.

Continuously evaluate

The cardiac team should continuously assess the acuity and severity of a patient’s condition, with the goals of maintaining end-organ perfusion and identifying the source of problems. Refractory cardiogenic shock, with tissue hypoperfusion despite vasoactive medications and treatment of the underlying cause, is associated with in-hospital mortality rates ranging from 30% to 50%.^1,2 The rates have actually increased over the past decade, as sicker patients are being treated.

When a patient presents with cardiogenic shock, we first try a series of vasoactive drugs and usually an intra-aortic balloon pump (Figure 2). We then tailor treatment depending on etiology. For example, a patient may have viral myocarditis and may even require a biopsy.

If cardiogenic shock is refractory, mechanical circulatory support devices can be a short-term bridge to either recovery or a new decision. A multidisciplinary team should be consulted to consider transplant, a long-term device, or palliative care. Sometimes a case requires “bridging to a bridge,” with several devices used short-term in turn.

Prognostic factors in cardiogenic shock

Several tools help predict outcome in a severely ill patient. End-organ function, indicated by blood lactate levels and estimated glomerular filtration rate, is perhaps the most informative and should be monitored serially.

CardShock³ is a simple scoring system based on age, mental status at presentation, laboratory values, and medical history. Patients receive 1 point for each of the following factors:

• Age > 75
• Confusion at presentation
• Previous myocardial infarction or coronary artery bypass grafting
• Acute coronary syndrome etiology
• Left ventricular ejection fraction < 40%
• Blood lactate level between 2 and 4 mmol/L, inclusively (2 points for lactate levels > 4 mmol/L)
• Estimated glomerular filtration rate between 30 and 60 mL/min/1.73 m², inclusively (2 points if < 30 mL/min/1.73 m²). 

Thus, scores range from 0 (best) to 9 (worst). A score of 0 to 3 points was associated with a 9% risk of death in the hospital, a score of 4 or 5 with a risk of 36%, and a score of 6 through 9 with a risk of 77%.³

The Survival After Veno-arterial ECMO (SAVE) score (www.save-score.com) is a prediction tool derived from a large international ECMO registry.⁴ It is based on patient age, diagnosis, and indicators of end-organ dysfunction. Scores range from –35 (worst) to +7 (best).

The mortality rate associated with postcardiotomy cardiogenic shock increases with the amount of inotropic support provided. In a 1996–1999 case series of patients who underwent open-heart surgery,⁵ the hospital mortality rate was 40% in those who received 2 inotropes in high doses and 80% in those who received 3. A strategy of early implementation of mechanical support is critical.

Selection criteria for destination therapy

Deciding whether a patient should receive a long-term device is frequently a challenge. The decision often must be based on limited information about not only the medical indications but also psychosocial factors that influence long-term success.

The Centers for Medicare and Medicaid Services have established criteria for candidates for left ventricular assist devices (LVADs) as destination therapy.⁶ Contraindications established for heart transplant should also be considered (Table 1).

CASE REVISITED

Several factors argued against LVAD placement in our patient. He had no health insurance and had been off medications. He smoked and said he consumed 3 hard liquor drinks per week. His Stanford Integrated Psychosocial Assessment for Transplantation score was 30 (minimally acceptable). He had hypoxia with subsegmental pulmonary edema, a strong contraindication to immediate transplant.

On the other hand, he had only mild right ventricular dysfunction. His CardShock score was 4 (intermediate risk, based on lactate 1.5 mmol/L and estimated glomerular filtration rate 52 mL/min/1.73 m²). His SAVE score was –9 (class IV), which overall is associated with a 30% risk of death (low enough to consider treatment).

During the patient’s time on temporary support, the team had the opportunity to better understand him and assess his family support and his ability to handle a permanent device. His surviving the acute course bolstered the team’s confidence that he could enjoy long-term survival with destination therapy.

CATHETERIZATION LABORATORY DEVICE CAPABILITIES

Although most implantation procedures are done in the operating room, they are often done in the catheterization laboratory because patients undergoing catheterization may not be stable enough for transfer, or an emergency intervention may be required during the night. Catheterization interventionists are also an important part of the team to help determine the best approach for long-term therapy.

The catheterization laboratory has multiple acute intervention options. Usually, decisions must be made quickly. In general, patients needing mechanical support are managed as follows:

• Those who need circulation support and oxygenation receive ECMO
• Those who need circulation support alone because of mechanical issues (eg, myocardial infarction) are considered for an intra-aortic balloon pump, Impella, or TandemHeart pump (Cardiac Assist, Pittsburgh, PA).

Factors that guide the selection of a temporary pump include:

• Left ventricular function
• Right ventricular function
• Aortic valve stenosis (some devices cannot be inserted through critical aortic stenosis)
• Aortic regurgitation (can affect some devices)
• Peripheral artery disease (some devices are large and must be placed percutaneously).

CHOOSING AMONG PERCUTANEOUS DEVICES

Circulatory support in cardiogenic shock improves outcomes, and devices play an important role in supporting high-risk procedures. The goal is not necessarily to use the device throughout the hospital stay. Acute stabilization is most important initially; a more considered decision about long-term therapy can be made when more is known about the patient.

Patient selection is the most important component of success. However, randomized data to support outcomes with the various devices are sparse and complicated by the critically ill state of the patient population.

SHORT-TERM CIRCULATORY SUPPORT: ECMO, IMPELLA, TANDEMHEART

A menu of options is available for temporary mechanical support. Options differ by their degree of circulatory support and ease of insertion (Table 2).

ECMO: A fast option with many advantages

ECMO has evolved and now can be placed quickly. A remote diagnostic platform such as CardioHub permits management at the bedside, in the medical unit, or in the cardiac intensive care unit.⁷

ECMO has several advantages. It can be used during cardiopulmonary bypass, it provides oxygenation, it is the only option in the setting of lung injury, it can be placed peripherally (without thoracotomy), and it is the only percutaneous option for biventricular support.

ECMO also has significant disadvantages

ECMO is a good device for acute resuscitation of a patient in shock, as it offers quick placement and resuscitation. But it is falling out of favor because of significant disadvantages.

Its major drawback is that it provides no left ventricular unloading. Although in a very unstable patient ECMO can stabilize end organs and restore their function, the lack of left ventricular unloading and reduced ventricular work threaten the myocardium. It creates extremely high afterload; therefore, in a left ventricle with poor function, wall tension and myocardial oxygen demand increase. Multiple studies have shown that coronary perfusion worsens, especially if the patient is cannulated peripherally. Because relative cerebral hypoxia occurs in many situations, it is imperative to check blood saturations at multiple sites to determine if perfusion is adequate everywhere.    

Ineffective left ventricular unloading with venoarterial ECMO is managed in several ways. Sometimes left ventricular distention is slight and the effects are subtle. Left ventricular distention causing pulmonary edema can be addressed with:

• Inotropes (in moderate doses)
• Anticoagulation to prevent left ventricular thrombus formation
• An intra-aortic balloon pump. Most patients on ECMO already have an intra-aortic balloon pump in place, and it should be left in to provide additional support. For those who do not have one, it should be placed via the contralateral femoral artery.

If problems persist despite these measures, apical cannulation or left ventricular septostomy can be performed.

Outcomes with ECMO have been disappointing. Studies show that whether ECMO was indicated for cardiac failure or for respiratory failure, survival is only about 25% at 5 years. Analyzing data only for arteriovenous ECMO, survival was 48% in bridged patients and 41% in patients who were weaned.

The Extracorporeal Life Support Organization Registry, in their international summary from 2010, found that 34% of cardiac patients on ECMO survived to discharge or transfer. Most of these patients had cardiogenic shock from acute myocardial infarction. Outcomes are so poor because of complications endemic to ECMO, eg, dialysis-dependent renal failure (about 40%) and neurologic complications (about 30%), often involving ischemic or hemorrhagic stroke.

Limb and pump complications were also significant in the past. These have been reduced with the new reperfusion cannula and the Quadrox oxygenator.  

Complications unique to ECMO should be understood and anticipated so that they can be avoided. Better tools are available, ie, Impella and TandemHeart.

Left-sided Impella: A longer-term temporary support

ECMO is a temporary fix that is usually used only for a few days. If longer support is needed, axillary placement of an Impella should be used as a bridge to recovery, transplant, or a durable LVAD.

The Impella device (Figure 3) is a miniature rotary blood pump increasingly used to treat cardiogenic shock. It is inserted retrograde across the aortic valve to provide short-term ventricular support. Most devices are approved by the US Food and Drug Administration (FDA) for less than 7 days of use, but we have experience using them up to 30 days. They are very hemocompatible, involving minimal hemolysis. Axillary placement allows early extubation and ambulation and is more stable than groin placement.

Several models are available: the 2.5 and 3.5 L/min devices can be placed percutaneously, while the 5 L/min model must be surgically placed in the axillary or groin region. Heparin is required with their use. They can replace ECMO. A right ventricular assist device (RVAD), Impella RP, is also available.

Physiologic impact of the Impella

The Impella fully unloads the left ventricle, reducing myocardial oxygen demand and increasing myocardial blood flow. It reduces end-diastolic volume and pressure, the mechanical work of the heart, and wall tension. Microvascular resistance is reduced, allowing increased coronary flow. Cardiac output and power are increased by multiple means.^8–11

The RECOVER 1 trial evaluated the 5L Impella placed after cardiac surgery. The cardiac index increased in all the patients, and the systemic vascular resistance and wedge pressure decreased.¹²

Unloading the ventricle is critical. Meyns  and colleagues¹³ found a fivefold reduction in infarct size from baseline in a left anterior descending occlusion model in pigs after off-loading the ventricle.

Impella has the advantage of simple percutaneous insertion (the 2.5 and CP models). It also tests right ventricular tolerance: if the right ventricle is doing well, one can predict with high certainty that it will tolerate an LVAD (eg, HeartWare, HeartMate 2 (Pleasanton, CA), or HeartMate 3 when available).

Disadvantages include that it provides only left ventricular support, although a right ventricular device can be inserted for dual support. Placement requires fluoroscopic or echocardiographic guidance.

TandemHeart requires septal puncture

The TandemHeart is approved for short-term and biventricular use. It consists of an extracorporeal centrifugal pump that withdraws blood from the left atrium via a trans-septal cannula placed through the femoral vein (Figure 4) and returns it to one or both femoral arteries. The blood is pumped at up to 5 L/min.

It is designed to reduce the pulmonary capillary wedge pressure, ventricular work, and myocardial oxygen demand and increase cardiac output and mean arterial pressure. It has the advantages of percutaneous placement and the ability to provide biventricular support with 2 devices. It can be used for up to 3 weeks. It can easily be converted to ECMO by either splicing in an oxygenator or adding another cannula.

Although the TandemHeart provides significant support, it is no longer often used. A 21F venous cannula must be passed to the left atrium by trans-septal puncture, which requires advanced skill and must be done in the catheterization laboratory. Insertion can take too much time and cause bleeding in patients taking an anticoagulant. Insertion usually destroys the septum, and removal requires a complete patch of the entire septum. Systemic anticoagulation is required. Other disadvantages are risks of hemolysis, limb ischemia, and infection with longer support times.

The CentriMag (Levitronix LLC; Framingham, MA) is an improved device that requires only 1 cannula instead of 2 to cover both areas.

DEVICES FOR RIGHT-SIDED SUPPORT

Most early devices were designed for left-sided support. The right heart, especially in failure, has been more difficult to manage. Previously the only option for a patient with right ventricular failure was venoarterial ECMO. This is more support than needed for a patient with isolated right ventricular failure and involves the risk of multiple complications from the device.

With more options available for the right heart (Table 3), we can choose the most appropriate device according to the underlying cause of right heart failure (eg, right ventricular infarct, pulmonary hypertension), the likelihood of recovery, and the expected time to recovery.

The ideal RVAD would be easy to implant, maintain, and remove. It would allow for chest closure and patient ambulation. It would be durable and biocompatible, so that it could remain implanted for months if necessary. It would cause little blood trauma, have the capability for adding an oxygenator for pulmonary support, and be cost-effective.

Although no single system has all these qualities, each available device fulfills certain combinations of these criteria, so the best one can be selected for each patient’s needs.

ECMO Rotaflow centrifugal pump: Fast, simple, inexpensive

A recent improvement to ECMO is the Rotaflow centrifugal pump (Maquet, Wayne, NJ), which is connected by sewing an 8-mm graft onto the pulmonary artery and placing a venous cannula in the femoral vein. If the patient is not bleeding, the chest can then be closed. This creates a fast, simple, and inexpensive temporary RVAD system. When the patient is ready to be weaned, the outflow graft can be disconnected at the bedside without reopening the chest.

The disadvantage is that the Rotaflow system contains a sapphire bearing. Although it is magnetically coupled, it generates heat and is a nidus for thrombus formation, which can lead to pump failure and embolization. This system can be used for patients who are expected to need support for less than 5 to 7 days. Beyond this duration, the incidence of complications increases. 

CentriMag Ventricular Assist System offers right, left, or bilateral support

The CentriMag Ventricular Assist System is a fully magnetically levitated pump containing no bearings or seals, and with the same technology as is found in many of the durable devices such as HeartMate 3. It is coupled with a reusable motor and is easy to use.

CentriMag offers versatility, allowing for right, left, or bilateral ventricular support. An oxygenator can be added for pulmonary edema and additional support. It is the most biocompatible device and is FDA-approved for use for 4 weeks, although it has been used successfully for much longer. It allows for chest closure and ambulation. It is especially important as a bridge to transplant. The main disadvantage is that insertion and removal require sternotomy.

Impella RP: One size does not fit all

The Impella RP (Figure 5) has an 11F catheter diameter, 23F pump, and a maximum flow rate of more than 4 L/minute. It has a unique 3-dimensional cannula design based on computed tomography 3-dimensional reconstructions from hundreds of patients.

The device is biocompatible and can be used for support for more than 7 days, although most patients require only 3 or 4 days. There is almost no priming volume, so there is no hemodilution.

The disadvantages are that it is more challenging to place than other devices, and some patients cannot use it because the cannula does not fit. It also does not provide pulmonary support. Finally, it is the most expensive of the 3 right-sided devices.

CASE REVISITED

The patient described at the beginning of this article was extubated on day 12 but was then reintubated. On day 20, a tracheotomy tube was placed. By day 24, he had improved so little that his family signed a “do-not-resuscitate–comfort-care-arrest” order (ie, if the patient’s heart or breathing stops, only comfort care is to be provided).

But slowly he got better, and the Impella was removed on day 30. Afterward, serum creatinine and liver function tests began rising again, requiring dobutamine for heart support.

On day 34, his family reversed the do-not-resuscitate order, and he was reevaluated for an LVAD as destination therapy. At this point, echocardiography showed a left ventricular ejection fraction of 10%, normal right ventricular function, with a normal heartbeat and valves. On day 47, a HeartMate II LVAD was placed.

On postoperative day 18, he was transferred out of the intensive care unit, then discharged to an acute rehabilitation facility 8 days later (hospital day 73). He was subsequently discharged.

At a recent follow-up appointment, the patient said that he was feeling “pretty good” and walked with no shortness of breath.

A 43-year-old man presented to a community hospital with acute chest pain and shortness of breath and was diagnosed with anterior ST-elevation myocardial infarction. He was a smoker with a history of alcohol abuse, hypertension, and hyperlipidemia, and in the past he had undergone percutaneous coronary interventions to the right coronary artery and the first obtuse marginal artery.

Angiography showed total occlusion in the left anterior descending artery, 90% stenosis in the right coronary artery, and mild disease in the left circumflex artery. A drug-eluting stent was placed in the left anterior descending artery, resulting in good blood flow. 

However, his left ventricle continued to have severe dysfunction. An intra-aortic balloon pump was inserted. Afterward, computed tomography showed subsegmental pulmonary embolism with congestion. His mean arterial pressure was 60 mm Hg (normal 70–110), central venous pressure 12 mm Hg (3–8), pulmonary artery pressure 38/26 mm Hg (15–30/4–12), pulmonary capillary wedge pressure 24 mm Hg (2–15), and cardiac index 1.4 L/min (2.5–4).

The patient was started on dobutamine and norepinephrine and transferred to Cleveland Clinic on day 2. Over the next day, he had runs of ventricular tachycardia, for which he was given amiodarone and lidocaine. His urine output was low, and his serum creatinine was elevated at 1.65 mg/dL (baseline 1.2, normal 0.5–1.5). Liver function tests were also elevated, with aspartate aminotransferase at 115 U/L(14–40) and alanine aminotransferase at 187 U/L (10–54).

Poor oxygenation was evident: his arterial partial pressure of oxygen was 64 mm Hg (normal 75–100). He was intubated and given 100% oxygen with positive end-expiratory pressure of 12 cm H₂O.

Echocardiography showed a left ventricular ejection fraction of 15% (normal 55%–70%) and mild right ventricular dysfunction.

ECMO and then Impella placement

On his third hospital day, a venoarterial extracorporeal membrane oxygenation (ECMO) device was placed peripherally (Figure 1).

His hemodynamic variables stabilized, and he was weaned off dobutamine and norepinephrine. Results of liver function tests normalized, his urinary output increased, and his serum creatinine dropped to a normal 1.0 mg/dL. However, a chest radiograph showed pulmonary congestion, and echocardiography now showed severe left ventricular dysfunction.

On hospital day 5, the patient underwent surgical placement of an Impella 5.0 device (Abiomed, Danvers, MA) through the right axillary artery in an effort to improve his pulmonary edema. The ECMO device was removed. Placement of a venovenous ECMO device was deemed unnecessary when oxygenation improved with the Impella.

Three days after Impella placement, radiography showed improved edema with some remaining pleural effusion.

ACUTE CARDIOGENIC SHOCK

Cardiogenic shock remains a challenging clinical problem: patients with it are among the sickest in the hospital, and many of them die. ECMO was once the only therapy available and is still widely used. However, it is a 2-edged sword; complications such as bleeding, infection, and thrombosis are almost inevitable if it is used for long. Importantly, patients are usually kept intubated and bedridden.

In recent years, new devices have become available that are easier to place (some in the catheterization laboratory or even at the bedside) and allow safer bridging to recovery, transplant, or other therapies.

This case illustrates the natural history of cardiogenic shock and the preferred clinical approach: ie, ongoing evaluation that permits rapid response to evolving challenges.

In general, acute cardiogenic shock occurs within 24 to 48 hours after the initial insult, so even if a procedure succeeds, the patient may develop progressive hypotension and organ dysfunction. Reduced cardiac output causes a downward spiral with multiple systemic and inflammatory processes as well as increased nitric oxide synthesis, leading to progressive decline and eventual end-organ dysfunction.

Continuously evaluate

The cardiac team should continuously assess the acuity and severity of a patient’s condition, with the goals of maintaining end-organ perfusion and identifying the source of problems. Refractory cardiogenic shock, with tissue hypoperfusion despite vasoactive medications and treatment of the underlying cause, is associated with in-hospital mortality rates ranging from 30% to 50%.^1,2 The rates have actually increased over the past decade, as sicker patients are being treated.

When a patient presents with cardiogenic shock, we first try a series of vasoactive drugs and usually an intra-aortic balloon pump (Figure 2). We then tailor treatment depending on etiology. For example, a patient may have viral myocarditis and may even require a biopsy.

If cardiogenic shock is refractory, mechanical circulatory support devices can be a short-term bridge to either recovery or a new decision. A multidisciplinary team should be consulted to consider transplant, a long-term device, or palliative care. Sometimes a case requires “bridging to a bridge,” with several devices used short-term in turn.

Prognostic factors in cardiogenic shock

Several tools help predict outcome in a severely ill patient. End-organ function, indicated by blood lactate levels and estimated glomerular filtration rate, is perhaps the most informative and should be monitored serially.

CardShock³ is a simple scoring system based on age, mental status at presentation, laboratory values, and medical history. Patients receive 1 point for each of the following factors:

• Age > 75
• Confusion at presentation
• Previous myocardial infarction or coronary artery bypass grafting
• Acute coronary syndrome etiology
• Left ventricular ejection fraction < 40%
• Blood lactate level between 2 and 4 mmol/L, inclusively (2 points for lactate levels > 4 mmol/L)
• Estimated glomerular filtration rate between 30 and 60 mL/min/1.73 m², inclusively (2 points if < 30 mL/min/1.73 m²). 

Thus, scores range from 0 (best) to 9 (worst). A score of 0 to 3 points was associated with a 9% risk of death in the hospital, a score of 4 or 5 with a risk of 36%, and a score of 6 through 9 with a risk of 77%.³

The Survival After Veno-arterial ECMO (SAVE) score (www.save-score.com) is a prediction tool derived from a large international ECMO registry.⁴ It is based on patient age, diagnosis, and indicators of end-organ dysfunction. Scores range from –35 (worst) to +7 (best).

The mortality rate associated with postcardiotomy cardiogenic shock increases with the amount of inotropic support provided. In a 1996–1999 case series of patients who underwent open-heart surgery,⁵ the hospital mortality rate was 40% in those who received 2 inotropes in high doses and 80% in those who received 3. A strategy of early implementation of mechanical support is critical.

Selection criteria for destination therapy

Deciding whether a patient should receive a long-term device is frequently a challenge. The decision often must be based on limited information about not only the medical indications but also psychosocial factors that influence long-term success.

The Centers for Medicare and Medicaid Services have established criteria for candidates for left ventricular assist devices (LVADs) as destination therapy.⁶ Contraindications established for heart transplant should also be considered (Table 1).

CASE REVISITED

Several factors argued against LVAD placement in our patient. He had no health insurance and had been off medications. He smoked and said he consumed 3 hard liquor drinks per week. His Stanford Integrated Psychosocial Assessment for Transplantation score was 30 (minimally acceptable). He had hypoxia with subsegmental pulmonary edema, a strong contraindication to immediate transplant.

On the other hand, he had only mild right ventricular dysfunction. His CardShock score was 4 (intermediate risk, based on lactate 1.5 mmol/L and estimated glomerular filtration rate 52 mL/min/1.73 m²). His SAVE score was –9 (class IV), which overall is associated with a 30% risk of death (low enough to consider treatment).

During the patient’s time on temporary support, the team had the opportunity to better understand him and assess his family support and his ability to handle a permanent device. His surviving the acute course bolstered the team’s confidence that he could enjoy long-term survival with destination therapy.

CATHETERIZATION LABORATORY DEVICE CAPABILITIES

Although most implantation procedures are done in the operating room, they are often done in the catheterization laboratory because patients undergoing catheterization may not be stable enough for transfer, or an emergency intervention may be required during the night. Catheterization interventionists are also an important part of the team to help determine the best approach for long-term therapy.

The catheterization laboratory has multiple acute intervention options. Usually, decisions must be made quickly. In general, patients needing mechanical support are managed as follows:

• Those who need circulation support and oxygenation receive ECMO
• Those who need circulation support alone because of mechanical issues (eg, myocardial infarction) are considered for an intra-aortic balloon pump, Impella, or TandemHeart pump (Cardiac Assist, Pittsburgh, PA).

Factors that guide the selection of a temporary pump include:

• Left ventricular function
• Right ventricular function
• Aortic valve stenosis (some devices cannot be inserted through critical aortic stenosis)
• Aortic regurgitation (can affect some devices)
• Peripheral artery disease (some devices are large and must be placed percutaneously).

CHOOSING AMONG PERCUTANEOUS DEVICES

Circulatory support in cardiogenic shock improves outcomes, and devices play an important role in supporting high-risk procedures. The goal is not necessarily to use the device throughout the hospital stay. Acute stabilization is most important initially; a more considered decision about long-term therapy can be made when more is known about the patient.

Patient selection is the most important component of success. However, randomized data to support outcomes with the various devices are sparse and complicated by the critically ill state of the patient population.

SHORT-TERM CIRCULATORY SUPPORT: ECMO, IMPELLA, TANDEMHEART

A menu of options is available for temporary mechanical support. Options differ by their degree of circulatory support and ease of insertion (Table 2).

ECMO: A fast option with many advantages

ECMO has evolved and now can be placed quickly. A remote diagnostic platform such as CardioHub permits management at the bedside, in the medical unit, or in the cardiac intensive care unit.⁷

ECMO has several advantages. It can be used during cardiopulmonary bypass, it provides oxygenation, it is the only option in the setting of lung injury, it can be placed peripherally (without thoracotomy), and it is the only percutaneous option for biventricular support.

ECMO also has significant disadvantages

ECMO is a good device for acute resuscitation of a patient in shock, as it offers quick placement and resuscitation. But it is falling out of favor because of significant disadvantages.

Its major drawback is that it provides no left ventricular unloading. Although in a very unstable patient ECMO can stabilize end organs and restore their function, the lack of left ventricular unloading and reduced ventricular work threaten the myocardium. It creates extremely high afterload; therefore, in a left ventricle with poor function, wall tension and myocardial oxygen demand increase. Multiple studies have shown that coronary perfusion worsens, especially if the patient is cannulated peripherally. Because relative cerebral hypoxia occurs in many situations, it is imperative to check blood saturations at multiple sites to determine if perfusion is adequate everywhere.    

Ineffective left ventricular unloading with venoarterial ECMO is managed in several ways. Sometimes left ventricular distention is slight and the effects are subtle. Left ventricular distention causing pulmonary edema can be addressed with:

• Inotropes (in moderate doses)
• Anticoagulation to prevent left ventricular thrombus formation
• An intra-aortic balloon pump. Most patients on ECMO already have an intra-aortic balloon pump in place, and it should be left in to provide additional support. For those who do not have one, it should be placed via the contralateral femoral artery.

If problems persist despite these measures, apical cannulation or left ventricular septostomy can be performed.

Outcomes with ECMO have been disappointing. Studies show that whether ECMO was indicated for cardiac failure or for respiratory failure, survival is only about 25% at 5 years. Analyzing data only for arteriovenous ECMO, survival was 48% in bridged patients and 41% in patients who were weaned.

The Extracorporeal Life Support Organization Registry, in their international summary from 2010, found that 34% of cardiac patients on ECMO survived to discharge or transfer. Most of these patients had cardiogenic shock from acute myocardial infarction. Outcomes are so poor because of complications endemic to ECMO, eg, dialysis-dependent renal failure (about 40%) and neurologic complications (about 30%), often involving ischemic or hemorrhagic stroke.

Limb and pump complications were also significant in the past. These have been reduced with the new reperfusion cannula and the Quadrox oxygenator.  

Complications unique to ECMO should be understood and anticipated so that they can be avoided. Better tools are available, ie, Impella and TandemHeart.

Left-sided Impella: A longer-term temporary support

ECMO is a temporary fix that is usually used only for a few days. If longer support is needed, axillary placement of an Impella should be used as a bridge to recovery, transplant, or a durable LVAD.

The Impella device (Figure 3) is a miniature rotary blood pump increasingly used to treat cardiogenic shock. It is inserted retrograde across the aortic valve to provide short-term ventricular support. Most devices are approved by the US Food and Drug Administration (FDA) for less than 7 days of use, but we have experience using them up to 30 days. They are very hemocompatible, involving minimal hemolysis. Axillary placement allows early extubation and ambulation and is more stable than groin placement.

Several models are available: the 2.5 and 3.5 L/min devices can be placed percutaneously, while the 5 L/min model must be surgically placed in the axillary or groin region. Heparin is required with their use. They can replace ECMO. A right ventricular assist device (RVAD), Impella RP, is also available.

Physiologic impact of the Impella

The Impella fully unloads the left ventricle, reducing myocardial oxygen demand and increasing myocardial blood flow. It reduces end-diastolic volume and pressure, the mechanical work of the heart, and wall tension. Microvascular resistance is reduced, allowing increased coronary flow. Cardiac output and power are increased by multiple means.^8–11

The RECOVER 1 trial evaluated the 5L Impella placed after cardiac surgery. The cardiac index increased in all the patients, and the systemic vascular resistance and wedge pressure decreased.¹²

Unloading the ventricle is critical. Meyns  and colleagues¹³ found a fivefold reduction in infarct size from baseline in a left anterior descending occlusion model in pigs after off-loading the ventricle.

Impella has the advantage of simple percutaneous insertion (the 2.5 and CP models). It also tests right ventricular tolerance: if the right ventricle is doing well, one can predict with high certainty that it will tolerate an LVAD (eg, HeartWare, HeartMate 2 (Pleasanton, CA), or HeartMate 3 when available).

Disadvantages include that it provides only left ventricular support, although a right ventricular device can be inserted for dual support. Placement requires fluoroscopic or echocardiographic guidance.

TandemHeart requires septal puncture

The TandemHeart is approved for short-term and biventricular use. It consists of an extracorporeal centrifugal pump that withdraws blood from the left atrium via a trans-septal cannula placed through the femoral vein (Figure 4) and returns it to one or both femoral arteries. The blood is pumped at up to 5 L/min.

It is designed to reduce the pulmonary capillary wedge pressure, ventricular work, and myocardial oxygen demand and increase cardiac output and mean arterial pressure. It has the advantages of percutaneous placement and the ability to provide biventricular support with 2 devices. It can be used for up to 3 weeks. It can easily be converted to ECMO by either splicing in an oxygenator or adding another cannula.

Although the TandemHeart provides significant support, it is no longer often used. A 21F venous cannula must be passed to the left atrium by trans-septal puncture, which requires advanced skill and must be done in the catheterization laboratory. Insertion can take too much time and cause bleeding in patients taking an anticoagulant. Insertion usually destroys the septum, and removal requires a complete patch of the entire septum. Systemic anticoagulation is required. Other disadvantages are risks of hemolysis, limb ischemia, and infection with longer support times.

The CentriMag (Levitronix LLC; Framingham, MA) is an improved device that requires only 1 cannula instead of 2 to cover both areas.

DEVICES FOR RIGHT-SIDED SUPPORT

Most early devices were designed for left-sided support. The right heart, especially in failure, has been more difficult to manage. Previously the only option for a patient with right ventricular failure was venoarterial ECMO. This is more support than needed for a patient with isolated right ventricular failure and involves the risk of multiple complications from the device.

With more options available for the right heart (Table 3), we can choose the most appropriate device according to the underlying cause of right heart failure (eg, right ventricular infarct, pulmonary hypertension), the likelihood of recovery, and the expected time to recovery.

The ideal RVAD would be easy to implant, maintain, and remove. It would allow for chest closure and patient ambulation. It would be durable and biocompatible, so that it could remain implanted for months if necessary. It would cause little blood trauma, have the capability for adding an oxygenator for pulmonary support, and be cost-effective.

Although no single system has all these qualities, each available device fulfills certain combinations of these criteria, so the best one can be selected for each patient’s needs.

ECMO Rotaflow centrifugal pump: Fast, simple, inexpensive

A recent improvement to ECMO is the Rotaflow centrifugal pump (Maquet, Wayne, NJ), which is connected by sewing an 8-mm graft onto the pulmonary artery and placing a venous cannula in the femoral vein. If the patient is not bleeding, the chest can then be closed. This creates a fast, simple, and inexpensive temporary RVAD system. When the patient is ready to be weaned, the outflow graft can be disconnected at the bedside without reopening the chest.

The disadvantage is that the Rotaflow system contains a sapphire bearing. Although it is magnetically coupled, it generates heat and is a nidus for thrombus formation, which can lead to pump failure and embolization. This system can be used for patients who are expected to need support for less than 5 to 7 days. Beyond this duration, the incidence of complications increases. 

CentriMag Ventricular Assist System offers right, left, or bilateral support

The CentriMag Ventricular Assist System is a fully magnetically levitated pump containing no bearings or seals, and with the same technology as is found in many of the durable devices such as HeartMate 3. It is coupled with a reusable motor and is easy to use.

CentriMag offers versatility, allowing for right, left, or bilateral ventricular support. An oxygenator can be added for pulmonary edema and additional support. It is the most biocompatible device and is FDA-approved for use for 4 weeks, although it has been used successfully for much longer. It allows for chest closure and ambulation. It is especially important as a bridge to transplant. The main disadvantage is that insertion and removal require sternotomy.

Impella RP: One size does not fit all

The Impella RP (Figure 5) has an 11F catheter diameter, 23F pump, and a maximum flow rate of more than 4 L/minute. It has a unique 3-dimensional cannula design based on computed tomography 3-dimensional reconstructions from hundreds of patients.

The device is biocompatible and can be used for support for more than 7 days, although most patients require only 3 or 4 days. There is almost no priming volume, so there is no hemodilution.

The disadvantages are that it is more challenging to place than other devices, and some patients cannot use it because the cannula does not fit. It also does not provide pulmonary support. Finally, it is the most expensive of the 3 right-sided devices.

CASE REVISITED

The patient described at the beginning of this article was extubated on day 12 but was then reintubated. On day 20, a tracheotomy tube was placed. By day 24, he had improved so little that his family signed a “do-not-resuscitate–comfort-care-arrest” order (ie, if the patient’s heart or breathing stops, only comfort care is to be provided).

But slowly he got better, and the Impella was removed on day 30. Afterward, serum creatinine and liver function tests began rising again, requiring dobutamine for heart support.

On day 34, his family reversed the do-not-resuscitate order, and he was reevaluated for an LVAD as destination therapy. At this point, echocardiography showed a left ventricular ejection fraction of 10%, normal right ventricular function, with a normal heartbeat and valves. On day 47, a HeartMate II LVAD was placed.

On postoperative day 18, he was transferred out of the intensive care unit, then discharged to an acute rehabilitation facility 8 days later (hospital day 73). He was subsequently discharged.

At a recent follow-up appointment, the patient said that he was feeling “pretty good” and walked with no shortness of breath.

A 43-year-old man presented to a community hospital with acute chest pain and shortness of breath and was diagnosed with anterior ST-elevation myocardial infarction. He was a smoker with a history of alcohol abuse, hypertension, and hyperlipidemia, and in the past he had undergone percutaneous coronary interventions to the right coronary artery and the first obtuse marginal artery.

Angiography showed total occlusion in the left anterior descending artery, 90% stenosis in the right coronary artery, and mild disease in the left circumflex artery. A drug-eluting stent was placed in the left anterior descending artery, resulting in good blood flow. 

However, his left ventricle continued to have severe dysfunction. An intra-aortic balloon pump was inserted. Afterward, computed tomography showed subsegmental pulmonary embolism with congestion. His mean arterial pressure was 60 mm Hg (normal 70–110), central venous pressure 12 mm Hg (3–8), pulmonary artery pressure 38/26 mm Hg (15–30/4–12), pulmonary capillary wedge pressure 24 mm Hg (2–15), and cardiac index 1.4 L/min (2.5–4).

The patient was started on dobutamine and norepinephrine and transferred to Cleveland Clinic on day 2. Over the next day, he had runs of ventricular tachycardia, for which he was given amiodarone and lidocaine. His urine output was low, and his serum creatinine was elevated at 1.65 mg/dL (baseline 1.2, normal 0.5–1.5). Liver function tests were also elevated, with aspartate aminotransferase at 115 U/L(14–40) and alanine aminotransferase at 187 U/L (10–54).

Poor oxygenation was evident: his arterial partial pressure of oxygen was 64 mm Hg (normal 75–100). He was intubated and given 100% oxygen with positive end-expiratory pressure of 12 cm H₂O.

Echocardiography showed a left ventricular ejection fraction of 15% (normal 55%–70%) and mild right ventricular dysfunction.

ECMO and then Impella placement

On his third hospital day, a venoarterial extracorporeal membrane oxygenation (ECMO) device was placed peripherally (Figure 1).

His hemodynamic variables stabilized, and he was weaned off dobutamine and norepinephrine. Results of liver function tests normalized, his urinary output increased, and his serum creatinine dropped to a normal 1.0 mg/dL. However, a chest radiograph showed pulmonary congestion, and echocardiography now showed severe left ventricular dysfunction.

On hospital day 5, the patient underwent surgical placement of an Impella 5.0 device (Abiomed, Danvers, MA) through the right axillary artery in an effort to improve his pulmonary edema. The ECMO device was removed. Placement of a venovenous ECMO device was deemed unnecessary when oxygenation improved with the Impella.

Three days after Impella placement, radiography showed improved edema with some remaining pleural effusion.

ACUTE CARDIOGENIC SHOCK

Cardiogenic shock remains a challenging clinical problem: patients with it are among the sickest in the hospital, and many of them die. ECMO was once the only therapy available and is still widely used. However, it is a 2-edged sword; complications such as bleeding, infection, and thrombosis are almost inevitable if it is used for long. Importantly, patients are usually kept intubated and bedridden.

In recent years, new devices have become available that are easier to place (some in the catheterization laboratory or even at the bedside) and allow safer bridging to recovery, transplant, or other therapies.

This case illustrates the natural history of cardiogenic shock and the preferred clinical approach: ie, ongoing evaluation that permits rapid response to evolving challenges.

In general, acute cardiogenic shock occurs within 24 to 48 hours after the initial insult, so even if a procedure succeeds, the patient may develop progressive hypotension and organ dysfunction. Reduced cardiac output causes a downward spiral with multiple systemic and inflammatory processes as well as increased nitric oxide synthesis, leading to progressive decline and eventual end-organ dysfunction.

Continuously evaluate

The cardiac team should continuously assess the acuity and severity of a patient’s condition, with the goals of maintaining end-organ perfusion and identifying the source of problems. Refractory cardiogenic shock, with tissue hypoperfusion despite vasoactive medications and treatment of the underlying cause, is associated with in-hospital mortality rates ranging from 30% to 50%.^1,2 The rates have actually increased over the past decade, as sicker patients are being treated.

When a patient presents with cardiogenic shock, we first try a series of vasoactive drugs and usually an intra-aortic balloon pump (Figure 2). We then tailor treatment depending on etiology. For example, a patient may have viral myocarditis and may even require a biopsy.

If cardiogenic shock is refractory, mechanical circulatory support devices can be a short-term bridge to either recovery or a new decision. A multidisciplinary team should be consulted to consider transplant, a long-term device, or palliative care. Sometimes a case requires “bridging to a bridge,” with several devices used short-term in turn.

Prognostic factors in cardiogenic shock

Several tools help predict outcome in a severely ill patient. End-organ function, indicated by blood lactate levels and estimated glomerular filtration rate, is perhaps the most informative and should be monitored serially.

CardShock³ is a simple scoring system based on age, mental status at presentation, laboratory values, and medical history. Patients receive 1 point for each of the following factors:

• Age > 75
• Confusion at presentation
• Previous myocardial infarction or coronary artery bypass grafting
• Acute coronary syndrome etiology
• Left ventricular ejection fraction < 40%
• Blood lactate level between 2 and 4 mmol/L, inclusively (2 points for lactate levels > 4 mmol/L)
• Estimated glomerular filtration rate between 30 and 60 mL/min/1.73 m², inclusively (2 points if < 30 mL/min/1.73 m²). 

Thus, scores range from 0 (best) to 9 (worst). A score of 0 to 3 points was associated with a 9% risk of death in the hospital, a score of 4 or 5 with a risk of 36%, and a score of 6 through 9 with a risk of 77%.³

The Survival After Veno-arterial ECMO (SAVE) score (www.save-score.com) is a prediction tool derived from a large international ECMO registry.⁴ It is based on patient age, diagnosis, and indicators of end-organ dysfunction. Scores range from –35 (worst) to +7 (best).

The mortality rate associated with postcardiotomy cardiogenic shock increases with the amount of inotropic support provided. In a 1996–1999 case series of patients who underwent open-heart surgery,⁵ the hospital mortality rate was 40% in those who received 2 inotropes in high doses and 80% in those who received 3. A strategy of early implementation of mechanical support is critical.

Selection criteria for destination therapy

Deciding whether a patient should receive a long-term device is frequently a challenge. The decision often must be based on limited information about not only the medical indications but also psychosocial factors that influence long-term success.

The Centers for Medicare and Medicaid Services have established criteria for candidates for left ventricular assist devices (LVADs) as destination therapy.⁶ Contraindications established for heart transplant should also be considered (Table 1).

CASE REVISITED

Several factors argued against LVAD placement in our patient. He had no health insurance and had been off medications. He smoked and said he consumed 3 hard liquor drinks per week. His Stanford Integrated Psychosocial Assessment for Transplantation score was 30 (minimally acceptable). He had hypoxia with subsegmental pulmonary edema, a strong contraindication to immediate transplant.

On the other hand, he had only mild right ventricular dysfunction. His CardShock score was 4 (intermediate risk, based on lactate 1.5 mmol/L and estimated glomerular filtration rate 52 mL/min/1.73 m²). His SAVE score was –9 (class IV), which overall is associated with a 30% risk of death (low enough to consider treatment).

During the patient’s time on temporary support, the team had the opportunity to better understand him and assess his family support and his ability to handle a permanent device. His surviving the acute course bolstered the team’s confidence that he could enjoy long-term survival with destination therapy.

CATHETERIZATION LABORATORY DEVICE CAPABILITIES

Although most implantation procedures are done in the operating room, they are often done in the catheterization laboratory because patients undergoing catheterization may not be stable enough for transfer, or an emergency intervention may be required during the night. Catheterization interventionists are also an important part of the team to help determine the best approach for long-term therapy.

The catheterization laboratory has multiple acute intervention options. Usually, decisions must be made quickly. In general, patients needing mechanical support are managed as follows:

• Those who need circulation support and oxygenation receive ECMO
• Those who need circulation support alone because of mechanical issues (eg, myocardial infarction) are considered for an intra-aortic balloon pump, Impella, or TandemHeart pump (Cardiac Assist, Pittsburgh, PA).

Factors that guide the selection of a temporary pump include:

• Left ventricular function
• Right ventricular function
• Aortic valve stenosis (some devices cannot be inserted through critical aortic stenosis)
• Aortic regurgitation (can affect some devices)
• Peripheral artery disease (some devices are large and must be placed percutaneously).

CHOOSING AMONG PERCUTANEOUS DEVICES

Circulatory support in cardiogenic shock improves outcomes, and devices play an important role in supporting high-risk procedures. The goal is not necessarily to use the device throughout the hospital stay. Acute stabilization is most important initially; a more considered decision about long-term therapy can be made when more is known about the patient.

Patient selection is the most important component of success. However, randomized data to support outcomes with the various devices are sparse and complicated by the critically ill state of the patient population.

SHORT-TERM CIRCULATORY SUPPORT: ECMO, IMPELLA, TANDEMHEART

A menu of options is available for temporary mechanical support. Options differ by their degree of circulatory support and ease of insertion (Table 2).

ECMO: A fast option with many advantages

ECMO has evolved and now can be placed quickly. A remote diagnostic platform such as CardioHub permits management at the bedside, in the medical unit, or in the cardiac intensive care unit.⁷

ECMO has several advantages. It can be used during cardiopulmonary bypass, it provides oxygenation, it is the only option in the setting of lung injury, it can be placed peripherally (without thoracotomy), and it is the only percutaneous option for biventricular support.

ECMO also has significant disadvantages

ECMO is a good device for acute resuscitation of a patient in shock, as it offers quick placement and resuscitation. But it is falling out of favor because of significant disadvantages.

Its major drawback is that it provides no left ventricular unloading. Although in a very unstable patient ECMO can stabilize end organs and restore their function, the lack of left ventricular unloading and reduced ventricular work threaten the myocardium. It creates extremely high afterload; therefore, in a left ventricle with poor function, wall tension and myocardial oxygen demand increase. Multiple studies have shown that coronary perfusion worsens, especially if the patient is cannulated peripherally. Because relative cerebral hypoxia occurs in many situations, it is imperative to check blood saturations at multiple sites to determine if perfusion is adequate everywhere.    

Ineffective left ventricular unloading with venoarterial ECMO is managed in several ways. Sometimes left ventricular distention is slight and the effects are subtle. Left ventricular distention causing pulmonary edema can be addressed with:

• Inotropes (in moderate doses)
• Anticoagulation to prevent left ventricular thrombus formation
• An intra-aortic balloon pump. Most patients on ECMO already have an intra-aortic balloon pump in place, and it should be left in to provide additional support. For those who do not have one, it should be placed via the contralateral femoral artery.

If problems persist despite these measures, apical cannulation or left ventricular septostomy can be performed.

Outcomes with ECMO have been disappointing. Studies show that whether ECMO was indicated for cardiac failure or for respiratory failure, survival is only about 25% at 5 years. Analyzing data only for arteriovenous ECMO, survival was 48% in bridged patients and 41% in patients who were weaned.

The Extracorporeal Life Support Organization Registry, in their international summary from 2010, found that 34% of cardiac patients on ECMO survived to discharge or transfer. Most of these patients had cardiogenic shock from acute myocardial infarction. Outcomes are so poor because of complications endemic to ECMO, eg, dialysis-dependent renal failure (about 40%) and neurologic complications (about 30%), often involving ischemic or hemorrhagic stroke.

Limb and pump complications were also significant in the past. These have been reduced with the new reperfusion cannula and the Quadrox oxygenator.  

Complications unique to ECMO should be understood and anticipated so that they can be avoided. Better tools are available, ie, Impella and TandemHeart.

Left-sided Impella: A longer-term temporary support

ECMO is a temporary fix that is usually used only for a few days. If longer support is needed, axillary placement of an Impella should be used as a bridge to recovery, transplant, or a durable LVAD.

The Impella device (Figure 3) is a miniature rotary blood pump increasingly used to treat cardiogenic shock. It is inserted retrograde across the aortic valve to provide short-term ventricular support. Most devices are approved by the US Food and Drug Administration (FDA) for less than 7 days of use, but we have experience using them up to 30 days. They are very hemocompatible, involving minimal hemolysis. Axillary placement allows early extubation and ambulation and is more stable than groin placement.

Several models are available: the 2.5 and 3.5 L/min devices can be placed percutaneously, while the 5 L/min model must be surgically placed in the axillary or groin region. Heparin is required with their use. They can replace ECMO. A right ventricular assist device (RVAD), Impella RP, is also available.

Physiologic impact of the Impella

The Impella fully unloads the left ventricle, reducing myocardial oxygen demand and increasing myocardial blood flow. It reduces end-diastolic volume and pressure, the mechanical work of the heart, and wall tension. Microvascular resistance is reduced, allowing increased coronary flow. Cardiac output and power are increased by multiple means.^8–11

The RECOVER 1 trial evaluated the 5L Impella placed after cardiac surgery. The cardiac index increased in all the patients, and the systemic vascular resistance and wedge pressure decreased.¹²

Unloading the ventricle is critical. Meyns  and colleagues¹³ found a fivefold reduction in infarct size from baseline in a left anterior descending occlusion model in pigs after off-loading the ventricle.

Impella has the advantage of simple percutaneous insertion (the 2.5 and CP models). It also tests right ventricular tolerance: if the right ventricle is doing well, one can predict with high certainty that it will tolerate an LVAD (eg, HeartWare, HeartMate 2 (Pleasanton, CA), or HeartMate 3 when available).

Disadvantages include that it provides only left ventricular support, although a right ventricular device can be inserted for dual support. Placement requires fluoroscopic or echocardiographic guidance.

TandemHeart requires septal puncture

The TandemHeart is approved for short-term and biventricular use. It consists of an extracorporeal centrifugal pump that withdraws blood from the left atrium via a trans-septal cannula placed through the femoral vein (Figure 4) and returns it to one or both femoral arteries. The blood is pumped at up to 5 L/min.

It is designed to reduce the pulmonary capillary wedge pressure, ventricular work, and myocardial oxygen demand and increase cardiac output and mean arterial pressure. It has the advantages of percutaneous placement and the ability to provide biventricular support with 2 devices. It can be used for up to 3 weeks. It can easily be converted to ECMO by either splicing in an oxygenator or adding another cannula.

Although the TandemHeart provides significant support, it is no longer often used. A 21F venous cannula must be passed to the left atrium by trans-septal puncture, which requires advanced skill and must be done in the catheterization laboratory. Insertion can take too much time and cause bleeding in patients taking an anticoagulant. Insertion usually destroys the septum, and removal requires a complete patch of the entire septum. Systemic anticoagulation is required. Other disadvantages are risks of hemolysis, limb ischemia, and infection with longer support times.

The CentriMag (Levitronix LLC; Framingham, MA) is an improved device that requires only 1 cannula instead of 2 to cover both areas.

DEVICES FOR RIGHT-SIDED SUPPORT

Most early devices were designed for left-sided support. The right heart, especially in failure, has been more difficult to manage. Previously the only option for a patient with right ventricular failure was venoarterial ECMO. This is more support than needed for a patient with isolated right ventricular failure and involves the risk of multiple complications from the device.

With more options available for the right heart (Table 3), we can choose the most appropriate device according to the underlying cause of right heart failure (eg, right ventricular infarct, pulmonary hypertension), the likelihood of recovery, and the expected time to recovery.

The ideal RVAD would be easy to implant, maintain, and remove. It would allow for chest closure and patient ambulation. It would be durable and biocompatible, so that it could remain implanted for months if necessary. It would cause little blood trauma, have the capability for adding an oxygenator for pulmonary support, and be cost-effective.

Although no single system has all these qualities, each available device fulfills certain combinations of these criteria, so the best one can be selected for each patient’s needs.

ECMO Rotaflow centrifugal pump: Fast, simple, inexpensive

A recent improvement to ECMO is the Rotaflow centrifugal pump (Maquet, Wayne, NJ), which is connected by sewing an 8-mm graft onto the pulmonary artery and placing a venous cannula in the femoral vein. If the patient is not bleeding, the chest can then be closed. This creates a fast, simple, and inexpensive temporary RVAD system. When the patient is ready to be weaned, the outflow graft can be disconnected at the bedside without reopening the chest.

The disadvantage is that the Rotaflow system contains a sapphire bearing. Although it is magnetically coupled, it generates heat and is a nidus for thrombus formation, which can lead to pump failure and embolization. This system can be used for patients who are expected to need support for less than 5 to 7 days. Beyond this duration, the incidence of complications increases. 

CentriMag Ventricular Assist System offers right, left, or bilateral support

The CentriMag Ventricular Assist System is a fully magnetically levitated pump containing no bearings or seals, and with the same technology as is found in many of the durable devices such as HeartMate 3. It is coupled with a reusable motor and is easy to use.

CentriMag offers versatility, allowing for right, left, or bilateral ventricular support. An oxygenator can be added for pulmonary edema and additional support. It is the most biocompatible device and is FDA-approved for use for 4 weeks, although it has been used successfully for much longer. It allows for chest closure and ambulation. It is especially important as a bridge to transplant. The main disadvantage is that insertion and removal require sternotomy.

Impella RP: One size does not fit all

The Impella RP (Figure 5) has an 11F catheter diameter, 23F pump, and a maximum flow rate of more than 4 L/minute. It has a unique 3-dimensional cannula design based on computed tomography 3-dimensional reconstructions from hundreds of patients.

The device is biocompatible and can be used for support for more than 7 days, although most patients require only 3 or 4 days. There is almost no priming volume, so there is no hemodilution.

The disadvantages are that it is more challenging to place than other devices, and some patients cannot use it because the cannula does not fit. It also does not provide pulmonary support. Finally, it is the most expensive of the 3 right-sided devices.

CASE REVISITED

The patient described at the beginning of this article was extubated on day 12 but was then reintubated. On day 20, a tracheotomy tube was placed. By day 24, he had improved so little that his family signed a “do-not-resuscitate–comfort-care-arrest” order (ie, if the patient’s heart or breathing stops, only comfort care is to be provided).

But slowly he got better, and the Impella was removed on day 30. Afterward, serum creatinine and liver function tests began rising again, requiring dobutamine for heart support.

On day 34, his family reversed the do-not-resuscitate order, and he was reevaluated for an LVAD as destination therapy. At this point, echocardiography showed a left ventricular ejection fraction of 10%, normal right ventricular function, with a normal heartbeat and valves. On day 47, a HeartMate II LVAD was placed.

On postoperative day 18, he was transferred out of the intensive care unit, then discharged to an acute rehabilitation facility 8 days later (hospital day 73). He was subsequently discharged.

At a recent follow-up appointment, the patient said that he was feeling “pretty good” and walked with no shortness of breath.

A retired 80-year-old man presented to the emergency department after 10 days of increasing polydipsia, polyuria, dry mouth, confusion, and slurred speech. He also reported that he had gradually and unintentionally lost 20 pounds and had loss of appetite, constipation, and chronic itching. He denied fevers, chills, night sweats, nausea, vomiting, and abdominal pain.

Medical history. He had type 2 diabetes mellitus that was well controlled by oral hypoglycemics, hypothyroidism treated with levothyroxine in stable doses, and chronic hepatitis C complicated by liver cirrhosis without focal hepatic lesions. He also had hypertension, well controlled with hydrochlorothiazide and losartan. For his long-standing pruritus he had tried prescription drugs including gabapentin and pregabalin without improvement. He had also seen a naturopathic practitioner, who had prescribed supplements that relieved the symptoms.

Examination. The patient was in no acute distress. He appeared thin, with a weight of 140 lb and a body mass index of 21 kg/m². His temperature was 36.8°C (98.2°F), blood pressure 198/82 mm Hg, heart rate 72 beats per minute, respiratory rate 16 breaths per minute, and oxygen saturation 97%. His skin was without jaundice or rashes. The mucous membranes in the oropharynx were dry.

Neurologic examination revealed mild confusion, dysarthria, and ataxic gait. Sensation to light touch, pinprick, and vibration was intact. Generalized weakness was noted. Cranial nerves II through XII were intact. Deep tendon reflexes were symmetrically globally suppressed. Asterixis was absent. The remainder of the physical examination was unremarkable.

Laboratory values in the emergency department. We initially suspected he had symptomatic hyperglycemia, but a bedside blood glucose value of 113 mg/dL ruled this out. Other initial laboratory values:

• Blood urea nitrogen 31 mg/dL (reference range 9–24)
• Serum creatinine 1.7 mg/dL (0.73–1.22; an earlier value had been 1.0 mg/dL)
• Total serum calcium 14.4 mg/dL (8.6–10.0)

Complete blood cell counts were unremarkable. Computed tomography of the head was negative for acute pathology.

In view of the patient’s hypercalcemia, he was given aggressive intravenous fluid resuscitation (2 L of normal saline over 2 hours) and was admitted to the hospital. His laboratory values on admission are shown in Table 1. Fluid resuscitation was continued while the laboratory results were pending.

CAUSES OF HYPERCALCEMIA

1. Based on this information, which is the most likely cause of this patient’s hypercalcemia?

• Primary hyperparathyroidism
• Malignancy
• Hyperthyroidism
• Hypervitaminosis D
• Sarcoidosis

Traditionally, the workup for hypercalcemia in an outpatient starts with measuring the serum parathyroid hormone (PTH) level. Based on the results, a further evaluation of PTH-mediated vs PTH-independent causes of hypercalcemia would be initiated.

Primary hyperparathyroidism and malignancy account for 90% of all cases of hypercalcemia. The serum PTH concentration is usually high in primary hyperparathyroidism but low in malignancy, which helps distinguish the conditions from each other.¹

Primary hyperparathyroidism

In primary hyperparathyroidism, there is overproduction of PTH, most commonly from a parathyroid adenoma, though parathyroid hyperplasia or, more rarely, parathyroid carcinoma can also overproduce the hormone.

PTH increases serum calcium levels through 3 primary mechanisms: increasing bone resorption, increasing intestinal absorption of calcium, and decreasing renal excretion of calcium. It also induces renal phosphorus excretion.

Typically, in primary hyperparathyroidism, the increases in serum calcium are small (with serum levels of total calcium rising to no higher than 11 mg/dL) and often intermittent.² Our patient had extremely high serum calcium, low PTH, and high phosphorus levels—all of which are inconsistent with primary hyperparathyroidism.

Malignancy

In some solid tumors, the major mechanism of hypercalcemia is secretion of PTH-related peptide (PTHrP) through promotion of osteoclast function and also increased renal absorption of calcium.³ Hematologic malignancies (eg, multiple myeloma) produce osteoclast-activating factors such as RANK ligand, lymphotoxin, and interleukin 6. Direct tumor invasion of bone can cause osteolysis and subsequent hypercalcemia.⁴ These mechanisms are usually associated with a fall in PTH.

Less commonly, tumors can also increase levels of 1,25-dihydroxyvitamin D or produce PTH independently of the parathyroid gland.⁵ There have also been reports of severe hypercalcemia from hepatocellular carcinoma due to PTHrP production.⁶

Our patient is certainly at risk for malignancy, given his long-standing history of hepatitis C and cirrhosis. He also had a mildly elevated alpha fetoprotein level and suppressed PTH. However, his PTHrP level was normal, and ultrasonography done recently to screen for hepatocellular carcinoma (recommended every 6 months by the American Association for the Study of Liver Diseases in high-risk patients) was negative.⁷

Multiple myeloma screening involves testing with serum protein electrophoresis with immunofixation in combination with either a serum free light chain assay or 24-hour urine protein electrophoresis with immunofixation. This provides a 97% sensitivity.⁸ In this patient, these tests for multiple myeloma were negative.

Hyperthyroidism

As many as half of all patients with hyperthyroidism have elevated levels of ionized serum calcium.⁹ Increased osteoclastic activity is the likely mechanism. Hyperthyroid patients have increased levels of serum interleukin 6 and increased sensitivity of bone to this factor. This cytokine induces differentiation of monocytic cells into osteoclast precursors.¹⁰ These patients also have normal or low PTH levels.⁹

Our patient was receiving levothyroxine for hypothyroidism, but there was no evidence that the dosage was too high, as his thyroid-stimulating hormone level was within an acceptable range.

Hypervitaminosis D

Vitamin D precursors arise from the skin and from the diet. These precursors are hydroxylated in the liver and then the kidneys to biologically active 1,25-dihydroxyvitamin D (Figure 1).¹¹ Vitamin D’s primary actions are in the intestines to increase absorption of calcium and in bone to induce osteoclast action. These actions raise the serum calcium level, which in turn lowers the PTH level through negative feedback on the parathyroid gland.

Most vitamin D supplements consist of the inactive precursor cholecalciferol (vitamin D₃). To assess the degree of supplementation, 25-hydroxyvitamin D levels, which indicate the size of the body’s vitamin D reservoir, are measured.^11,12

Our patient’s 25-hydroxyvitamin D level is extremely elevated, well beyond the 250-ng/mL upper limit that is considered safe.¹³ His low PTH level, lack of other likely causes, and history of supplement use point toward the diagnosis of hypervitaminosis D.

Sarcoidosis

Up to 10% of patients with sarcoidosis have hypercalcemia that is not mediated by PTH. Hypercalcemia in sarcoidosis has several potential mechanisms, including increased activity of the enzyme 1-alpha hydroxylase with a subsequent increase in physiologically active 1,25-dihydroxyvitamin D₃ production.¹⁴

Our patient had elevated levels of 25-hydroxyvitamin D, but his biologically active 1,25-dihydroxyvitamin D level remained within the laboratory’s reference range.

LESS LIKELY CAUSES OF HYPERCALCEMIA

2. Which of the following would be least likely to cause hypercalcemia?

• Thiazide diuretics
• Over-the-counter antacid tablets
• Lithium
• Vitamin A supplementation
• Proton pump inhibitors

Thiazide diuretics

This class of drugs is well known to cause hypercalcemia. The most familiar of the mechanisms is a reduction in urinary calcium excretion. There is also an increase in intestinal absorption of dietary calcium. Evidence is increasing that most patients (as many as two-thirds) who develop hypercal­cemia while using a thiazide diuretic have subclinical primary hyperparathyroidism that is uncovered with use of the diuretic.

Of importance, the hypercalcemia that thiazide diuretics cause is mild. In a series of 72 patients with thiazide-induced hypercalcemia, the average serum calcium level was 10.7 mg/dL.¹⁵

Our patient was receiving a thiazide diuretic but presented with severe hypercalcemia, which is inconsistent with thiazide-induced hypercalcemia.

Over-the-counter antacid tablets

Calcium carbonate, a popular over-the-counter antacid, can cause a milk-alkali syndrome that is defined by ingestion of excessive calcium and alkalotic substances, leading to metabolic alkalosis, hypercalcemia, and renal insufficiency. To induce this syndrome generally requires up to 4 g of calcium intake daily, but even lower levels (1.0 to 1.5 g) are known to cause it.¹⁶

Lithium

Lithium is known to cause hypercalcemia. Multiple mechanisms have been proposed, including direct action on renal tubules and the intestines leading to calcium reabsorption and stimulation of PTH release. Interestingly, parathyroid gland hyperplasia has been noted in long-term users of lithium. An often-proposed mechanism is that lithium increases the threshold at which the parathyroid glands slow their production of PTH, making them less sensitive to serum calcium levels.¹⁷

Vitamin A supplementation

Multiple case reports have linked hypercalcemia to ingestion of large doses of vitamin A. The mechanism is thought to be increased bone resorption.^18.19

Although our patient reported supplement use, he denied taking vitamin A in any form.

Proton pump inhibitors

Proton pump inhibitors are not known to cause hypercalcemia. On the contrary, case reports suggest that prolonged use of proton pump inhibitors is associated with hypocalcemia and hypomagnesemia, although the mechanism is still not fully understood. A low magnesium level is known to reduce PTH secretion and also skeletal responsiveness to PTH, which can lead to profound hypocalcemia.²⁰

CASE CONTINUED

On further questioning, the patient revealed that the supplement prescribed by his naturopathic practitioner contained vitamin D. Although he had been instructed to take 1 tablet weekly, he had begun taking it daily with his other routine medications, resulting in a daily dose in excess of 60,000 IU of cholecalciferol (vitamin D₃). The recommended dose is no more than 4,000 IU/day.

The supplement was immediately discontinued. His hydrochlorothiazide was also held due to its known effect of reducing urinary calcium excretion.

INITIAL TREATMENT OF HYPERCALCEMIA

3. Which of the following treatments is not recommended as part of this patient’s initial treatment?

• Bisphosphonates
• Calcitonin
• Intravenous fluids
• Furosemide

Our patient met the criteria for the diagnosis of hypercalcemic crisis, usually defined as an albumin-corrected serum calcium level higher than 14 mg/dL associated with multiorgan dysfunction resulting from the hypercalcemia.²¹ The mnemonic “stones, bones, abdominal moans, and psychic groans” captures the renal, skeletal, gastrointestinal, and neurologic manifestations.¹

Bisphosphonates

Bisphosphonates are analogues of pyrophosphonates, which are normally incorporated into bone. Unlike pyrophosphonates, bisphosphonates inhibit osteoclast function. They are often used to treat hypercalcemia of any cause, although they are currently approved by the US Food and Drug Administration for treating hypercalcemia of malignancy only. As intravenous monotherapy, they are superior to other forms of treatment and are among the first-line agents in management.

Two bisphosphonates shown to be effective in hypercalcemia are zoledronate and pamidronate. Pamidronate begins to lower serum calcium levels within 2 days, with a peak effect at around 6 days.²² However, in studies comparing the 2 drugs, zoledronate has been shown to be more effective in normalizing serum calcium, with the additional benefit of having a much more rapid infusion time.²³ Zoledronate is contraindicated in patients with creatinine clearance less than 30 mL/min; however, pamidronate may continue to be used.²⁴

Calcitonin

This hormone inhibits bone resorption and increases excretion of calcium in the kidneys. It is not recommended for use alone because of its short duration of action and tachyphylaxis, but it can be used in combination with other agents, particularly in hypercalcemic crisis.²² It has the most rapid onset (within 2 hours) of the available medications, and when used in combination with bisphosphonates it produces a more substantial and rapid reduction in serum calcium.^25,26

In a patient such as ours, with severe hypercalcemia and evidence of neurologic consequences, calcitonin should be used for its rapid and effective action in lowering serum calcium as other interventions take effect.

Intravenous fluids

Like our patient, many patients with significant hypercalcemia have volume depletion as a result of calciuresis-induced polyuria. Many also have nephrogenic diabetes insipidus from the cytotoxic effect of calcium on renal cells, leading to further volume depletion.²⁷

All management approaches call for fluid repletion as an initial step in hypercalcemia. However, for severe hypercalcemia, volume resuscitation alone is unlikely to completely correct the imbalance. In addition to correcting dehydration, giving fluids increases glomerular filtration, allowing for increased secretion of calcium at the distal tubule.²⁸ The recommendation is 2.5 to 4 L of normal saline over the first 24 hours, with continued aggressive hydration until good urine output is established.²¹

Our patient, in addition to having acute kidney injury thought to be due to prerenal azotemia, appeared to be volume-depleted and was given aggressive intravenous hydration.

Furosemide

Furosemide inhibits calcium reabsorption at the thick ascending loop of Henle, but this effect depends on the glomerular filtration rate. While our patient would likely eventually benefit from furosemide, it should not be considered the first-line therapy, as diuretic use in the setting of volume depletion can cause circulatory collapse.²⁹ A relative contraindication was his presentation with acute kidney injury.

LONG-TERM TREATMENT

4. In the continued management of a patient with vitamin D toxicity with severe hypercalcemia, which of the following provides prolonged benefit?

• Intravenous hydrocortisone
• Fluid repletion
• Pamidronate
• Calcium-restricted diet

Much has been postulated concerning the mechanism of vitamin D intoxication and subsequent hypercalcemia. Studies have shown it is not an increase in dietary calcium absorption that drives the hypercalcemia but rather an increase in bone resorption. As such, bisphosphonates such as pamidronate have been shown to have a dramatic and rapid effect on severe hypercalcemia from vitamin D toxicity. The duration of action varies but is typically between 1 and 2 weeks.^22,30

Corticosteroids such as hydrocortisone are also indicated in situations of severe toxicity. They block the action of 1-alpha-hydroxylase, which converts inactive 25-hydroxyvitamin D to the active 1,25-dihydroxyvitamin D. Corticosteroids have also been shown to more directly reduce calcium resorption from bone and intestine in addition to increasing calciuresis.³¹ A small study in the United Kingdom noted that while bisphosphonates and steroids were equally effective in reducing serum calcium levels, bisphosphonates accomplished this reduction more rapidly, with a time to therapeutic effect of 9 days as opposed to 22 days.­

Fluid hydration, though necessary, is unlikely to produce complete correction on its own, as previously discussed.

THE PATIENT RECOVERS

The patient was treated with intravenous fluids over 3 days and received 1 dose of pamidronate. Calcitonin was provided over the first 48 hours after presentation to more rapidly reduce his calcium levels. He was advised to avoid taking the supplements prescribed by his naturopathic practitioner.

On follow-up with an endocrinologist 1 week later, his symptoms had entirely resolved, and his calcium level was 10.5 mg/dL.

TAKE-AWAY POINTS

• A good medication history includes over-the-counter products such as vitamin D supplements, as more and more people are taking them.
• The level of 25-hydroxyvitamin D should be monitored within 3 to 4 months after initiating treatment for vitamin D deficiency.¹¹
• Vitamin D toxicity can have profound consequences, which are usually seen when levels of 25-hydroxyvitamin D rise above 250 ng/mL.¹³
• The Institute of Medicine recommends that the dosage of vitamin D supplements be no more than 4,000 IU/day and that doses may need to be lowered to account for concurrent use of hypercalcemia-inducing drugs and other vitamin D-containing supplements.³²

A retired 80-year-old man presented to the emergency department after 10 days of increasing polydipsia, polyuria, dry mouth, confusion, and slurred speech. He also reported that he had gradually and unintentionally lost 20 pounds and had loss of appetite, constipation, and chronic itching. He denied fevers, chills, night sweats, nausea, vomiting, and abdominal pain.

Medical history. He had type 2 diabetes mellitus that was well controlled by oral hypoglycemics, hypothyroidism treated with levothyroxine in stable doses, and chronic hepatitis C complicated by liver cirrhosis without focal hepatic lesions. He also had hypertension, well controlled with hydrochlorothiazide and losartan. For his long-standing pruritus he had tried prescription drugs including gabapentin and pregabalin without improvement. He had also seen a naturopathic practitioner, who had prescribed supplements that relieved the symptoms.

Examination. The patient was in no acute distress. He appeared thin, with a weight of 140 lb and a body mass index of 21 kg/m². His temperature was 36.8°C (98.2°F), blood pressure 198/82 mm Hg, heart rate 72 beats per minute, respiratory rate 16 breaths per minute, and oxygen saturation 97%. His skin was without jaundice or rashes. The mucous membranes in the oropharynx were dry.

Neurologic examination revealed mild confusion, dysarthria, and ataxic gait. Sensation to light touch, pinprick, and vibration was intact. Generalized weakness was noted. Cranial nerves II through XII were intact. Deep tendon reflexes were symmetrically globally suppressed. Asterixis was absent. The remainder of the physical examination was unremarkable.

Laboratory values in the emergency department. We initially suspected he had symptomatic hyperglycemia, but a bedside blood glucose value of 113 mg/dL ruled this out. Other initial laboratory values:

• Blood urea nitrogen 31 mg/dL (reference range 9–24)
• Serum creatinine 1.7 mg/dL (0.73–1.22; an earlier value had been 1.0 mg/dL)
• Total serum calcium 14.4 mg/dL (8.6–10.0)

Complete blood cell counts were unremarkable. Computed tomography of the head was negative for acute pathology.

In view of the patient’s hypercalcemia, he was given aggressive intravenous fluid resuscitation (2 L of normal saline over 2 hours) and was admitted to the hospital. His laboratory values on admission are shown in Table 1. Fluid resuscitation was continued while the laboratory results were pending.

CAUSES OF HYPERCALCEMIA

1. Based on this information, which is the most likely cause of this patient’s hypercalcemia?

• Primary hyperparathyroidism
• Malignancy
• Hyperthyroidism
• Hypervitaminosis D
• Sarcoidosis

Traditionally, the workup for hypercalcemia in an outpatient starts with measuring the serum parathyroid hormone (PTH) level. Based on the results, a further evaluation of PTH-mediated vs PTH-independent causes of hypercalcemia would be initiated.

Primary hyperparathyroidism and malignancy account for 90% of all cases of hypercalcemia. The serum PTH concentration is usually high in primary hyperparathyroidism but low in malignancy, which helps distinguish the conditions from each other.¹

Primary hyperparathyroidism

In primary hyperparathyroidism, there is overproduction of PTH, most commonly from a parathyroid adenoma, though parathyroid hyperplasia or, more rarely, parathyroid carcinoma can also overproduce the hormone.

PTH increases serum calcium levels through 3 primary mechanisms: increasing bone resorption, increasing intestinal absorption of calcium, and decreasing renal excretion of calcium. It also induces renal phosphorus excretion.

Typically, in primary hyperparathyroidism, the increases in serum calcium are small (with serum levels of total calcium rising to no higher than 11 mg/dL) and often intermittent.² Our patient had extremely high serum calcium, low PTH, and high phosphorus levels—all of which are inconsistent with primary hyperparathyroidism.

Malignancy

In some solid tumors, the major mechanism of hypercalcemia is secretion of PTH-related peptide (PTHrP) through promotion of osteoclast function and also increased renal absorption of calcium.³ Hematologic malignancies (eg, multiple myeloma) produce osteoclast-activating factors such as RANK ligand, lymphotoxin, and interleukin 6. Direct tumor invasion of bone can cause osteolysis and subsequent hypercalcemia.⁴ These mechanisms are usually associated with a fall in PTH.

Less commonly, tumors can also increase levels of 1,25-dihydroxyvitamin D or produce PTH independently of the parathyroid gland.⁵ There have also been reports of severe hypercalcemia from hepatocellular carcinoma due to PTHrP production.⁶

Our patient is certainly at risk for malignancy, given his long-standing history of hepatitis C and cirrhosis. He also had a mildly elevated alpha fetoprotein level and suppressed PTH. However, his PTHrP level was normal, and ultrasonography done recently to screen for hepatocellular carcinoma (recommended every 6 months by the American Association for the Study of Liver Diseases in high-risk patients) was negative.⁷

Multiple myeloma screening involves testing with serum protein electrophoresis with immunofixation in combination with either a serum free light chain assay or 24-hour urine protein electrophoresis with immunofixation. This provides a 97% sensitivity.⁸ In this patient, these tests for multiple myeloma were negative.

Hyperthyroidism

As many as half of all patients with hyperthyroidism have elevated levels of ionized serum calcium.⁹ Increased osteoclastic activity is the likely mechanism. Hyperthyroid patients have increased levels of serum interleukin 6 and increased sensitivity of bone to this factor. This cytokine induces differentiation of monocytic cells into osteoclast precursors.¹⁰ These patients also have normal or low PTH levels.⁹

Our patient was receiving levothyroxine for hypothyroidism, but there was no evidence that the dosage was too high, as his thyroid-stimulating hormone level was within an acceptable range.

Hypervitaminosis D

Vitamin D precursors arise from the skin and from the diet. These precursors are hydroxylated in the liver and then the kidneys to biologically active 1,25-dihydroxyvitamin D (Figure 1).¹¹ Vitamin D’s primary actions are in the intestines to increase absorption of calcium and in bone to induce osteoclast action. These actions raise the serum calcium level, which in turn lowers the PTH level through negative feedback on the parathyroid gland.

Most vitamin D supplements consist of the inactive precursor cholecalciferol (vitamin D₃). To assess the degree of supplementation, 25-hydroxyvitamin D levels, which indicate the size of the body’s vitamin D reservoir, are measured.^11,12

Our patient’s 25-hydroxyvitamin D level is extremely elevated, well beyond the 250-ng/mL upper limit that is considered safe.¹³ His low PTH level, lack of other likely causes, and history of supplement use point toward the diagnosis of hypervitaminosis D.

Sarcoidosis

Up to 10% of patients with sarcoidosis have hypercalcemia that is not mediated by PTH. Hypercalcemia in sarcoidosis has several potential mechanisms, including increased activity of the enzyme 1-alpha hydroxylase with a subsequent increase in physiologically active 1,25-dihydroxyvitamin D₃ production.¹⁴

Our patient had elevated levels of 25-hydroxyvitamin D, but his biologically active 1,25-dihydroxyvitamin D level remained within the laboratory’s reference range.

LESS LIKELY CAUSES OF HYPERCALCEMIA

2. Which of the following would be least likely to cause hypercalcemia?

• Thiazide diuretics
• Over-the-counter antacid tablets
• Lithium
• Vitamin A supplementation
• Proton pump inhibitors

Thiazide diuretics

This class of drugs is well known to cause hypercalcemia. The most familiar of the mechanisms is a reduction in urinary calcium excretion. There is also an increase in intestinal absorption of dietary calcium. Evidence is increasing that most patients (as many as two-thirds) who develop hypercal­cemia while using a thiazide diuretic have subclinical primary hyperparathyroidism that is uncovered with use of the diuretic.

Of importance, the hypercalcemia that thiazide diuretics cause is mild. In a series of 72 patients with thiazide-induced hypercalcemia, the average serum calcium level was 10.7 mg/dL.¹⁵

Our patient was receiving a thiazide diuretic but presented with severe hypercalcemia, which is inconsistent with thiazide-induced hypercalcemia.

Over-the-counter antacid tablets

Calcium carbonate, a popular over-the-counter antacid, can cause a milk-alkali syndrome that is defined by ingestion of excessive calcium and alkalotic substances, leading to metabolic alkalosis, hypercalcemia, and renal insufficiency. To induce this syndrome generally requires up to 4 g of calcium intake daily, but even lower levels (1.0 to 1.5 g) are known to cause it.¹⁶

Lithium

Lithium is known to cause hypercalcemia. Multiple mechanisms have been proposed, including direct action on renal tubules and the intestines leading to calcium reabsorption and stimulation of PTH release. Interestingly, parathyroid gland hyperplasia has been noted in long-term users of lithium. An often-proposed mechanism is that lithium increases the threshold at which the parathyroid glands slow their production of PTH, making them less sensitive to serum calcium levels.¹⁷

Vitamin A supplementation

Multiple case reports have linked hypercalcemia to ingestion of large doses of vitamin A. The mechanism is thought to be increased bone resorption.^18.19

Although our patient reported supplement use, he denied taking vitamin A in any form.

Proton pump inhibitors

Proton pump inhibitors are not known to cause hypercalcemia. On the contrary, case reports suggest that prolonged use of proton pump inhibitors is associated with hypocalcemia and hypomagnesemia, although the mechanism is still not fully understood. A low magnesium level is known to reduce PTH secretion and also skeletal responsiveness to PTH, which can lead to profound hypocalcemia.²⁰

CASE CONTINUED

On further questioning, the patient revealed that the supplement prescribed by his naturopathic practitioner contained vitamin D. Although he had been instructed to take 1 tablet weekly, he had begun taking it daily with his other routine medications, resulting in a daily dose in excess of 60,000 IU of cholecalciferol (vitamin D₃). The recommended dose is no more than 4,000 IU/day.

The supplement was immediately discontinued. His hydrochlorothiazide was also held due to its known effect of reducing urinary calcium excretion.

INITIAL TREATMENT OF HYPERCALCEMIA

3. Which of the following treatments is not recommended as part of this patient’s initial treatment?

• Bisphosphonates
• Calcitonin
• Intravenous fluids
• Furosemide

Our patient met the criteria for the diagnosis of hypercalcemic crisis, usually defined as an albumin-corrected serum calcium level higher than 14 mg/dL associated with multiorgan dysfunction resulting from the hypercalcemia.²¹ The mnemonic “stones, bones, abdominal moans, and psychic groans” captures the renal, skeletal, gastrointestinal, and neurologic manifestations.¹

Bisphosphonates

Bisphosphonates are analogues of pyrophosphonates, which are normally incorporated into bone. Unlike pyrophosphonates, bisphosphonates inhibit osteoclast function. They are often used to treat hypercalcemia of any cause, although they are currently approved by the US Food and Drug Administration for treating hypercalcemia of malignancy only. As intravenous monotherapy, they are superior to other forms of treatment and are among the first-line agents in management.

Two bisphosphonates shown to be effective in hypercalcemia are zoledronate and pamidronate. Pamidronate begins to lower serum calcium levels within 2 days, with a peak effect at around 6 days.²² However, in studies comparing the 2 drugs, zoledronate has been shown to be more effective in normalizing serum calcium, with the additional benefit of having a much more rapid infusion time.²³ Zoledronate is contraindicated in patients with creatinine clearance less than 30 mL/min; however, pamidronate may continue to be used.²⁴

Calcitonin

This hormone inhibits bone resorption and increases excretion of calcium in the kidneys. It is not recommended for use alone because of its short duration of action and tachyphylaxis, but it can be used in combination with other agents, particularly in hypercalcemic crisis.²² It has the most rapid onset (within 2 hours) of the available medications, and when used in combination with bisphosphonates it produces a more substantial and rapid reduction in serum calcium.^25,26

In a patient such as ours, with severe hypercalcemia and evidence of neurologic consequences, calcitonin should be used for its rapid and effective action in lowering serum calcium as other interventions take effect.

Intravenous fluids

Like our patient, many patients with significant hypercalcemia have volume depletion as a result of calciuresis-induced polyuria. Many also have nephrogenic diabetes insipidus from the cytotoxic effect of calcium on renal cells, leading to further volume depletion.²⁷

All management approaches call for fluid repletion as an initial step in hypercalcemia. However, for severe hypercalcemia, volume resuscitation alone is unlikely to completely correct the imbalance. In addition to correcting dehydration, giving fluids increases glomerular filtration, allowing for increased secretion of calcium at the distal tubule.²⁸ The recommendation is 2.5 to 4 L of normal saline over the first 24 hours, with continued aggressive hydration until good urine output is established.²¹

Our patient, in addition to having acute kidney injury thought to be due to prerenal azotemia, appeared to be volume-depleted and was given aggressive intravenous hydration.

Furosemide

Furosemide inhibits calcium reabsorption at the thick ascending loop of Henle, but this effect depends on the glomerular filtration rate. While our patient would likely eventually benefit from furosemide, it should not be considered the first-line therapy, as diuretic use in the setting of volume depletion can cause circulatory collapse.²⁹ A relative contraindication was his presentation with acute kidney injury.

LONG-TERM TREATMENT

4. In the continued management of a patient with vitamin D toxicity with severe hypercalcemia, which of the following provides prolonged benefit?

• Intravenous hydrocortisone
• Fluid repletion
• Pamidronate
• Calcium-restricted diet

Much has been postulated concerning the mechanism of vitamin D intoxication and subsequent hypercalcemia. Studies have shown it is not an increase in dietary calcium absorption that drives the hypercalcemia but rather an increase in bone resorption. As such, bisphosphonates such as pamidronate have been shown to have a dramatic and rapid effect on severe hypercalcemia from vitamin D toxicity. The duration of action varies but is typically between 1 and 2 weeks.^22,30

Corticosteroids such as hydrocortisone are also indicated in situations of severe toxicity. They block the action of 1-alpha-hydroxylase, which converts inactive 25-hydroxyvitamin D to the active 1,25-dihydroxyvitamin D. Corticosteroids have also been shown to more directly reduce calcium resorption from bone and intestine in addition to increasing calciuresis.³¹ A small study in the United Kingdom noted that while bisphosphonates and steroids were equally effective in reducing serum calcium levels, bisphosphonates accomplished this reduction more rapidly, with a time to therapeutic effect of 9 days as opposed to 22 days.­

Fluid hydration, though necessary, is unlikely to produce complete correction on its own, as previously discussed.

THE PATIENT RECOVERS

The patient was treated with intravenous fluids over 3 days and received 1 dose of pamidronate. Calcitonin was provided over the first 48 hours after presentation to more rapidly reduce his calcium levels. He was advised to avoid taking the supplements prescribed by his naturopathic practitioner.

On follow-up with an endocrinologist 1 week later, his symptoms had entirely resolved, and his calcium level was 10.5 mg/dL.

TAKE-AWAY POINTS

• A good medication history includes over-the-counter products such as vitamin D supplements, as more and more people are taking them.
• The level of 25-hydroxyvitamin D should be monitored within 3 to 4 months after initiating treatment for vitamin D deficiency.¹¹
• Vitamin D toxicity can have profound consequences, which are usually seen when levels of 25-hydroxyvitamin D rise above 250 ng/mL.¹³
• The Institute of Medicine recommends that the dosage of vitamin D supplements be no more than 4,000 IU/day and that doses may need to be lowered to account for concurrent use of hypercalcemia-inducing drugs and other vitamin D-containing supplements.³²

A retired 80-year-old man presented to the emergency department after 10 days of increasing polydipsia, polyuria, dry mouth, confusion, and slurred speech. He also reported that he had gradually and unintentionally lost 20 pounds and had loss of appetite, constipation, and chronic itching. He denied fevers, chills, night sweats, nausea, vomiting, and abdominal pain.

Medical history. He had type 2 diabetes mellitus that was well controlled by oral hypoglycemics, hypothyroidism treated with levothyroxine in stable doses, and chronic hepatitis C complicated by liver cirrhosis without focal hepatic lesions. He also had hypertension, well controlled with hydrochlorothiazide and losartan. For his long-standing pruritus he had tried prescription drugs including gabapentin and pregabalin without improvement. He had also seen a naturopathic practitioner, who had prescribed supplements that relieved the symptoms.

Examination. The patient was in no acute distress. He appeared thin, with a weight of 140 lb and a body mass index of 21 kg/m². His temperature was 36.8°C (98.2°F), blood pressure 198/82 mm Hg, heart rate 72 beats per minute, respiratory rate 16 breaths per minute, and oxygen saturation 97%. His skin was without jaundice or rashes. The mucous membranes in the oropharynx were dry.

Neurologic examination revealed mild confusion, dysarthria, and ataxic gait. Sensation to light touch, pinprick, and vibration was intact. Generalized weakness was noted. Cranial nerves II through XII were intact. Deep tendon reflexes were symmetrically globally suppressed. Asterixis was absent. The remainder of the physical examination was unremarkable.

Laboratory values in the emergency department. We initially suspected he had symptomatic hyperglycemia, but a bedside blood glucose value of 113 mg/dL ruled this out. Other initial laboratory values:

• Blood urea nitrogen 31 mg/dL (reference range 9–24)
• Serum creatinine 1.7 mg/dL (0.73–1.22; an earlier value had been 1.0 mg/dL)
• Total serum calcium 14.4 mg/dL (8.6–10.0)

Complete blood cell counts were unremarkable. Computed tomography of the head was negative for acute pathology.

In view of the patient’s hypercalcemia, he was given aggressive intravenous fluid resuscitation (2 L of normal saline over 2 hours) and was admitted to the hospital. His laboratory values on admission are shown in Table 1. Fluid resuscitation was continued while the laboratory results were pending.

CAUSES OF HYPERCALCEMIA

1. Based on this information, which is the most likely cause of this patient’s hypercalcemia?

• Primary hyperparathyroidism
• Malignancy
• Hyperthyroidism
• Hypervitaminosis D
• Sarcoidosis

Traditionally, the workup for hypercalcemia in an outpatient starts with measuring the serum parathyroid hormone (PTH) level. Based on the results, a further evaluation of PTH-mediated vs PTH-independent causes of hypercalcemia would be initiated.

Primary hyperparathyroidism and malignancy account for 90% of all cases of hypercalcemia. The serum PTH concentration is usually high in primary hyperparathyroidism but low in malignancy, which helps distinguish the conditions from each other.¹

Primary hyperparathyroidism

In primary hyperparathyroidism, there is overproduction of PTH, most commonly from a parathyroid adenoma, though parathyroid hyperplasia or, more rarely, parathyroid carcinoma can also overproduce the hormone.

PTH increases serum calcium levels through 3 primary mechanisms: increasing bone resorption, increasing intestinal absorption of calcium, and decreasing renal excretion of calcium. It also induces renal phosphorus excretion.

Typically, in primary hyperparathyroidism, the increases in serum calcium are small (with serum levels of total calcium rising to no higher than 11 mg/dL) and often intermittent.² Our patient had extremely high serum calcium, low PTH, and high phosphorus levels—all of which are inconsistent with primary hyperparathyroidism.

Malignancy

In some solid tumors, the major mechanism of hypercalcemia is secretion of PTH-related peptide (PTHrP) through promotion of osteoclast function and also increased renal absorption of calcium.³ Hematologic malignancies (eg, multiple myeloma) produce osteoclast-activating factors such as RANK ligand, lymphotoxin, and interleukin 6. Direct tumor invasion of bone can cause osteolysis and subsequent hypercalcemia.⁴ These mechanisms are usually associated with a fall in PTH.

Less commonly, tumors can also increase levels of 1,25-dihydroxyvitamin D or produce PTH independently of the parathyroid gland.⁵ There have also been reports of severe hypercalcemia from hepatocellular carcinoma due to PTHrP production.⁶

Our patient is certainly at risk for malignancy, given his long-standing history of hepatitis C and cirrhosis. He also had a mildly elevated alpha fetoprotein level and suppressed PTH. However, his PTHrP level was normal, and ultrasonography done recently to screen for hepatocellular carcinoma (recommended every 6 months by the American Association for the Study of Liver Diseases in high-risk patients) was negative.⁷

Multiple myeloma screening involves testing with serum protein electrophoresis with immunofixation in combination with either a serum free light chain assay or 24-hour urine protein electrophoresis with immunofixation. This provides a 97% sensitivity.⁸ In this patient, these tests for multiple myeloma were negative.

Hyperthyroidism

As many as half of all patients with hyperthyroidism have elevated levels of ionized serum calcium.⁹ Increased osteoclastic activity is the likely mechanism. Hyperthyroid patients have increased levels of serum interleukin 6 and increased sensitivity of bone to this factor. This cytokine induces differentiation of monocytic cells into osteoclast precursors.¹⁰ These patients also have normal or low PTH levels.⁹

Our patient was receiving levothyroxine for hypothyroidism, but there was no evidence that the dosage was too high, as his thyroid-stimulating hormone level was within an acceptable range.

Hypervitaminosis D

Vitamin D precursors arise from the skin and from the diet. These precursors are hydroxylated in the liver and then the kidneys to biologically active 1,25-dihydroxyvitamin D (Figure 1).¹¹ Vitamin D’s primary actions are in the intestines to increase absorption of calcium and in bone to induce osteoclast action. These actions raise the serum calcium level, which in turn lowers the PTH level through negative feedback on the parathyroid gland.

Most vitamin D supplements consist of the inactive precursor cholecalciferol (vitamin D₃). To assess the degree of supplementation, 25-hydroxyvitamin D levels, which indicate the size of the body’s vitamin D reservoir, are measured.^11,12

Our patient’s 25-hydroxyvitamin D level is extremely elevated, well beyond the 250-ng/mL upper limit that is considered safe.¹³ His low PTH level, lack of other likely causes, and history of supplement use point toward the diagnosis of hypervitaminosis D.

Sarcoidosis

Up to 10% of patients with sarcoidosis have hypercalcemia that is not mediated by PTH. Hypercalcemia in sarcoidosis has several potential mechanisms, including increased activity of the enzyme 1-alpha hydroxylase with a subsequent increase in physiologically active 1,25-dihydroxyvitamin D₃ production.¹⁴

Our patient had elevated levels of 25-hydroxyvitamin D, but his biologically active 1,25-dihydroxyvitamin D level remained within the laboratory’s reference range.

LESS LIKELY CAUSES OF HYPERCALCEMIA

2. Which of the following would be least likely to cause hypercalcemia?

• Thiazide diuretics
• Over-the-counter antacid tablets
• Lithium
• Vitamin A supplementation
• Proton pump inhibitors

Thiazide diuretics

This class of drugs is well known to cause hypercalcemia. The most familiar of the mechanisms is a reduction in urinary calcium excretion. There is also an increase in intestinal absorption of dietary calcium. Evidence is increasing that most patients (as many as two-thirds) who develop hypercal­cemia while using a thiazide diuretic have subclinical primary hyperparathyroidism that is uncovered with use of the diuretic.

Of importance, the hypercalcemia that thiazide diuretics cause is mild. In a series of 72 patients with thiazide-induced hypercalcemia, the average serum calcium level was 10.7 mg/dL.¹⁵

Our patient was receiving a thiazide diuretic but presented with severe hypercalcemia, which is inconsistent with thiazide-induced hypercalcemia.

Over-the-counter antacid tablets

Calcium carbonate, a popular over-the-counter antacid, can cause a milk-alkali syndrome that is defined by ingestion of excessive calcium and alkalotic substances, leading to metabolic alkalosis, hypercalcemia, and renal insufficiency. To induce this syndrome generally requires up to 4 g of calcium intake daily, but even lower levels (1.0 to 1.5 g) are known to cause it.¹⁶

Lithium

Lithium is known to cause hypercalcemia. Multiple mechanisms have been proposed, including direct action on renal tubules and the intestines leading to calcium reabsorption and stimulation of PTH release. Interestingly, parathyroid gland hyperplasia has been noted in long-term users of lithium. An often-proposed mechanism is that lithium increases the threshold at which the parathyroid glands slow their production of PTH, making them less sensitive to serum calcium levels.¹⁷

Vitamin A supplementation

Multiple case reports have linked hypercalcemia to ingestion of large doses of vitamin A. The mechanism is thought to be increased bone resorption.^18.19

Although our patient reported supplement use, he denied taking vitamin A in any form.

Proton pump inhibitors

Proton pump inhibitors are not known to cause hypercalcemia. On the contrary, case reports suggest that prolonged use of proton pump inhibitors is associated with hypocalcemia and hypomagnesemia, although the mechanism is still not fully understood. A low magnesium level is known to reduce PTH secretion and also skeletal responsiveness to PTH, which can lead to profound hypocalcemia.²⁰

CASE CONTINUED

On further questioning, the patient revealed that the supplement prescribed by his naturopathic practitioner contained vitamin D. Although he had been instructed to take 1 tablet weekly, he had begun taking it daily with his other routine medications, resulting in a daily dose in excess of 60,000 IU of cholecalciferol (vitamin D₃). The recommended dose is no more than 4,000 IU/day.

The supplement was immediately discontinued. His hydrochlorothiazide was also held due to its known effect of reducing urinary calcium excretion.

INITIAL TREATMENT OF HYPERCALCEMIA

3. Which of the following treatments is not recommended as part of this patient’s initial treatment?

• Bisphosphonates
• Calcitonin
• Intravenous fluids
• Furosemide

Our patient met the criteria for the diagnosis of hypercalcemic crisis, usually defined as an albumin-corrected serum calcium level higher than 14 mg/dL associated with multiorgan dysfunction resulting from the hypercalcemia.²¹ The mnemonic “stones, bones, abdominal moans, and psychic groans” captures the renal, skeletal, gastrointestinal, and neurologic manifestations.¹

Bisphosphonates

Bisphosphonates are analogues of pyrophosphonates, which are normally incorporated into bone. Unlike pyrophosphonates, bisphosphonates inhibit osteoclast function. They are often used to treat hypercalcemia of any cause, although they are currently approved by the US Food and Drug Administration for treating hypercalcemia of malignancy only. As intravenous monotherapy, they are superior to other forms of treatment and are among the first-line agents in management.

Two bisphosphonates shown to be effective in hypercalcemia are zoledronate and pamidronate. Pamidronate begins to lower serum calcium levels within 2 days, with a peak effect at around 6 days.²² However, in studies comparing the 2 drugs, zoledronate has been shown to be more effective in normalizing serum calcium, with the additional benefit of having a much more rapid infusion time.²³ Zoledronate is contraindicated in patients with creatinine clearance less than 30 mL/min; however, pamidronate may continue to be used.²⁴

Calcitonin

This hormone inhibits bone resorption and increases excretion of calcium in the kidneys. It is not recommended for use alone because of its short duration of action and tachyphylaxis, but it can be used in combination with other agents, particularly in hypercalcemic crisis.²² It has the most rapid onset (within 2 hours) of the available medications, and when used in combination with bisphosphonates it produces a more substantial and rapid reduction in serum calcium.^25,26

In a patient such as ours, with severe hypercalcemia and evidence of neurologic consequences, calcitonin should be used for its rapid and effective action in lowering serum calcium as other interventions take effect.

Intravenous fluids

Like our patient, many patients with significant hypercalcemia have volume depletion as a result of calciuresis-induced polyuria. Many also have nephrogenic diabetes insipidus from the cytotoxic effect of calcium on renal cells, leading to further volume depletion.²⁷

All management approaches call for fluid repletion as an initial step in hypercalcemia. However, for severe hypercalcemia, volume resuscitation alone is unlikely to completely correct the imbalance. In addition to correcting dehydration, giving fluids increases glomerular filtration, allowing for increased secretion of calcium at the distal tubule.²⁸ The recommendation is 2.5 to 4 L of normal saline over the first 24 hours, with continued aggressive hydration until good urine output is established.²¹

Our patient, in addition to having acute kidney injury thought to be due to prerenal azotemia, appeared to be volume-depleted and was given aggressive intravenous hydration.

Furosemide

Furosemide inhibits calcium reabsorption at the thick ascending loop of Henle, but this effect depends on the glomerular filtration rate. While our patient would likely eventually benefit from furosemide, it should not be considered the first-line therapy, as diuretic use in the setting of volume depletion can cause circulatory collapse.²⁹ A relative contraindication was his presentation with acute kidney injury.

LONG-TERM TREATMENT

4. In the continued management of a patient with vitamin D toxicity with severe hypercalcemia, which of the following provides prolonged benefit?

• Intravenous hydrocortisone
• Fluid repletion
• Pamidronate
• Calcium-restricted diet

Much has been postulated concerning the mechanism of vitamin D intoxication and subsequent hypercalcemia. Studies have shown it is not an increase in dietary calcium absorption that drives the hypercalcemia but rather an increase in bone resorption. As such, bisphosphonates such as pamidronate have been shown to have a dramatic and rapid effect on severe hypercalcemia from vitamin D toxicity. The duration of action varies but is typically between 1 and 2 weeks.^22,30

Corticosteroids such as hydrocortisone are also indicated in situations of severe toxicity. They block the action of 1-alpha-hydroxylase, which converts inactive 25-hydroxyvitamin D to the active 1,25-dihydroxyvitamin D. Corticosteroids have also been shown to more directly reduce calcium resorption from bone and intestine in addition to increasing calciuresis.³¹ A small study in the United Kingdom noted that while bisphosphonates and steroids were equally effective in reducing serum calcium levels, bisphosphonates accomplished this reduction more rapidly, with a time to therapeutic effect of 9 days as opposed to 22 days.­

Fluid hydration, though necessary, is unlikely to produce complete correction on its own, as previously discussed.

THE PATIENT RECOVERS

The patient was treated with intravenous fluids over 3 days and received 1 dose of pamidronate. Calcitonin was provided over the first 48 hours after presentation to more rapidly reduce his calcium levels. He was advised to avoid taking the supplements prescribed by his naturopathic practitioner.

On follow-up with an endocrinologist 1 week later, his symptoms had entirely resolved, and his calcium level was 10.5 mg/dL.

TAKE-AWAY POINTS

• A good medication history includes over-the-counter products such as vitamin D supplements, as more and more people are taking them.
• The level of 25-hydroxyvitamin D should be monitored within 3 to 4 months after initiating treatment for vitamin D deficiency.¹¹
• Vitamin D toxicity can have profound consequences, which are usually seen when levels of 25-hydroxyvitamin D rise above 250 ng/mL.¹³
• The Institute of Medicine recommends that the dosage of vitamin D supplements be no more than 4,000 IU/day and that doses may need to be lowered to account for concurrent use of hypercalcemia-inducing drugs and other vitamin D-containing supplements.³²

A 58-year-old woman who sustained right-sided traumatic rib fractures after falling down stairs 8 months earlier presented with right shoulder pain that had been present for 6 months. She received nonsteroidal anti-inflammatory drugs at another hospital, which were partially effective. Magnetic resonance imaging of the neck and right shoulder had shown no abnormalities.

See related editorial

On physical examination, her right scapula was found to protrude abnormally (ie, to “wing”) during forward flexion and abduction of the right arm (Figure 1). Electromyography showed evidence of right serratus anterior paralysis and denervation of the right long thoracic nerve, leading to a diagnosis of traumatic long thoracic nerve paralysis. A course of physical therapy was initiated to improve her symptoms.

LONG THORACIC NERVE PARALYSIS

Scapular winging is caused by dysfunction of any of the 3 main muscles that attach the scapula to the posterior thoracic wall—the serratus anterior, the trapezius, and the rhomboid. The problem is most often in the serratus anterior muscle, innervated by the long thoracic nerve, a pure motor nerve that originates from the fifth, sixth, and seventh cervical nerves and descends along the lateral thoracic wall.

Long thoracic nerve paralysis can have traumatic, nontraumatic, or iatrogenic causes. Traumatic injuries result from blunt trauma to the neck, shoulder girdle, and thorax, while nontraumatic causes include viral illness, toxic exposure, apical pulmonary tumor, and C7 radiculopathy.^1–3 Iatrogenic injuries may be caused by mastectomy with axillary dissection, chest tube thoracostomy, first-rib resection, or scalenotomy, or occur after general anesthesia.^1,2,4

Scapular winging due to paralysis of the serratus anterior muscle is accentuated by forward elevation and—particularly—by pushing against a wall, and the entire scapula is displaced more medially and superiorly.² The compensatory muscular activity required for shoulder stability induces secondary shoulder pain.⁵

The diagnosis is often delayed, as the clinical presentation may mimic the symptoms of shoulder joint or rotator cuff pathology. Although physical therapy resolves the pain and improves the function of the arm, mild endurance deficits and asymptomatic scapular winging may persist. Tendon transfer surgery is considered if adequate recovery is not achieved after a 6- to-24-month course of physical therapy.²

A 58-year-old woman who sustained right-sided traumatic rib fractures after falling down stairs 8 months earlier presented with right shoulder pain that had been present for 6 months. She received nonsteroidal anti-inflammatory drugs at another hospital, which were partially effective. Magnetic resonance imaging of the neck and right shoulder had shown no abnormalities.

See related editorial

On physical examination, her right scapula was found to protrude abnormally (ie, to “wing”) during forward flexion and abduction of the right arm (Figure 1). Electromyography showed evidence of right serratus anterior paralysis and denervation of the right long thoracic nerve, leading to a diagnosis of traumatic long thoracic nerve paralysis. A course of physical therapy was initiated to improve her symptoms.

LONG THORACIC NERVE PARALYSIS

Scapular winging is caused by dysfunction of any of the 3 main muscles that attach the scapula to the posterior thoracic wall—the serratus anterior, the trapezius, and the rhomboid. The problem is most often in the serratus anterior muscle, innervated by the long thoracic nerve, a pure motor nerve that originates from the fifth, sixth, and seventh cervical nerves and descends along the lateral thoracic wall.

Long thoracic nerve paralysis can have traumatic, nontraumatic, or iatrogenic causes. Traumatic injuries result from blunt trauma to the neck, shoulder girdle, and thorax, while nontraumatic causes include viral illness, toxic exposure, apical pulmonary tumor, and C7 radiculopathy.^1–3 Iatrogenic injuries may be caused by mastectomy with axillary dissection, chest tube thoracostomy, first-rib resection, or scalenotomy, or occur after general anesthesia.^1,2,4

Scapular winging due to paralysis of the serratus anterior muscle is accentuated by forward elevation and—particularly—by pushing against a wall, and the entire scapula is displaced more medially and superiorly.² The compensatory muscular activity required for shoulder stability induces secondary shoulder pain.⁵

The diagnosis is often delayed, as the clinical presentation may mimic the symptoms of shoulder joint or rotator cuff pathology. Although physical therapy resolves the pain and improves the function of the arm, mild endurance deficits and asymptomatic scapular winging may persist. Tendon transfer surgery is considered if adequate recovery is not achieved after a 6- to-24-month course of physical therapy.²

A 58-year-old woman who sustained right-sided traumatic rib fractures after falling down stairs 8 months earlier presented with right shoulder pain that had been present for 6 months. She received nonsteroidal anti-inflammatory drugs at another hospital, which were partially effective. Magnetic resonance imaging of the neck and right shoulder had shown no abnormalities.

See related editorial

On physical examination, her right scapula was found to protrude abnormally (ie, to “wing”) during forward flexion and abduction of the right arm (Figure 1). Electromyography showed evidence of right serratus anterior paralysis and denervation of the right long thoracic nerve, leading to a diagnosis of traumatic long thoracic nerve paralysis. A course of physical therapy was initiated to improve her symptoms.

LONG THORACIC NERVE PARALYSIS

Scapular winging is caused by dysfunction of any of the 3 main muscles that attach the scapula to the posterior thoracic wall—the serratus anterior, the trapezius, and the rhomboid. The problem is most often in the serratus anterior muscle, innervated by the long thoracic nerve, a pure motor nerve that originates from the fifth, sixth, and seventh cervical nerves and descends along the lateral thoracic wall.

Long thoracic nerve paralysis can have traumatic, nontraumatic, or iatrogenic causes. Traumatic injuries result from blunt trauma to the neck, shoulder girdle, and thorax, while nontraumatic causes include viral illness, toxic exposure, apical pulmonary tumor, and C7 radiculopathy.^1–3 Iatrogenic injuries may be caused by mastectomy with axillary dissection, chest tube thoracostomy, first-rib resection, or scalenotomy, or occur after general anesthesia.^1,2,4

Scapular winging due to paralysis of the serratus anterior muscle is accentuated by forward elevation and—particularly—by pushing against a wall, and the entire scapula is displaced more medially and superiorly.² The compensatory muscular activity required for shoulder stability induces secondary shoulder pain.⁵

The diagnosis is often delayed, as the clinical presentation may mimic the symptoms of shoulder joint or rotator cuff pathology. Although physical therapy resolves the pain and improves the function of the arm, mild endurance deficits and asymptomatic scapular winging may persist. Tendon transfer surgery is considered if adequate recovery is not achieved after a 6- to-24-month course of physical therapy.²

“... with the rapid extension of laboratory tests of greater accuracy, there is a tendency for some clinicians and hence for some students in reaching a diagnosis to rely more on laboratory reports and less on the history of the illness, the examination and behavior of the patient and clinical judgment. While in many cases laboratory findings are invaluable for reaching correct conclusions, the student should never be allowed to forget that it takes a man, not a machine, to understand a man.”

—Raymond B. Allen, MD, PhD, 1946¹

From Hippocrates onward, accurate diagnosis has always been the prerequisite for prognosis and treatment. Physicians typically diagnosed through astute interviewing, deductive reasoning, and skillful use of observation and touch. Then, in the past 250 years they added 2 more tools to their diagnostic skill set: percussion and auscultation, the dual foundation of bedside assessment. Intriguingly, both these skills were first envisioned by multifaceted minds: percussion by Leopold Auenbrugger, an Austrian music-lover who even wrote librettos for operas; and stethoscopy by René Laennec, a Breton flutist, poet, and dancer—not exactly the kind of doctors we tend to produce today.

See related article

Still, the point of this preamble is not to say that eclecticism may help creativity (it does), but to remind ourselves that it has only been for a century or so that physicians have been able to rely on laboratory and radiologic studies. In fact, the now ubiquitous and almost obligatory imaging tests (computed tomography, magnetic resonance imaging, positron-emission tomography, and ultrasonography) have been available to practitioners for only threescore years or less. Yet tests have become so dominant in our culture that it is hard to imagine a time when physicians could count only on their wit and senses.

CLINICAL SKILLS ARE STILL RELEVANT

Ironically, many studies tell us that history and bedside examination can still deliver most diagnoses.^2,3 In fact, clinical skills can solve even the most perplexing dilemmas. In an automated analysis of the clinicopathologic conference cases presented in the New England Journal of Medicine,⁴ history and physical examination still yielded a correct diagnosis in 64% of those very challenging patients.

Bedside examination may be especially important in the hospital. In a study of inpatients,⁵ physical examination detected crucial findings in one-fourth of the cases and prompted management changes in many others. As the authors concluded, sick patients need careful examination, the more skilled the better.

Unfortunately, errors in physical examination are common. In a recent review of 208 cases, 63% of oversights were due to failure to perform an examination, while 25% were either missed or misinterpreted findings.⁶ These errors interfered with diagnosis in three-fourths of the cases, and with treatment in half.

Which brings us to the interesting observation by Kondo et al,⁷ who in this issue of the Journal report how the lowly physical examination proved more helpful than expensive magnetic resonance imaging in evaluating a perplexing case of refractory shoulder pain.

This is not an isolated instance. To get back to Laennec, whose stethoscope just turned 200, auscultation too can help the 21st-century physician. For example, posturally induced crackles, a recently discovered phenomenon, are the third-best predictor of outcome following myocardial infarction, immediately after the number of diseased vessels and pulmonary capillary wedge pressure.⁸

The time-honored art of observation can also yield new and important clues. From the earlobe crease of Dr. Frank, to the elfin face of Dr. Williams, there are lots of diseases out there waiting for our name—if only we could see them. As William Osler put it, “The whole art of medicine is in observation.”⁹

But how can residents truly “observe” when they have to spend 40% of their time looking at computer screens and only 12% looking at people?¹⁰ To quote Osler again, “To educate the eye to see, the ear to hear, and the finger to feel takes time.”⁹ Yet time in medicine is at a premium. In a large national survey, the average ambulatory care visit to a general practitioner lasted 16 minutes,¹¹ which makes it difficult to use inexpensive but time-consuming maneuvers. Detection of posturally induced crackles, for example, may require as much as 9 minutes, and a thorough breast examination up to 10.¹² On the other hand, ordering tests costs little time to the physician but a huge sum to patients and society. Paradoxically, “tests” may be quite profitable for the medical-industrial complex. Hence the erosion of clinical skills.

Overreliance on diagnostic technology is particularly concerning when the cost of medicine has skyrocketed. The United States now spends $3.2 trillion a year for healthcare, and much of this money goes into technology.

In fact, high-tech might hurt us even more than in the pocket. It is a sad fact of modern medicine that when unguided by clinical skills, technology can take us down a rabbit hole, wherein tests beget tests, and where at the end there is usually a surgeon, often a lawyer, and sometimes even an undertaker. The literature is full of such cases, to the point that the risk of unnecessary tests has spawned a charming new acronym: VOMIT (victims of modern imaging technology).¹³

I’m not suggesting that we discard appropriate laboratory and radiologic testing. To the contrary. Yet contributions like those of Kondo et al remind us that even in today’s medicine, the bedside remains not only the royal road to diagnosis, but also the best filter for a more judicious and cost-effective use of technology.

That filter starts with history-taking (“Listen to the patient” said Osler, “he is telling you the diagnosis.”),⁹ and continues with the physical examination. In fact, the history typically guides the physical examination. Hence, when the patient’s symptoms point away from a particular organ, the examination of that organ may be reduced to a minimum. For instance, in neurologic patients whose history made certain findings unlikely, a Canadian group was able to cut in half the number of core items of their neurologic examination.¹⁴

Yet when the history flags a system, the clinician needs to go deeper into the examination. It’s very much what we do with laboratory tests, moving from screening tests to more advanced inquiries as we tailor our diagnostic studies to the patient’s presentation. For that we need validated maneuvers. Recent efforts in this direction have turned the art of physical examination into a science.¹⁵

Lastly, patients expect to be examined, and in fact they resent when this doesn’t happen.¹⁶ Lewis Thomas called touching our “real professional secret” and “the oldest and most effective art of doctors.”¹⁷ It may even have therapeutic value.

TEACHING BEDSIDE DIAGNOSIS

So, if bedside diagnosis is important, what can we do to rekindle it? Probably anything but continue in the old ways. Studies have consistently shown that auscultation does not improve with years of training, and that in fact attending physicians may be no more proficient than third-year medical students.¹⁸ Other areas of the examination have shown similarly depressing trends,¹⁹ thus suggesting that the traditional apprenticeship mode of learning from both faculty and senior trainees may not be helpful. In fact, it may be akin to Bruegel the Elder’s painting of the blind leading the blind, and all ending up in a ditch.

Advanced physical diagnosis courses have thus been advocated, and indeed implemented at many institutions, but usually as electives. Faculty development programs have also been recommended. Still, these interventions may not suffice.

Cutting the cord to technology by serving in a developing country

My hunch is that the rekindling of physical diagnosis may require extreme measures, like putting ourselves in a zero-tech, zero-tests environment. Years ago, I had that kind of cold-turkey experience when I spent a month in a remote Nepali clinic with neither electricity nor running water—and, of course, no cell phone and no Internet. In fact, my only tools were a translator, a stethoscope, and my brain and senses. It was both terrifying and instructive, very much like the time my uncle tried to teach me how to swim by suddenly throwing me into the Mediterranean.

Maybe we should offer that kind of “immersion” to our students. A senior rotation in a technology-depleted country might do a lot of good for a young medical mind. For one, it could remind students that physicians are not only the “natural attorneys of the poor,” as Virchow famously put it,²⁰ but also the ultimate citizens of the world. To quote Dr. Osler again, “Distinctions of race, nationality, color, and creed are unknown within the portals of the temple of Æsculapius.”²¹ Such an experience might also foster empathy and tolerance for ambiguity, 2 other traits whose absence we lament in today’s medicine. More importantly, if preceded by an advanced physical diagnosis course, a rotation in a developing country could work miracles for honing bedside skills, especially if the students are accompanied by a faculty member who can be both inspiring and gifted in the art and science of bedside diagnosis.

Ultimately, this experience could remind our young that the art of medicine is much harder to acquire than the science, and that medicine is indeed a calling and not a trade. Osler said it too, and these are indeed provocative thoughts, but short of provocations and out-of-the-box ideas, the tail will continue to wag the dog. And in the end it will cost us more than money. It will cost us the art of medicine.

“... with the rapid extension of laboratory tests of greater accuracy, there is a tendency for some clinicians and hence for some students in reaching a diagnosis to rely more on laboratory reports and less on the history of the illness, the examination and behavior of the patient and clinical judgment. While in many cases laboratory findings are invaluable for reaching correct conclusions, the student should never be allowed to forget that it takes a man, not a machine, to understand a man.”

—Raymond B. Allen, MD, PhD, 1946¹

From Hippocrates onward, accurate diagnosis has always been the prerequisite for prognosis and treatment. Physicians typically diagnosed through astute interviewing, deductive reasoning, and skillful use of observation and touch. Then, in the past 250 years they added 2 more tools to their diagnostic skill set: percussion and auscultation, the dual foundation of bedside assessment. Intriguingly, both these skills were first envisioned by multifaceted minds: percussion by Leopold Auenbrugger, an Austrian music-lover who even wrote librettos for operas; and stethoscopy by René Laennec, a Breton flutist, poet, and dancer—not exactly the kind of doctors we tend to produce today.

See related article

Still, the point of this preamble is not to say that eclecticism may help creativity (it does), but to remind ourselves that it has only been for a century or so that physicians have been able to rely on laboratory and radiologic studies. In fact, the now ubiquitous and almost obligatory imaging tests (computed tomography, magnetic resonance imaging, positron-emission tomography, and ultrasonography) have been available to practitioners for only threescore years or less. Yet tests have become so dominant in our culture that it is hard to imagine a time when physicians could count only on their wit and senses.

CLINICAL SKILLS ARE STILL RELEVANT

Ironically, many studies tell us that history and bedside examination can still deliver most diagnoses.^2,3 In fact, clinical skills can solve even the most perplexing dilemmas. In an automated analysis of the clinicopathologic conference cases presented in the New England Journal of Medicine,⁴ history and physical examination still yielded a correct diagnosis in 64% of those very challenging patients.

Bedside examination may be especially important in the hospital. In a study of inpatients,⁵ physical examination detected crucial findings in one-fourth of the cases and prompted management changes in many others. As the authors concluded, sick patients need careful examination, the more skilled the better.

Unfortunately, errors in physical examination are common. In a recent review of 208 cases, 63% of oversights were due to failure to perform an examination, while 25% were either missed or misinterpreted findings.⁶ These errors interfered with diagnosis in three-fourths of the cases, and with treatment in half.

Which brings us to the interesting observation by Kondo et al,⁷ who in this issue of the Journal report how the lowly physical examination proved more helpful than expensive magnetic resonance imaging in evaluating a perplexing case of refractory shoulder pain.

This is not an isolated instance. To get back to Laennec, whose stethoscope just turned 200, auscultation too can help the 21st-century physician. For example, posturally induced crackles, a recently discovered phenomenon, are the third-best predictor of outcome following myocardial infarction, immediately after the number of diseased vessels and pulmonary capillary wedge pressure.⁸

The time-honored art of observation can also yield new and important clues. From the earlobe crease of Dr. Frank, to the elfin face of Dr. Williams, there are lots of diseases out there waiting for our name—if only we could see them. As William Osler put it, “The whole art of medicine is in observation.”⁹

But how can residents truly “observe” when they have to spend 40% of their time looking at computer screens and only 12% looking at people?¹⁰ To quote Osler again, “To educate the eye to see, the ear to hear, and the finger to feel takes time.”⁹ Yet time in medicine is at a premium. In a large national survey, the average ambulatory care visit to a general practitioner lasted 16 minutes,¹¹ which makes it difficult to use inexpensive but time-consuming maneuvers. Detection of posturally induced crackles, for example, may require as much as 9 minutes, and a thorough breast examination up to 10.¹² On the other hand, ordering tests costs little time to the physician but a huge sum to patients and society. Paradoxically, “tests” may be quite profitable for the medical-industrial complex. Hence the erosion of clinical skills.

Overreliance on diagnostic technology is particularly concerning when the cost of medicine has skyrocketed. The United States now spends $3.2 trillion a year for healthcare, and much of this money goes into technology.

In fact, high-tech might hurt us even more than in the pocket. It is a sad fact of modern medicine that when unguided by clinical skills, technology can take us down a rabbit hole, wherein tests beget tests, and where at the end there is usually a surgeon, often a lawyer, and sometimes even an undertaker. The literature is full of such cases, to the point that the risk of unnecessary tests has spawned a charming new acronym: VOMIT (victims of modern imaging technology).¹³

I’m not suggesting that we discard appropriate laboratory and radiologic testing. To the contrary. Yet contributions like those of Kondo et al remind us that even in today’s medicine, the bedside remains not only the royal road to diagnosis, but also the best filter for a more judicious and cost-effective use of technology.

That filter starts with history-taking (“Listen to the patient” said Osler, “he is telling you the diagnosis.”),⁹ and continues with the physical examination. In fact, the history typically guides the physical examination. Hence, when the patient’s symptoms point away from a particular organ, the examination of that organ may be reduced to a minimum. For instance, in neurologic patients whose history made certain findings unlikely, a Canadian group was able to cut in half the number of core items of their neurologic examination.¹⁴

Yet when the history flags a system, the clinician needs to go deeper into the examination. It’s very much what we do with laboratory tests, moving from screening tests to more advanced inquiries as we tailor our diagnostic studies to the patient’s presentation. For that we need validated maneuvers. Recent efforts in this direction have turned the art of physical examination into a science.¹⁵

Lastly, patients expect to be examined, and in fact they resent when this doesn’t happen.¹⁶ Lewis Thomas called touching our “real professional secret” and “the oldest and most effective art of doctors.”¹⁷ It may even have therapeutic value.

TEACHING BEDSIDE DIAGNOSIS

So, if bedside diagnosis is important, what can we do to rekindle it? Probably anything but continue in the old ways. Studies have consistently shown that auscultation does not improve with years of training, and that in fact attending physicians may be no more proficient than third-year medical students.¹⁸ Other areas of the examination have shown similarly depressing trends,¹⁹ thus suggesting that the traditional apprenticeship mode of learning from both faculty and senior trainees may not be helpful. In fact, it may be akin to Bruegel the Elder’s painting of the blind leading the blind, and all ending up in a ditch.

Advanced physical diagnosis courses have thus been advocated, and indeed implemented at many institutions, but usually as electives. Faculty development programs have also been recommended. Still, these interventions may not suffice.

Cutting the cord to technology by serving in a developing country

My hunch is that the rekindling of physical diagnosis may require extreme measures, like putting ourselves in a zero-tech, zero-tests environment. Years ago, I had that kind of cold-turkey experience when I spent a month in a remote Nepali clinic with neither electricity nor running water—and, of course, no cell phone and no Internet. In fact, my only tools were a translator, a stethoscope, and my brain and senses. It was both terrifying and instructive, very much like the time my uncle tried to teach me how to swim by suddenly throwing me into the Mediterranean.

Maybe we should offer that kind of “immersion” to our students. A senior rotation in a technology-depleted country might do a lot of good for a young medical mind. For one, it could remind students that physicians are not only the “natural attorneys of the poor,” as Virchow famously put it,²⁰ but also the ultimate citizens of the world. To quote Dr. Osler again, “Distinctions of race, nationality, color, and creed are unknown within the portals of the temple of Æsculapius.”²¹ Such an experience might also foster empathy and tolerance for ambiguity, 2 other traits whose absence we lament in today’s medicine. More importantly, if preceded by an advanced physical diagnosis course, a rotation in a developing country could work miracles for honing bedside skills, especially if the students are accompanied by a faculty member who can be both inspiring and gifted in the art and science of bedside diagnosis.

Ultimately, this experience could remind our young that the art of medicine is much harder to acquire than the science, and that medicine is indeed a calling and not a trade. Osler said it too, and these are indeed provocative thoughts, but short of provocations and out-of-the-box ideas, the tail will continue to wag the dog. And in the end it will cost us more than money. It will cost us the art of medicine.

“... with the rapid extension of laboratory tests of greater accuracy, there is a tendency for some clinicians and hence for some students in reaching a diagnosis to rely more on laboratory reports and less on the history of the illness, the examination and behavior of the patient and clinical judgment. While in many cases laboratory findings are invaluable for reaching correct conclusions, the student should never be allowed to forget that it takes a man, not a machine, to understand a man.”

—Raymond B. Allen, MD, PhD, 1946¹

From Hippocrates onward, accurate diagnosis has always been the prerequisite for prognosis and treatment. Physicians typically diagnosed through astute interviewing, deductive reasoning, and skillful use of observation and touch. Then, in the past 250 years they added 2 more tools to their diagnostic skill set: percussion and auscultation, the dual foundation of bedside assessment. Intriguingly, both these skills were first envisioned by multifaceted minds: percussion by Leopold Auenbrugger, an Austrian music-lover who even wrote librettos for operas; and stethoscopy by René Laennec, a Breton flutist, poet, and dancer—not exactly the kind of doctors we tend to produce today.

See related article

Still, the point of this preamble is not to say that eclecticism may help creativity (it does), but to remind ourselves that it has only been for a century or so that physicians have been able to rely on laboratory and radiologic studies. In fact, the now ubiquitous and almost obligatory imaging tests (computed tomography, magnetic resonance imaging, positron-emission tomography, and ultrasonography) have been available to practitioners for only threescore years or less. Yet tests have become so dominant in our culture that it is hard to imagine a time when physicians could count only on their wit and senses.

CLINICAL SKILLS ARE STILL RELEVANT

Ironically, many studies tell us that history and bedside examination can still deliver most diagnoses.^2,3 In fact, clinical skills can solve even the most perplexing dilemmas. In an automated analysis of the clinicopathologic conference cases presented in the New England Journal of Medicine,⁴ history and physical examination still yielded a correct diagnosis in 64% of those very challenging patients.

Bedside examination may be especially important in the hospital. In a study of inpatients,⁵ physical examination detected crucial findings in one-fourth of the cases and prompted management changes in many others. As the authors concluded, sick patients need careful examination, the more skilled the better.

Unfortunately, errors in physical examination are common. In a recent review of 208 cases, 63% of oversights were due to failure to perform an examination, while 25% were either missed or misinterpreted findings.⁶ These errors interfered with diagnosis in three-fourths of the cases, and with treatment in half.

Which brings us to the interesting observation by Kondo et al,⁷ who in this issue of the Journal report how the lowly physical examination proved more helpful than expensive magnetic resonance imaging in evaluating a perplexing case of refractory shoulder pain.

This is not an isolated instance. To get back to Laennec, whose stethoscope just turned 200, auscultation too can help the 21st-century physician. For example, posturally induced crackles, a recently discovered phenomenon, are the third-best predictor of outcome following myocardial infarction, immediately after the number of diseased vessels and pulmonary capillary wedge pressure.⁸

The time-honored art of observation can also yield new and important clues. From the earlobe crease of Dr. Frank, to the elfin face of Dr. Williams, there are lots of diseases out there waiting for our name—if only we could see them. As William Osler put it, “The whole art of medicine is in observation.”⁹

But how can residents truly “observe” when they have to spend 40% of their time looking at computer screens and only 12% looking at people?¹⁰ To quote Osler again, “To educate the eye to see, the ear to hear, and the finger to feel takes time.”⁹ Yet time in medicine is at a premium. In a large national survey, the average ambulatory care visit to a general practitioner lasted 16 minutes,¹¹ which makes it difficult to use inexpensive but time-consuming maneuvers. Detection of posturally induced crackles, for example, may require as much as 9 minutes, and a thorough breast examination up to 10.¹² On the other hand, ordering tests costs little time to the physician but a huge sum to patients and society. Paradoxically, “tests” may be quite profitable for the medical-industrial complex. Hence the erosion of clinical skills.

Overreliance on diagnostic technology is particularly concerning when the cost of medicine has skyrocketed. The United States now spends $3.2 trillion a year for healthcare, and much of this money goes into technology.

In fact, high-tech might hurt us even more than in the pocket. It is a sad fact of modern medicine that when unguided by clinical skills, technology can take us down a rabbit hole, wherein tests beget tests, and where at the end there is usually a surgeon, often a lawyer, and sometimes even an undertaker. The literature is full of such cases, to the point that the risk of unnecessary tests has spawned a charming new acronym: VOMIT (victims of modern imaging technology).¹³

I’m not suggesting that we discard appropriate laboratory and radiologic testing. To the contrary. Yet contributions like those of Kondo et al remind us that even in today’s medicine, the bedside remains not only the royal road to diagnosis, but also the best filter for a more judicious and cost-effective use of technology.

That filter starts with history-taking (“Listen to the patient” said Osler, “he is telling you the diagnosis.”),⁹ and continues with the physical examination. In fact, the history typically guides the physical examination. Hence, when the patient’s symptoms point away from a particular organ, the examination of that organ may be reduced to a minimum. For instance, in neurologic patients whose history made certain findings unlikely, a Canadian group was able to cut in half the number of core items of their neurologic examination.¹⁴

Yet when the history flags a system, the clinician needs to go deeper into the examination. It’s very much what we do with laboratory tests, moving from screening tests to more advanced inquiries as we tailor our diagnostic studies to the patient’s presentation. For that we need validated maneuvers. Recent efforts in this direction have turned the art of physical examination into a science.¹⁵

Lastly, patients expect to be examined, and in fact they resent when this doesn’t happen.¹⁶ Lewis Thomas called touching our “real professional secret” and “the oldest and most effective art of doctors.”¹⁷ It may even have therapeutic value.

TEACHING BEDSIDE DIAGNOSIS

So, if bedside diagnosis is important, what can we do to rekindle it? Probably anything but continue in the old ways. Studies have consistently shown that auscultation does not improve with years of training, and that in fact attending physicians may be no more proficient than third-year medical students.¹⁸ Other areas of the examination have shown similarly depressing trends,¹⁹ thus suggesting that the traditional apprenticeship mode of learning from both faculty and senior trainees may not be helpful. In fact, it may be akin to Bruegel the Elder’s painting of the blind leading the blind, and all ending up in a ditch.

Advanced physical diagnosis courses have thus been advocated, and indeed implemented at many institutions, but usually as electives. Faculty development programs have also been recommended. Still, these interventions may not suffice.

Cutting the cord to technology by serving in a developing country

My hunch is that the rekindling of physical diagnosis may require extreme measures, like putting ourselves in a zero-tech, zero-tests environment. Years ago, I had that kind of cold-turkey experience when I spent a month in a remote Nepali clinic with neither electricity nor running water—and, of course, no cell phone and no Internet. In fact, my only tools were a translator, a stethoscope, and my brain and senses. It was both terrifying and instructive, very much like the time my uncle tried to teach me how to swim by suddenly throwing me into the Mediterranean.

Maybe we should offer that kind of “immersion” to our students. A senior rotation in a technology-depleted country might do a lot of good for a young medical mind. For one, it could remind students that physicians are not only the “natural attorneys of the poor,” as Virchow famously put it,²⁰ but also the ultimate citizens of the world. To quote Dr. Osler again, “Distinctions of race, nationality, color, and creed are unknown within the portals of the temple of Æsculapius.”²¹ Such an experience might also foster empathy and tolerance for ambiguity, 2 other traits whose absence we lament in today’s medicine. More importantly, if preceded by an advanced physical diagnosis course, a rotation in a developing country could work miracles for honing bedside skills, especially if the students are accompanied by a faculty member who can be both inspiring and gifted in the art and science of bedside diagnosis.

Ultimately, this experience could remind our young that the art of medicine is much harder to acquire than the science, and that medicine is indeed a calling and not a trade. Osler said it too, and these are indeed provocative thoughts, but short of provocations and out-of-the-box ideas, the tail will continue to wag the dog. And in the end it will cost us more than money. It will cost us the art of medicine.

Now that we can order MRI studies on a break from rounds walking to Starbucks, utilize portable ultrasounds to direct IV line placement, and use dual-energy CT to detect a gout attack that has not yet occurred, it seems like a romantic anachronism to extol the ongoing virtues of the seemingly lost art of the physical examination. Back “in the day,” the giants of medicine roamed the halls with their natural instruments of palpation and percussion and their skills in observation and auscultation. They were giants because they stood out then, just as skilled diagnosticians stand out today using an upgraded set of tools. Some physicians a few decades ago were able to recognize, describe, and diagnose late-stage endocarditis with a stethoscope, a magnifying glass, and an ophthalmoscope. The giants of today recognize the patient with endocarditis and document its presence using transesophageal echocardiography before the peripheral eponymous stigmata of Janeway and Osler appear or the blood cultures turn positive. The physical examination, history, diagnostic reasoning, and clinical technology are all essential for a blend that provides efficient and effective medical care. The blending is the challenge.

Clinicians are not created equal. We learn and prioritize our skills in different ways. But if we are not taught to value and trust the physical examination, if we don’t have the opportunity to see it influence patient management in positive ways, we may eschew it and instead indiscriminately use easily available laboratory and imaging tests—a more expensive and often misleading strategic approach. Today while in clinic, I saw a 54-year-old woman for evaluation of possible lupus who had arthritis of the hands and a high positive antinuclear antibody titer, but negative or normal results on other, previously ordered tests, including anti-DNA, rheumatoid factor, anti-cyclic citrullinated peptide, hepatitis C studies, complement levels, and another half-dozen immune serologic tests. On examination, she had typical nodular osteoarthritis of the proximal and distal interphalangeal joints of her hand with squaring of her thumbs. The antinuclear antibody was most likely associated with her previously diagnosed autoimmune thyroid disease.

In an editorial in this issue of the Journal, Dr. Salvatore Mangione, the author of a book on physical diagnosis,¹ cites a recent study indicating that the most common recognized diagnostic error related to the physical examination is that the appropriate examination isn’t done.² I would add to that my concerns over the new common custom of cutting and pasting the findings from earlier physical examinations into later progress notes in the electronic record. So much for the value of being able to recognize “changing murmurs” when diagnosing infectious endocarditis.

The apparent efficiency (reflected in length of stay) and availability of technology, as well as a lack of physician skill and time, are often cited as reasons for the demise of the physical examination. Yet this does not need to be the case. If I had trained with portable ultrasonography readily available to confirm or refute my impressions, my skills at detecting low-grade synovitis would surely be better than they are. With a gold standard at hand, which may be technology or at times a skilled mentor, our examinations can be refined if we want them to be.

But the issue of limited physician time must be addressed. Efficiency is a critical concept in preserving how we practice and perform the physical examination. When we know what we are looking for, we are more likely to find it if it is present, or to have confidence that it is not present. I am far more likely to recognize a loud pulmonic second heart sound if I suspect that the dyspneic patient I am examining has pulmonary hypertension associated with her scleroderma than if I am doing a perfunctory cardiac auscultation in a patient admitted with cellulitis. Appropriate focus provides power to the directed physical examination. If I am looking for the cause of unexplained fevers, I will do a purposeful axillary and epitrochlear lymph node examination. I am not mindlessly probing the flesh.

Nishigori and colleagues have written of the “hypothesis-driven” physical examination.³ Busy clinicians, they say, don’t have time to perform a head-to-toe, by-the-book physical examination. Instead, we should, by a dynamic process, formulate a differential diagnosis from the history and other initial information, and then perform the directed physical examination in earnest, looking for evidence to support or refute our diagnostic hypothesis—and thus redirect it. Plus, in a nice break from electronic charting, we can actually explain our thought processes to the patient as we perform the examination.

This approach makes sense to me as both intellectually satisfying and clinically efficient. And then we can consider which lab tests and technologic gadgetry we should order, while walking to get the café latte we ordered with our cell phone app.

New technology can support and not necessarily replace old habits.

Now that we can order MRI studies on a break from rounds walking to Starbucks, utilize portable ultrasounds to direct IV line placement, and use dual-energy CT to detect a gout attack that has not yet occurred, it seems like a romantic anachronism to extol the ongoing virtues of the seemingly lost art of the physical examination. Back “in the day,” the giants of medicine roamed the halls with their natural instruments of palpation and percussion and their skills in observation and auscultation. They were giants because they stood out then, just as skilled diagnosticians stand out today using an upgraded set of tools. Some physicians a few decades ago were able to recognize, describe, and diagnose late-stage endocarditis with a stethoscope, a magnifying glass, and an ophthalmoscope. The giants of today recognize the patient with endocarditis and document its presence using transesophageal echocardiography before the peripheral eponymous stigmata of Janeway and Osler appear or the blood cultures turn positive. The physical examination, history, diagnostic reasoning, and clinical technology are all essential for a blend that provides efficient and effective medical care. The blending is the challenge.

Clinicians are not created equal. We learn and prioritize our skills in different ways. But if we are not taught to value and trust the physical examination, if we don’t have the opportunity to see it influence patient management in positive ways, we may eschew it and instead indiscriminately use easily available laboratory and imaging tests—a more expensive and often misleading strategic approach. Today while in clinic, I saw a 54-year-old woman for evaluation of possible lupus who had arthritis of the hands and a high positive antinuclear antibody titer, but negative or normal results on other, previously ordered tests, including anti-DNA, rheumatoid factor, anti-cyclic citrullinated peptide, hepatitis C studies, complement levels, and another half-dozen immune serologic tests. On examination, she had typical nodular osteoarthritis of the proximal and distal interphalangeal joints of her hand with squaring of her thumbs. The antinuclear antibody was most likely associated with her previously diagnosed autoimmune thyroid disease.

In an editorial in this issue of the Journal, Dr. Salvatore Mangione, the author of a book on physical diagnosis,¹ cites a recent study indicating that the most common recognized diagnostic error related to the physical examination is that the appropriate examination isn’t done.² I would add to that my concerns over the new common custom of cutting and pasting the findings from earlier physical examinations into later progress notes in the electronic record. So much for the value of being able to recognize “changing murmurs” when diagnosing infectious endocarditis.

The apparent efficiency (reflected in length of stay) and availability of technology, as well as a lack of physician skill and time, are often cited as reasons for the demise of the physical examination. Yet this does not need to be the case. If I had trained with portable ultrasonography readily available to confirm or refute my impressions, my skills at detecting low-grade synovitis would surely be better than they are. With a gold standard at hand, which may be technology or at times a skilled mentor, our examinations can be refined if we want them to be.

But the issue of limited physician time must be addressed. Efficiency is a critical concept in preserving how we practice and perform the physical examination. When we know what we are looking for, we are more likely to find it if it is present, or to have confidence that it is not present. I am far more likely to recognize a loud pulmonic second heart sound if I suspect that the dyspneic patient I am examining has pulmonary hypertension associated with her scleroderma than if I am doing a perfunctory cardiac auscultation in a patient admitted with cellulitis. Appropriate focus provides power to the directed physical examination. If I am looking for the cause of unexplained fevers, I will do a purposeful axillary and epitrochlear lymph node examination. I am not mindlessly probing the flesh.

Nishigori and colleagues have written of the “hypothesis-driven” physical examination.³ Busy clinicians, they say, don’t have time to perform a head-to-toe, by-the-book physical examination. Instead, we should, by a dynamic process, formulate a differential diagnosis from the history and other initial information, and then perform the directed physical examination in earnest, looking for evidence to support or refute our diagnostic hypothesis—and thus redirect it. Plus, in a nice break from electronic charting, we can actually explain our thought processes to the patient as we perform the examination.

This approach makes sense to me as both intellectually satisfying and clinically efficient. And then we can consider which lab tests and technologic gadgetry we should order, while walking to get the café latte we ordered with our cell phone app.

New technology can support and not necessarily replace old habits.

Now that we can order MRI studies on a break from rounds walking to Starbucks, utilize portable ultrasounds to direct IV line placement, and use dual-energy CT to detect a gout attack that has not yet occurred, it seems like a romantic anachronism to extol the ongoing virtues of the seemingly lost art of the physical examination. Back “in the day,” the giants of medicine roamed the halls with their natural instruments of palpation and percussion and their skills in observation and auscultation. They were giants because they stood out then, just as skilled diagnosticians stand out today using an upgraded set of tools. Some physicians a few decades ago were able to recognize, describe, and diagnose late-stage endocarditis with a stethoscope, a magnifying glass, and an ophthalmoscope. The giants of today recognize the patient with endocarditis and document its presence using transesophageal echocardiography before the peripheral eponymous stigmata of Janeway and Osler appear or the blood cultures turn positive. The physical examination, history, diagnostic reasoning, and clinical technology are all essential for a blend that provides efficient and effective medical care. The blending is the challenge.

Clinicians are not created equal. We learn and prioritize our skills in different ways. But if we are not taught to value and trust the physical examination, if we don’t have the opportunity to see it influence patient management in positive ways, we may eschew it and instead indiscriminately use easily available laboratory and imaging tests—a more expensive and often misleading strategic approach. Today while in clinic, I saw a 54-year-old woman for evaluation of possible lupus who had arthritis of the hands and a high positive antinuclear antibody titer, but negative or normal results on other, previously ordered tests, including anti-DNA, rheumatoid factor, anti-cyclic citrullinated peptide, hepatitis C studies, complement levels, and another half-dozen immune serologic tests. On examination, she had typical nodular osteoarthritis of the proximal and distal interphalangeal joints of her hand with squaring of her thumbs. The antinuclear antibody was most likely associated with her previously diagnosed autoimmune thyroid disease.

In an editorial in this issue of the Journal, Dr. Salvatore Mangione, the author of a book on physical diagnosis,¹ cites a recent study indicating that the most common recognized diagnostic error related to the physical examination is that the appropriate examination isn’t done.² I would add to that my concerns over the new common custom of cutting and pasting the findings from earlier physical examinations into later progress notes in the electronic record. So much for the value of being able to recognize “changing murmurs” when diagnosing infectious endocarditis.

The apparent efficiency (reflected in length of stay) and availability of technology, as well as a lack of physician skill and time, are often cited as reasons for the demise of the physical examination. Yet this does not need to be the case. If I had trained with portable ultrasonography readily available to confirm or refute my impressions, my skills at detecting low-grade synovitis would surely be better than they are. With a gold standard at hand, which may be technology or at times a skilled mentor, our examinations can be refined if we want them to be.

But the issue of limited physician time must be addressed. Efficiency is a critical concept in preserving how we practice and perform the physical examination. When we know what we are looking for, we are more likely to find it if it is present, or to have confidence that it is not present. I am far more likely to recognize a loud pulmonic second heart sound if I suspect that the dyspneic patient I am examining has pulmonary hypertension associated with her scleroderma than if I am doing a perfunctory cardiac auscultation in a patient admitted with cellulitis. Appropriate focus provides power to the directed physical examination. If I am looking for the cause of unexplained fevers, I will do a purposeful axillary and epitrochlear lymph node examination. I am not mindlessly probing the flesh.

Nishigori and colleagues have written of the “hypothesis-driven” physical examination.³ Busy clinicians, they say, don’t have time to perform a head-to-toe, by-the-book physical examination. Instead, we should, by a dynamic process, formulate a differential diagnosis from the history and other initial information, and then perform the directed physical examination in earnest, looking for evidence to support or refute our diagnostic hypothesis—and thus redirect it. Plus, in a nice break from electronic charting, we can actually explain our thought processes to the patient as we perform the examination.

This approach makes sense to me as both intellectually satisfying and clinically efficient. And then we can consider which lab tests and technologic gadgetry we should order, while walking to get the café latte we ordered with our cell phone app.

New technology can support and not necessarily replace old habits.

In 2015, about 1.6 million Americans received a diagnosis of cancer.¹ In 2012, when 13.7 million people were living with cancer in the United States, the estimated 5-year survival rate of all cancers was 66.5%.¹ Today, breast, prostate, and colon cancers have 5-year survival rates of 89.4%, 98.9%, and 64.9%, respectively.

With this rising trend in survival, primary care physicians have been steadily assuming the long-term care of these patients. The phrase “cancer survivorship” was coined by the National Comprehensive Cancer Network to describe the experience of living with, through, and beyond a cancer diagnosis.²

As cancer becomes a chronic medical condition, the primary care physician assumes a vital role in the treatment of the unique and evolving needs of this patient population.

This article discusses the specific needs of patients surviving breast, prostate, and colon cancer with special focus on surveillance guidelines for recurrence, development of concomitant malignancies, assessment of psychosocial and physical effects, and disease conditions related to the treatment of cancer itself.

FOLLOW-UP CARE AND SURVEILLANCE

Follow-up care in patients being treated for cancer is vital to survivorship. It includes promoting healthy living, managing treatment side effects, and monitoring for long-term side effects and possible recurrence.

Patients previously treated for malignancy are more susceptible to second primary cancers, for an array of reasons including the effects of prior treatment, shared environmental exposures such as smoking, and genetic susceptibility.² Therefore, it is important for the primary care physician to recognize signs and symptoms and to screen cancer survivors appropriately. The American Society of Clinical Oncology (ASCO) has developed evidence-based recommendations for follow-up care,³ which we review here.

Breast cancer

For breast cancer patients, history and physical examinations are recommended every 3 to 6 months for the first 3 years, every 6 to 12 months in years 4 and 5, and annually thereafter.³

A repeat mammogram should be performed 1 year after the initial mammogram that led to the diagnosis. If the patient underwent radiation therapy, a repeat mammogram of the affected breast should be done 6 months after completion of radiation. Finally, a mammogram should be done every 6 to 12 months thereafter.³ It is also recommended that patients perform a monthly breast self-examination, but this does not replace the annual mammogram.³

Women who are treated with tamoxifen should have an annual gynecologic assessment if they have a uterus and should be encouraged to discuss any abnormal vaginal bleeding with their physician, given the increased risk of uterine cancer.²

ASCO does not recommend routine use of complete blood cell counts, complete metabolic panels, bone scans, chest radiography, computed tomography, ultrasonography, positron-emission tomography, or tumor markers in patients who are asymptomatic.³

Prostate cancer

ASCO’s recommendations for patients recovering from prostate cancer include regular histories and physical examinations and general health promotion. Prostate-specific antigen (PSA) testing is recommended every 6 to 12 months for the first 5 years after treatment and annually thereafter. More frequent PSA testing may be required in men at higher risk of recurrence or in patients who may undergo additional treatment, including radiation and surgery.⁴ Higher risk of disease recurrence is thought to depend on disease-specific factors at the time of original diagnosis including pretreatment PSA, Gleason score, and tumor stage.⁴ This should be discussed between the oncologist and primary care physician.

In regard to digital rectal examinations, the oncologist and primary care physician should jointly determine the frequency of examination. The frequency of digital rectal examinations remains an area of controversy due to their low sensitivity for detecting recurrences. Digital rectal examinations may be omitted in patients with undetectable levels of PSA.⁴

In regard to second primary malignancies, prostate cancer survivors who have undergone pelvic radiation therapy have a slightly higher risk of bladder and colorectal cancer. The lifetime incidence of bladder cancer after pelvic radiation is 5% to 6%, compared with 2.4% in the general population.^1,5 A prostate cancer survivor presenting with hematuria should be referred to a urologist for cystoscopy and evaluation of the upper urinary tract to rule out cancer.⁴

Similarly, patients presenting with rectal bleeding should be referred to a gastroenterologist and the treating radiation oncologist for complete evaluation. The risk of rectal cancer after pelvic radiation therapy increases to about the same level as in someone who has a first-degree relative with colorectal cancer.⁵ Therefore, it is recommended that patients undergo screening for colorectal cancer in conjunction with existing evidence-based guidelines. There is no evidence to suggest that increased intensity of screening improves overall or disease-specific survival.⁴

Colon cancer

In patients with resected colorectal cancer, continued surveillance is important to evaluate for recurrent cancer as well as for metachronous neoplasms. Consensus statements indicate that surveillance colonoscopy should be continued for those who have undergone surgical resection for stage I, II, or III colon or rectal cancers, and for those patients with stage IV who have undergone surgical resection with curative intent.⁶

Patients who undergo curative resection of rectal or colon cancer should have a colonoscopy 1 year after resection or 1 year after the colonoscopy was performed, to clear the colon of synchronous disease. Subsequently, if the colonoscopy done at 1 year is normal, the interval before the next colonoscopy is 3 years. If that colonoscopy is normal, the next colonoscopy is in 5 years. Time intervals may be shorter if there is evidence of hereditary nonpolyposis colorectal cancer or adenoma.

Patients who underwent low anterior resection of rectal cancer should undergo periodic examination of the rectum to evaluate for local recurrence. Although effectiveness is not proven, endoscopic ultrasonography or flexible sigmoidoscopy is suggested at 3- to 6-month intervals for the first 2 to 3 years after resection. This is independent of colonoscopy.^6,7

Additionally, ASCO recommends a history and physical examination and carcinoembryonic antigen testing every 3 to 6 months for the first 5 years. Computed tomography  of the chest, abdomen, and pelvis should be done annually for the first 3 years after the end of treatment.⁷

Maintaining a healthy body weight and a nutritionally balanced diet should be encouraged in all cancer survivors. Poor diet, lack of exercise, excessive alcohol consumption, and smoking reduce quality of life and increase the risk of cancer.²

Diet

Numerous studies have looked at dietary modifications and risk reduction, and although there is no consensus on specific dietary guidelines, there is consensus that diet modification to maintain normal body weight will improve overall quality of life.⁸ Patients should be encouraged to consume a well-balanced diet consisting mostly of fruits, vegetables, whole grains, and beans, and to limit consumption of animal protein.⁸

There is little evidence to support taking vitamins or other dietary supplements to prevent or control cancer or to prevent its recurrence. The primary care physician should assess supplement use on a regular basis during office visits.²

Exercise

Rest is an important component of the initial recovery process. Too much inactivity, however, leads to loss of physical conditioning and muscle strength. This in turn may negatively affect a patient’s ability to perform activities of daily living and may worsen fatigue associated with treatment.

Accordingly, the National Comprehensive Cancer Network recommends at least 150 minutes of moderate activity and up to 75 minutes of more rigorous activity divided throughout the week.^2,8 The regimen should include endurance and muscle strength training, which aid in balance, bone, health, and functional status. The intensity of exercise should be increased in a stepwise fashion, taking into account individual capabilities and limitations.²

Cancer survivors may need specific exercise recommendations and supervised programs to ensure safety and limit long-term side effects of their treatment. For example:

Patients with neuropathy should have their stability, balance, and gait assessed before starting a new program. These patients may benefit from an aerobic exercise program that includes riding a stationary bike rather than running.

Patients with poor bone health should have their fracture risk assessed.

Those with an ostomy bag should empty the bag before physical activity. They should avoid contact sports and activities that increase intra-abdominal pressure.

Patients suffering from lymphedema should wear compression garments when engaging in physical activity. They should undergo baseline and periodic reevaluation of the lymphedema and initiate strength training in the affected body part only if the lymphedema is stable (ie, no need for therapy for 3 months, no recent infections requiring antibiotics, and no change in circumference > 10%).²

Mental health

Health promotion should focus not only on the physical health of the patient, but also on his or her emotional and psychological well-being. As they make the transition from cancer patient to survivor, many individuals may develop or have worsening depression and anxiety due to fear of recurrence. These feelings of powerlessness can linger for years after the initial treatment.

Patients should be screened regularly for signs and symptoms of depression by asking about their family and social support. Referral to support groups, psychologists, and psychiatrists may be warranted.⁹

MITIGATING CANCER-RELATED FATIGUE

Cancer-related fatigue involves a patient’s subjective sense of physical, emotional, and cognitive exhaustion related to cancer or treatment that is disproportionate to that expected from recent daily activity.² Fatigue is a common complaint among survivors and can occur months to years after treatment ends.¹⁰

Patients should be screened for fatigue at regular intervals. The primary care physician should focus the history to include information regarding the onset, pattern, duration, associated factors, assessment of other treatable comorbidities, medications, psychological well-being, nutritional status, and pain level of each patient who complains of fatigue.

Laboratory tests for treatable causes of fatigue include:

• A complete blood cell count to evaluate for anemia
• A comprehensive metabolic panel to evaluate electrolytes, renal function, and hepatic function
• The thyroid-stimulating hormone level to evaluate thyroid function, particularly in breast cancer patients who have received radiation therapy.²

If no organic cause is uncovered, the focus should shift to lifestyle interventions as the treatment of choice. The treatment of fatigue in this situation is increased physical activity with the goals discussed above. Psychological intervention may be required with cognitive behavioral therapy, psychological and supportive therapies, education on sleep hygiene, and possible sleep restriction.

If alternative causes of fatigue are ruled out and physical and psychological support fails to reduce symptoms, the practitioner can consider a psychostimulant such as methylphenidate, but this should be used cautiously.²

SEXUAL DYSFUNCTION

Intimate relationships and sexuality are an important part of life and are affected by a variety of factors including physical health, psychological well-being, body image perception, and overall status of relationships. As a side effect of chemotherapy, cancer survivors may complain of erectile dysfunction, penile shortening, dyspareunia, vaginal dryness, decreased libido, anorgasmy, and changes in body image. These issues are frequently unaddressed, whether due to the physician’s discomfort in discussing the topic or to the patient’s embarrassment and reluctance to discuss the matter.¹¹

Breast cancer patients may experience sexual dysfunction both during and after treatment due to a combination of systemic effects of treatment, changes in physical appearance leading to impaired body image, strains on partner relationships, and psychological sequelae of diagnosis and treatment of cancer.¹² Manipulation and radiation to the breast affect sexual functioning by altering body contour and image. Additionally, chemotherapy can lead to early menopause and hormonal alterations due to endocrine therapies, which can negatively affect sexual organs.¹¹

Studies have shown that treatment with tamoxifen causes less sexual dysfunction than do aromatase inhibitors. In the Arimidex, Tamoxifen, Alone or in Combination trial, therapy with anastrozole was associated with more vaginal dryness, dyspareunia, and decreased libido compared with tamoxifen.¹²

Treatment requires a comprehensive history, a physical examination, and a discussion of relationship satisfaction with the patient.

Vaginal dryness and dyspareunia can be treated with vaginal lubricants and moisturizers. Moisturizers are effective if used multiple times per week, whereas lubricants can be used on demand. Low-dose vaginal estrogen preparations can be used in select patients with severe vaginal dryness; the goal should be discussed. Hormone replacement therapy is contraindicated in breast cancer survivors due to the risk of recurrence.¹¹

Prostate cancer survivors. Up to 70% of men felt their quality of life and sexual function were adversely affected after the diagnosis and treatment.^13,14 Erectile dysfunction following radical prostatectomy and radiation therapy remains one of the leading causes of sexual dysfunction.^14–15 Erectile dysfunction is multifactorial, with both psychogenic and organic causes. Comorbidities must be considered including hypertension, diabetes, hyperlipidemia, and smoking. Early penile rehabilitation is a proposed treatment strategy.¹⁴

First-line therapy for penile rehabilitation includes introduction of daily low-dose phosphodiesterase type 5 inhibitors as early as the time of catheter removal to within the first month after surgery. The need for daily dosing vs on-demand dosing has been controversial.¹⁵ Two large multicenter, double-blind studies had conflicting outcomes. The first reported that in men receiving nightly sildenafil (50 or 100 mg) after radical prostatectomy, 27% had increased return of spontaneous erectile function vs 4% with placebo¹⁶; the second study showed no difference between nightly and on-demand dosing.¹⁷ The consensus is that a phosphodiesterase type 5 inhibitor should be initiated early.

Second-line therapy includes intracavernosal injections and vacuum erection devices. Finally, a penile prosthesis implant can be offered to patients who have responded poorly to medical therapy.¹³

Colorectal cancer survivors suffer from sexually related problems similar to those stated above, including erectile dysfunction, ejaculation problems, dyspareunia, vaginal dryness, and decreased enjoyment.¹⁸ These patients should be provided treatments similar to those described above. In addition, they may suffer from body image issues, particularly those with a permanent ostomy.⁹

Sexual dysfunction is a multifaceted problem for patients. Encouraging couples to discuss sexual intimacy frequently helps to reveal and cope with the problems, whether physical or psychological. It is the primary care physician’s role to recognize any sexual concerns and refer to the appropriate specialist.

Osteoporosis is a metabolic bone disease characterized by low bone mineral density. As a result, bones become weak and fracture more easily from minor injuries.

Risk factors for osteoporosis include female sex, family history, advanced age, low body weight, low calcium and vitamin D levels, sedentary lifestyle, smoking, and low estrogen levels.¹⁹ Cancer treatment places patients at a greater risk for osteoporosis, particularly for those patients with chemotherapy-induced ovarian failure, those treated with aromatase inhibitors, men receiving androgen-deprivation therapy, and patients on glucocorticoid therapy. The morbidity and mortality associated with bone loss can be prevented with appropriate screening, lifestyle changes, and therapy.²

According to the National Osteoporosis Foundation Guideline for Preventing and Treating Osteoporosis, all men and postmenopausal women age 50 and older should be evaluated clinically for osteoporosis risk to determine the need for bone mineral density testing.^2,19 The US Preventive Services Task Force recommends bone mineral density testing in all women age 65 and older, and for women 60 to 64 who are at high risk for bone loss. ASCO agrees, and further suggests bone mineral density screening for women with breast cancer who have risk factors such as positive family history, body weight less than 70 kg, and prior nontraumatic fracture, as well as for postmenopausal women of any age receiving aromatase inhibitors and for premenopausal women with therapy-induced ovarian failure.¹¹

Androgen deprivation therapy is a mainstay of treatment in recurrent and metastatic prostate cancer. The effect is severe hypogonadism with reductions in serum testosterone levels. Androgen deprivation therapy accelerates bone turnover, decreases bone mineral density, and contributes to fracture risk. The National Comprehensive Cancer Network additionally suggests measuring bone mineral density at baseline for all men receiving androgen deprivation therapy or other medications associated with bone loss, repeating it 1 year after androgen deprivation therapy and then every 2 years, or as clinically indicated.²⁰

The gold standard for measuring bone mineral density is dual-energy x-ray absorptiometry. The World Health Organization FRAX tool uses bone mineral density and several clinical factors to estimate the risk of fracture in the next 10 years, which can help guide therapy. Cancer patients with elevated fracture risk should be evaluated every 2 years. Counseling should be provided to address modifiable risk factors such as smoking, alcohol consumption, physical inactivity, and low calcium and vitamin D intake. Therapy should be strongly considered in patients with a bone mineral density below a T-score of –2.0. ^2,19

Treatment begins with lifestyle modifications such as weight-bearing exercises to improve balance and muscle strength and to prevent falls, and adequate intake of calcium (≥ 1,200 mg daily) and vitamin D (800–1,000 IU daily) for adults age 50 and older. Treatment with bisphosphonates may be required.^2,11,20

NEUROPATHY

Many chemotherapeutic agents can lead to neuropathy and can result in long-term disability in patients. Patients treated with taxane- and platinum-based chemotherapy are at particular risk.

Paclitaxel, used in the treatment of breast, ovarian, and lung cancer, can lead to distal neuropathy. This neuropathy commonly has a stocking-and-glove distribution and is primarily sensory; however, it may have motor and autonomic components. The neuropathy typically lessens when the medication is stopped, although in some patients it can persist and lead to long-term disability.

Treatment can include massage. Medications such as gabapentin and pregabalin can also be used, but randomized controlled trials do not support them, as they predominantly treat the tingling rather than the numbness.¹¹

BLADDER AND BOWEL DYSFUNCTION

Urinary incontinence and dysfunction are frequent complications in prostate cancer survivors. Urinary function should be discussed regularly with patients, addressing quality of the urinary stream, difficulty emptying the bladder, timing, and incontinence.⁴ Urinary incontinence is frequently seen in postprostatectomy patients.

The cornerstone of treating urinary incontinence is determining the cause of the incontinence, whether it is stress or urge incontinence, or both.²¹ For those patients with urge incontinence alone, practitioners can address the problem with a combination of behavior modification, pelvic floor exercises, and anticholinergic medications such as oxybutynin. If the problem stems from difficulty initiating or a slow stream, physicians may consider alpha-blockers.^4,21 If the incontinence is persistent, bothersome, and has components of stress incontinence, the patient should be referred to a urologist for urodynamic testing, cystoscopy, and surgical evaluation for possible placement of a male urethral sling or artificial urinary sphincter.²¹

Colorectal cancer survivors, particularly those who received radiation therapy, are at high risk of bowel dysfunction such as chronic diarrhea and stool incontinence. Patients should be educated about this possible side effect. Symptoms of bowel dysfunction can affect body image and interfere with social functioning and overall quality of life. Patients should be provided with coping tools such as antidiarrheal medication, stool bulking agents, changes in diet, and protective underwear.

CARDIOVASCULAR DISEASE

Evidence suggests that certain types of chemotherapy and radiation therapy increase the risk of cardiovascular disease. Prostate cancer survivors treated with androgen deprivation therapy, particularly those more than 75 years old, are at increased risk of cardiovascular disease and diabetes.²²

It is recommended that men be screened with fasting plasma glucose at baseline and yearly thereafter while receiving androgen deprivation therapy. Lipid panel testing should be done 1 year from initiation of androgen deprivation therapy and then, if results are normal, every 5 years or as clinically warranted. The focus should be on primary prevention with emphasis on smoking cessation, treating hypertension per guidelines, lifestyle modifications, and treatment with aspirin and statins when clinically appropriate.²⁰

Radiation therapy, chemotherapy, and endocrine therapy have all been suggested to lead to cardiotoxicity in breast cancer patients. Anthracycline-based chemotherapies have a well-recognized association with cardiomyopathy. Factors associated with increased risk of anthracycline-induced cardiomyopathy include older age, hypertension, pre-existing coronary artery disease, and previous mediastinal radiation.

Early detection of cardiomyopathy may lead to avoidance of irreversible cardiotoxicity, but there are currently no clear guidelines for cardiac screening in breast cancer survivors. If cardiomyopathy is detected, treatment should include beta-blockers and angiotensin-converting enzyme inhibitors as well as modification of other cardiovascular risk factors.¹¹

A SURVIVORSHIP CARE PLAN

There is life beyond the diagnosis of cancer. As patients are living longer, with an estimated 5-year survival rate of 66.5% of all cancers in the United States, there must be a transition of care from the oncologist to the primary care physician.¹ While the oncologist will remain involved in the initial years of follow-up care, these visits will go from twice a year to once a year, and eventually the patient will make a full transition to care by the primary care physician. The timing of this changeover varies from physician to physician, but the primary care physician is ultimately responsible for the follow-up.

A tool to ease this transition is a survivorship care plan. The goal of a survivorship care plan is to individualize a follow-up plan while keeping in mind the necessary surveillance as outlined. These care plans are created with the patient and oncologist and then brought to the primary care physician. While there is an abundance of literature regarding the creation and initiation of survivorship care plans, the success of these plans is uncertain. Ultimately, the goal of a survivorship care plan is to create open dialogue among the oncologist, the primary care physician, and the patient. This unique patient population requires close follow-up by a multidisciplinary team with the primary care physician serving as the steward.

In 2015, about 1.6 million Americans received a diagnosis of cancer.¹ In 2012, when 13.7 million people were living with cancer in the United States, the estimated 5-year survival rate of all cancers was 66.5%.¹ Today, breast, prostate, and colon cancers have 5-year survival rates of 89.4%, 98.9%, and 64.9%, respectively.

With this rising trend in survival, primary care physicians have been steadily assuming the long-term care of these patients. The phrase “cancer survivorship” was coined by the National Comprehensive Cancer Network to describe the experience of living with, through, and beyond a cancer diagnosis.²

As cancer becomes a chronic medical condition, the primary care physician assumes a vital role in the treatment of the unique and evolving needs of this patient population.

This article discusses the specific needs of patients surviving breast, prostate, and colon cancer with special focus on surveillance guidelines for recurrence, development of concomitant malignancies, assessment of psychosocial and physical effects, and disease conditions related to the treatment of cancer itself.

FOLLOW-UP CARE AND SURVEILLANCE

Follow-up care in patients being treated for cancer is vital to survivorship. It includes promoting healthy living, managing treatment side effects, and monitoring for long-term side effects and possible recurrence.

Patients previously treated for malignancy are more susceptible to second primary cancers, for an array of reasons including the effects of prior treatment, shared environmental exposures such as smoking, and genetic susceptibility.² Therefore, it is important for the primary care physician to recognize signs and symptoms and to screen cancer survivors appropriately. The American Society of Clinical Oncology (ASCO) has developed evidence-based recommendations for follow-up care,³ which we review here.

Breast cancer

For breast cancer patients, history and physical examinations are recommended every 3 to 6 months for the first 3 years, every 6 to 12 months in years 4 and 5, and annually thereafter.³

A repeat mammogram should be performed 1 year after the initial mammogram that led to the diagnosis. If the patient underwent radiation therapy, a repeat mammogram of the affected breast should be done 6 months after completion of radiation. Finally, a mammogram should be done every 6 to 12 months thereafter.³ It is also recommended that patients perform a monthly breast self-examination, but this does not replace the annual mammogram.³

Women who are treated with tamoxifen should have an annual gynecologic assessment if they have a uterus and should be encouraged to discuss any abnormal vaginal bleeding with their physician, given the increased risk of uterine cancer.²

ASCO does not recommend routine use of complete blood cell counts, complete metabolic panels, bone scans, chest radiography, computed tomography, ultrasonography, positron-emission tomography, or tumor markers in patients who are asymptomatic.³

Prostate cancer

ASCO’s recommendations for patients recovering from prostate cancer include regular histories and physical examinations and general health promotion. Prostate-specific antigen (PSA) testing is recommended every 6 to 12 months for the first 5 years after treatment and annually thereafter. More frequent PSA testing may be required in men at higher risk of recurrence or in patients who may undergo additional treatment, including radiation and surgery.⁴ Higher risk of disease recurrence is thought to depend on disease-specific factors at the time of original diagnosis including pretreatment PSA, Gleason score, and tumor stage.⁴ This should be discussed between the oncologist and primary care physician.

In regard to digital rectal examinations, the oncologist and primary care physician should jointly determine the frequency of examination. The frequency of digital rectal examinations remains an area of controversy due to their low sensitivity for detecting recurrences. Digital rectal examinations may be omitted in patients with undetectable levels of PSA.⁴

In regard to second primary malignancies, prostate cancer survivors who have undergone pelvic radiation therapy have a slightly higher risk of bladder and colorectal cancer. The lifetime incidence of bladder cancer after pelvic radiation is 5% to 6%, compared with 2.4% in the general population.^1,5 A prostate cancer survivor presenting with hematuria should be referred to a urologist for cystoscopy and evaluation of the upper urinary tract to rule out cancer.⁴

Similarly, patients presenting with rectal bleeding should be referred to a gastroenterologist and the treating radiation oncologist for complete evaluation. The risk of rectal cancer after pelvic radiation therapy increases to about the same level as in someone who has a first-degree relative with colorectal cancer.⁵ Therefore, it is recommended that patients undergo screening for colorectal cancer in conjunction with existing evidence-based guidelines. There is no evidence to suggest that increased intensity of screening improves overall or disease-specific survival.⁴

Colon cancer

In patients with resected colorectal cancer, continued surveillance is important to evaluate for recurrent cancer as well as for metachronous neoplasms. Consensus statements indicate that surveillance colonoscopy should be continued for those who have undergone surgical resection for stage I, II, or III colon or rectal cancers, and for those patients with stage IV who have undergone surgical resection with curative intent.⁶

Patients who undergo curative resection of rectal or colon cancer should have a colonoscopy 1 year after resection or 1 year after the colonoscopy was performed, to clear the colon of synchronous disease. Subsequently, if the colonoscopy done at 1 year is normal, the interval before the next colonoscopy is 3 years. If that colonoscopy is normal, the next colonoscopy is in 5 years. Time intervals may be shorter if there is evidence of hereditary nonpolyposis colorectal cancer or adenoma.

Patients who underwent low anterior resection of rectal cancer should undergo periodic examination of the rectum to evaluate for local recurrence. Although effectiveness is not proven, endoscopic ultrasonography or flexible sigmoidoscopy is suggested at 3- to 6-month intervals for the first 2 to 3 years after resection. This is independent of colonoscopy.^6,7

Additionally, ASCO recommends a history and physical examination and carcinoembryonic antigen testing every 3 to 6 months for the first 5 years. Computed tomography  of the chest, abdomen, and pelvis should be done annually for the first 3 years after the end of treatment.⁷

Maintaining a healthy body weight and a nutritionally balanced diet should be encouraged in all cancer survivors. Poor diet, lack of exercise, excessive alcohol consumption, and smoking reduce quality of life and increase the risk of cancer.²

Diet

Numerous studies have looked at dietary modifications and risk reduction, and although there is no consensus on specific dietary guidelines, there is consensus that diet modification to maintain normal body weight will improve overall quality of life.⁸ Patients should be encouraged to consume a well-balanced diet consisting mostly of fruits, vegetables, whole grains, and beans, and to limit consumption of animal protein.⁸

There is little evidence to support taking vitamins or other dietary supplements to prevent or control cancer or to prevent its recurrence. The primary care physician should assess supplement use on a regular basis during office visits.²

Exercise

Rest is an important component of the initial recovery process. Too much inactivity, however, leads to loss of physical conditioning and muscle strength. This in turn may negatively affect a patient’s ability to perform activities of daily living and may worsen fatigue associated with treatment.

Accordingly, the National Comprehensive Cancer Network recommends at least 150 minutes of moderate activity and up to 75 minutes of more rigorous activity divided throughout the week.^2,8 The regimen should include endurance and muscle strength training, which aid in balance, bone, health, and functional status. The intensity of exercise should be increased in a stepwise fashion, taking into account individual capabilities and limitations.²

Cancer survivors may need specific exercise recommendations and supervised programs to ensure safety and limit long-term side effects of their treatment. For example:

Patients with neuropathy should have their stability, balance, and gait assessed before starting a new program. These patients may benefit from an aerobic exercise program that includes riding a stationary bike rather than running.

Patients with poor bone health should have their fracture risk assessed.

Those with an ostomy bag should empty the bag before physical activity. They should avoid contact sports and activities that increase intra-abdominal pressure.

Patients suffering from lymphedema should wear compression garments when engaging in physical activity. They should undergo baseline and periodic reevaluation of the lymphedema and initiate strength training in the affected body part only if the lymphedema is stable (ie, no need for therapy for 3 months, no recent infections requiring antibiotics, and no change in circumference > 10%).²

Mental health

Health promotion should focus not only on the physical health of the patient, but also on his or her emotional and psychological well-being. As they make the transition from cancer patient to survivor, many individuals may develop or have worsening depression and anxiety due to fear of recurrence. These feelings of powerlessness can linger for years after the initial treatment.

Patients should be screened regularly for signs and symptoms of depression by asking about their family and social support. Referral to support groups, psychologists, and psychiatrists may be warranted.⁹

MITIGATING CANCER-RELATED FATIGUE

Cancer-related fatigue involves a patient’s subjective sense of physical, emotional, and cognitive exhaustion related to cancer or treatment that is disproportionate to that expected from recent daily activity.² Fatigue is a common complaint among survivors and can occur months to years after treatment ends.¹⁰

Patients should be screened for fatigue at regular intervals. The primary care physician should focus the history to include information regarding the onset, pattern, duration, associated factors, assessment of other treatable comorbidities, medications, psychological well-being, nutritional status, and pain level of each patient who complains of fatigue.

Laboratory tests for treatable causes of fatigue include:

• A complete blood cell count to evaluate for anemia
• A comprehensive metabolic panel to evaluate electrolytes, renal function, and hepatic function
• The thyroid-stimulating hormone level to evaluate thyroid function, particularly in breast cancer patients who have received radiation therapy.²

If no organic cause is uncovered, the focus should shift to lifestyle interventions as the treatment of choice. The treatment of fatigue in this situation is increased physical activity with the goals discussed above. Psychological intervention may be required with cognitive behavioral therapy, psychological and supportive therapies, education on sleep hygiene, and possible sleep restriction.

If alternative causes of fatigue are ruled out and physical and psychological support fails to reduce symptoms, the practitioner can consider a psychostimulant such as methylphenidate, but this should be used cautiously.²

SEXUAL DYSFUNCTION

Intimate relationships and sexuality are an important part of life and are affected by a variety of factors including physical health, psychological well-being, body image perception, and overall status of relationships. As a side effect of chemotherapy, cancer survivors may complain of erectile dysfunction, penile shortening, dyspareunia, vaginal dryness, decreased libido, anorgasmy, and changes in body image. These issues are frequently unaddressed, whether due to the physician’s discomfort in discussing the topic or to the patient’s embarrassment and reluctance to discuss the matter.¹¹

Breast cancer patients may experience sexual dysfunction both during and after treatment due to a combination of systemic effects of treatment, changes in physical appearance leading to impaired body image, strains on partner relationships, and psychological sequelae of diagnosis and treatment of cancer.¹² Manipulation and radiation to the breast affect sexual functioning by altering body contour and image. Additionally, chemotherapy can lead to early menopause and hormonal alterations due to endocrine therapies, which can negatively affect sexual organs.¹¹

Studies have shown that treatment with tamoxifen causes less sexual dysfunction than do aromatase inhibitors. In the Arimidex, Tamoxifen, Alone or in Combination trial, therapy with anastrozole was associated with more vaginal dryness, dyspareunia, and decreased libido compared with tamoxifen.¹²

Treatment requires a comprehensive history, a physical examination, and a discussion of relationship satisfaction with the patient.

Vaginal dryness and dyspareunia can be treated with vaginal lubricants and moisturizers. Moisturizers are effective if used multiple times per week, whereas lubricants can be used on demand. Low-dose vaginal estrogen preparations can be used in select patients with severe vaginal dryness; the goal should be discussed. Hormone replacement therapy is contraindicated in breast cancer survivors due to the risk of recurrence.¹¹

Prostate cancer survivors. Up to 70% of men felt their quality of life and sexual function were adversely affected after the diagnosis and treatment.^13,14 Erectile dysfunction following radical prostatectomy and radiation therapy remains one of the leading causes of sexual dysfunction.^14–15 Erectile dysfunction is multifactorial, with both psychogenic and organic causes. Comorbidities must be considered including hypertension, diabetes, hyperlipidemia, and smoking. Early penile rehabilitation is a proposed treatment strategy.¹⁴

First-line therapy for penile rehabilitation includes introduction of daily low-dose phosphodiesterase type 5 inhibitors as early as the time of catheter removal to within the first month after surgery. The need for daily dosing vs on-demand dosing has been controversial.¹⁵ Two large multicenter, double-blind studies had conflicting outcomes. The first reported that in men receiving nightly sildenafil (50 or 100 mg) after radical prostatectomy, 27% had increased return of spontaneous erectile function vs 4% with placebo¹⁶; the second study showed no difference between nightly and on-demand dosing.¹⁷ The consensus is that a phosphodiesterase type 5 inhibitor should be initiated early.

Second-line therapy includes intracavernosal injections and vacuum erection devices. Finally, a penile prosthesis implant can be offered to patients who have responded poorly to medical therapy.¹³

Colorectal cancer survivors suffer from sexually related problems similar to those stated above, including erectile dysfunction, ejaculation problems, dyspareunia, vaginal dryness, and decreased enjoyment.¹⁸ These patients should be provided treatments similar to those described above. In addition, they may suffer from body image issues, particularly those with a permanent ostomy.⁹

Sexual dysfunction is a multifaceted problem for patients. Encouraging couples to discuss sexual intimacy frequently helps to reveal and cope with the problems, whether physical or psychological. It is the primary care physician’s role to recognize any sexual concerns and refer to the appropriate specialist.

Osteoporosis is a metabolic bone disease characterized by low bone mineral density. As a result, bones become weak and fracture more easily from minor injuries.

Risk factors for osteoporosis include female sex, family history, advanced age, low body weight, low calcium and vitamin D levels, sedentary lifestyle, smoking, and low estrogen levels.¹⁹ Cancer treatment places patients at a greater risk for osteoporosis, particularly for those patients with chemotherapy-induced ovarian failure, those treated with aromatase inhibitors, men receiving androgen-deprivation therapy, and patients on glucocorticoid therapy. The morbidity and mortality associated with bone loss can be prevented with appropriate screening, lifestyle changes, and therapy.²

According to the National Osteoporosis Foundation Guideline for Preventing and Treating Osteoporosis, all men and postmenopausal women age 50 and older should be evaluated clinically for osteoporosis risk to determine the need for bone mineral density testing.^2,19 The US Preventive Services Task Force recommends bone mineral density testing in all women age 65 and older, and for women 60 to 64 who are at high risk for bone loss. ASCO agrees, and further suggests bone mineral density screening for women with breast cancer who have risk factors such as positive family history, body weight less than 70 kg, and prior nontraumatic fracture, as well as for postmenopausal women of any age receiving aromatase inhibitors and for premenopausal women with therapy-induced ovarian failure.¹¹

Androgen deprivation therapy is a mainstay of treatment in recurrent and metastatic prostate cancer. The effect is severe hypogonadism with reductions in serum testosterone levels. Androgen deprivation therapy accelerates bone turnover, decreases bone mineral density, and contributes to fracture risk. The National Comprehensive Cancer Network additionally suggests measuring bone mineral density at baseline for all men receiving androgen deprivation therapy or other medications associated with bone loss, repeating it 1 year after androgen deprivation therapy and then every 2 years, or as clinically indicated.²⁰

The gold standard for measuring bone mineral density is dual-energy x-ray absorptiometry. The World Health Organization FRAX tool uses bone mineral density and several clinical factors to estimate the risk of fracture in the next 10 years, which can help guide therapy. Cancer patients with elevated fracture risk should be evaluated every 2 years. Counseling should be provided to address modifiable risk factors such as smoking, alcohol consumption, physical inactivity, and low calcium and vitamin D intake. Therapy should be strongly considered in patients with a bone mineral density below a T-score of –2.0. ^2,19

Treatment begins with lifestyle modifications such as weight-bearing exercises to improve balance and muscle strength and to prevent falls, and adequate intake of calcium (≥ 1,200 mg daily) and vitamin D (800–1,000 IU daily) for adults age 50 and older. Treatment with bisphosphonates may be required.^2,11,20

NEUROPATHY

Many chemotherapeutic agents can lead to neuropathy and can result in long-term disability in patients. Patients treated with taxane- and platinum-based chemotherapy are at particular risk.

Paclitaxel, used in the treatment of breast, ovarian, and lung cancer, can lead to distal neuropathy. This neuropathy commonly has a stocking-and-glove distribution and is primarily sensory; however, it may have motor and autonomic components. The neuropathy typically lessens when the medication is stopped, although in some patients it can persist and lead to long-term disability.

Treatment can include massage. Medications such as gabapentin and pregabalin can also be used, but randomized controlled trials do not support them, as they predominantly treat the tingling rather than the numbness.¹¹

BLADDER AND BOWEL DYSFUNCTION

Urinary incontinence and dysfunction are frequent complications in prostate cancer survivors. Urinary function should be discussed regularly with patients, addressing quality of the urinary stream, difficulty emptying the bladder, timing, and incontinence.⁴ Urinary incontinence is frequently seen in postprostatectomy patients.

The cornerstone of treating urinary incontinence is determining the cause of the incontinence, whether it is stress or urge incontinence, or both.²¹ For those patients with urge incontinence alone, practitioners can address the problem with a combination of behavior modification, pelvic floor exercises, and anticholinergic medications such as oxybutynin. If the problem stems from difficulty initiating or a slow stream, physicians may consider alpha-blockers.^4,21 If the incontinence is persistent, bothersome, and has components of stress incontinence, the patient should be referred to a urologist for urodynamic testing, cystoscopy, and surgical evaluation for possible placement of a male urethral sling or artificial urinary sphincter.²¹

Colorectal cancer survivors, particularly those who received radiation therapy, are at high risk of bowel dysfunction such as chronic diarrhea and stool incontinence. Patients should be educated about this possible side effect. Symptoms of bowel dysfunction can affect body image and interfere with social functioning and overall quality of life. Patients should be provided with coping tools such as antidiarrheal medication, stool bulking agents, changes in diet, and protective underwear.

CARDIOVASCULAR DISEASE

Evidence suggests that certain types of chemotherapy and radiation therapy increase the risk of cardiovascular disease. Prostate cancer survivors treated with androgen deprivation therapy, particularly those more than 75 years old, are at increased risk of cardiovascular disease and diabetes.²²

It is recommended that men be screened with fasting plasma glucose at baseline and yearly thereafter while receiving androgen deprivation therapy. Lipid panel testing should be done 1 year from initiation of androgen deprivation therapy and then, if results are normal, every 5 years or as clinically warranted. The focus should be on primary prevention with emphasis on smoking cessation, treating hypertension per guidelines, lifestyle modifications, and treatment with aspirin and statins when clinically appropriate.²⁰

Radiation therapy, chemotherapy, and endocrine therapy have all been suggested to lead to cardiotoxicity in breast cancer patients. Anthracycline-based chemotherapies have a well-recognized association with cardiomyopathy. Factors associated with increased risk of anthracycline-induced cardiomyopathy include older age, hypertension, pre-existing coronary artery disease, and previous mediastinal radiation.

Early detection of cardiomyopathy may lead to avoidance of irreversible cardiotoxicity, but there are currently no clear guidelines for cardiac screening in breast cancer survivors. If cardiomyopathy is detected, treatment should include beta-blockers and angiotensin-converting enzyme inhibitors as well as modification of other cardiovascular risk factors.¹¹

A SURVIVORSHIP CARE PLAN

There is life beyond the diagnosis of cancer. As patients are living longer, with an estimated 5-year survival rate of 66.5% of all cancers in the United States, there must be a transition of care from the oncologist to the primary care physician.¹ While the oncologist will remain involved in the initial years of follow-up care, these visits will go from twice a year to once a year, and eventually the patient will make a full transition to care by the primary care physician. The timing of this changeover varies from physician to physician, but the primary care physician is ultimately responsible for the follow-up.

A tool to ease this transition is a survivorship care plan. The goal of a survivorship care plan is to individualize a follow-up plan while keeping in mind the necessary surveillance as outlined. These care plans are created with the patient and oncologist and then brought to the primary care physician. While there is an abundance of literature regarding the creation and initiation of survivorship care plans, the success of these plans is uncertain. Ultimately, the goal of a survivorship care plan is to create open dialogue among the oncologist, the primary care physician, and the patient. This unique patient population requires close follow-up by a multidisciplinary team with the primary care physician serving as the steward.

In 2015, about 1.6 million Americans received a diagnosis of cancer.¹ In 2012, when 13.7 million people were living with cancer in the United States, the estimated 5-year survival rate of all cancers was 66.5%.¹ Today, breast, prostate, and colon cancers have 5-year survival rates of 89.4%, 98.9%, and 64.9%, respectively.

With this rising trend in survival, primary care physicians have been steadily assuming the long-term care of these patients. The phrase “cancer survivorship” was coined by the National Comprehensive Cancer Network to describe the experience of living with, through, and beyond a cancer diagnosis.²

As cancer becomes a chronic medical condition, the primary care physician assumes a vital role in the treatment of the unique and evolving needs of this patient population.

This article discusses the specific needs of patients surviving breast, prostate, and colon cancer with special focus on surveillance guidelines for recurrence, development of concomitant malignancies, assessment of psychosocial and physical effects, and disease conditions related to the treatment of cancer itself.

FOLLOW-UP CARE AND SURVEILLANCE

Follow-up care in patients being treated for cancer is vital to survivorship. It includes promoting healthy living, managing treatment side effects, and monitoring for long-term side effects and possible recurrence.

Patients previously treated for malignancy are more susceptible to second primary cancers, for an array of reasons including the effects of prior treatment, shared environmental exposures such as smoking, and genetic susceptibility.² Therefore, it is important for the primary care physician to recognize signs and symptoms and to screen cancer survivors appropriately. The American Society of Clinical Oncology (ASCO) has developed evidence-based recommendations for follow-up care,³ which we review here.

Breast cancer

For breast cancer patients, history and physical examinations are recommended every 3 to 6 months for the first 3 years, every 6 to 12 months in years 4 and 5, and annually thereafter.³

A repeat mammogram should be performed 1 year after the initial mammogram that led to the diagnosis. If the patient underwent radiation therapy, a repeat mammogram of the affected breast should be done 6 months after completion of radiation. Finally, a mammogram should be done every 6 to 12 months thereafter.³ It is also recommended that patients perform a monthly breast self-examination, but this does not replace the annual mammogram.³

Women who are treated with tamoxifen should have an annual gynecologic assessment if they have a uterus and should be encouraged to discuss any abnormal vaginal bleeding with their physician, given the increased risk of uterine cancer.²

ASCO does not recommend routine use of complete blood cell counts, complete metabolic panels, bone scans, chest radiography, computed tomography, ultrasonography, positron-emission tomography, or tumor markers in patients who are asymptomatic.³

Prostate cancer

ASCO’s recommendations for patients recovering from prostate cancer include regular histories and physical examinations and general health promotion. Prostate-specific antigen (PSA) testing is recommended every 6 to 12 months for the first 5 years after treatment and annually thereafter. More frequent PSA testing may be required in men at higher risk of recurrence or in patients who may undergo additional treatment, including radiation and surgery.⁴ Higher risk of disease recurrence is thought to depend on disease-specific factors at the time of original diagnosis including pretreatment PSA, Gleason score, and tumor stage.⁴ This should be discussed between the oncologist and primary care physician.

In regard to digital rectal examinations, the oncologist and primary care physician should jointly determine the frequency of examination. The frequency of digital rectal examinations remains an area of controversy due to their low sensitivity for detecting recurrences. Digital rectal examinations may be omitted in patients with undetectable levels of PSA.⁴

In regard to second primary malignancies, prostate cancer survivors who have undergone pelvic radiation therapy have a slightly higher risk of bladder and colorectal cancer. The lifetime incidence of bladder cancer after pelvic radiation is 5% to 6%, compared with 2.4% in the general population.^1,5 A prostate cancer survivor presenting with hematuria should be referred to a urologist for cystoscopy and evaluation of the upper urinary tract to rule out cancer.⁴

Similarly, patients presenting with rectal bleeding should be referred to a gastroenterologist and the treating radiation oncologist for complete evaluation. The risk of rectal cancer after pelvic radiation therapy increases to about the same level as in someone who has a first-degree relative with colorectal cancer.⁵ Therefore, it is recommended that patients undergo screening for colorectal cancer in conjunction with existing evidence-based guidelines. There is no evidence to suggest that increased intensity of screening improves overall or disease-specific survival.⁴

Colon cancer

In patients with resected colorectal cancer, continued surveillance is important to evaluate for recurrent cancer as well as for metachronous neoplasms. Consensus statements indicate that surveillance colonoscopy should be continued for those who have undergone surgical resection for stage I, II, or III colon or rectal cancers, and for those patients with stage IV who have undergone surgical resection with curative intent.⁶

Patients who undergo curative resection of rectal or colon cancer should have a colonoscopy 1 year after resection or 1 year after the colonoscopy was performed, to clear the colon of synchronous disease. Subsequently, if the colonoscopy done at 1 year is normal, the interval before the next colonoscopy is 3 years. If that colonoscopy is normal, the next colonoscopy is in 5 years. Time intervals may be shorter if there is evidence of hereditary nonpolyposis colorectal cancer or adenoma.

Patients who underwent low anterior resection of rectal cancer should undergo periodic examination of the rectum to evaluate for local recurrence. Although effectiveness is not proven, endoscopic ultrasonography or flexible sigmoidoscopy is suggested at 3- to 6-month intervals for the first 2 to 3 years after resection. This is independent of colonoscopy.^6,7

Additionally, ASCO recommends a history and physical examination and carcinoembryonic antigen testing every 3 to 6 months for the first 5 years. Computed tomography  of the chest, abdomen, and pelvis should be done annually for the first 3 years after the end of treatment.⁷

Maintaining a healthy body weight and a nutritionally balanced diet should be encouraged in all cancer survivors. Poor diet, lack of exercise, excessive alcohol consumption, and smoking reduce quality of life and increase the risk of cancer.²

Diet

Numerous studies have looked at dietary modifications and risk reduction, and although there is no consensus on specific dietary guidelines, there is consensus that diet modification to maintain normal body weight will improve overall quality of life.⁸ Patients should be encouraged to consume a well-balanced diet consisting mostly of fruits, vegetables, whole grains, and beans, and to limit consumption of animal protein.⁸

There is little evidence to support taking vitamins or other dietary supplements to prevent or control cancer or to prevent its recurrence. The primary care physician should assess supplement use on a regular basis during office visits.²

Exercise

Rest is an important component of the initial recovery process. Too much inactivity, however, leads to loss of physical conditioning and muscle strength. This in turn may negatively affect a patient’s ability to perform activities of daily living and may worsen fatigue associated with treatment.

Accordingly, the National Comprehensive Cancer Network recommends at least 150 minutes of moderate activity and up to 75 minutes of more rigorous activity divided throughout the week.^2,8 The regimen should include endurance and muscle strength training, which aid in balance, bone, health, and functional status. The intensity of exercise should be increased in a stepwise fashion, taking into account individual capabilities and limitations.²

Cancer survivors may need specific exercise recommendations and supervised programs to ensure safety and limit long-term side effects of their treatment. For example:

Patients with neuropathy should have their stability, balance, and gait assessed before starting a new program. These patients may benefit from an aerobic exercise program that includes riding a stationary bike rather than running.

Patients with poor bone health should have their fracture risk assessed.

Those with an ostomy bag should empty the bag before physical activity. They should avoid contact sports and activities that increase intra-abdominal pressure.

Patients suffering from lymphedema should wear compression garments when engaging in physical activity. They should undergo baseline and periodic reevaluation of the lymphedema and initiate strength training in the affected body part only if the lymphedema is stable (ie, no need for therapy for 3 months, no recent infections requiring antibiotics, and no change in circumference > 10%).²

Mental health

Health promotion should focus not only on the physical health of the patient, but also on his or her emotional and psychological well-being. As they make the transition from cancer patient to survivor, many individuals may develop or have worsening depression and anxiety due to fear of recurrence. These feelings of powerlessness can linger for years after the initial treatment.

Patients should be screened regularly for signs and symptoms of depression by asking about their family and social support. Referral to support groups, psychologists, and psychiatrists may be warranted.⁹

MITIGATING CANCER-RELATED FATIGUE

Cancer-related fatigue involves a patient’s subjective sense of physical, emotional, and cognitive exhaustion related to cancer or treatment that is disproportionate to that expected from recent daily activity.² Fatigue is a common complaint among survivors and can occur months to years after treatment ends.¹⁰

Patients should be screened for fatigue at regular intervals. The primary care physician should focus the history to include information regarding the onset, pattern, duration, associated factors, assessment of other treatable comorbidities, medications, psychological well-being, nutritional status, and pain level of each patient who complains of fatigue.

Laboratory tests for treatable causes of fatigue include:

• A complete blood cell count to evaluate for anemia
• A comprehensive metabolic panel to evaluate electrolytes, renal function, and hepatic function
• The thyroid-stimulating hormone level to evaluate thyroid function, particularly in breast cancer patients who have received radiation therapy.²

If no organic cause is uncovered, the focus should shift to lifestyle interventions as the treatment of choice. The treatment of fatigue in this situation is increased physical activity with the goals discussed above. Psychological intervention may be required with cognitive behavioral therapy, psychological and supportive therapies, education on sleep hygiene, and possible sleep restriction.

If alternative causes of fatigue are ruled out and physical and psychological support fails to reduce symptoms, the practitioner can consider a psychostimulant such as methylphenidate, but this should be used cautiously.²

SEXUAL DYSFUNCTION

Intimate relationships and sexuality are an important part of life and are affected by a variety of factors including physical health, psychological well-being, body image perception, and overall status of relationships. As a side effect of chemotherapy, cancer survivors may complain of erectile dysfunction, penile shortening, dyspareunia, vaginal dryness, decreased libido, anorgasmy, and changes in body image. These issues are frequently unaddressed, whether due to the physician’s discomfort in discussing the topic or to the patient’s embarrassment and reluctance to discuss the matter.¹¹

Breast cancer patients may experience sexual dysfunction both during and after treatment due to a combination of systemic effects of treatment, changes in physical appearance leading to impaired body image, strains on partner relationships, and psychological sequelae of diagnosis and treatment of cancer.¹² Manipulation and radiation to the breast affect sexual functioning by altering body contour and image. Additionally, chemotherapy can lead to early menopause and hormonal alterations due to endocrine therapies, which can negatively affect sexual organs.¹¹

Studies have shown that treatment with tamoxifen causes less sexual dysfunction than do aromatase inhibitors. In the Arimidex, Tamoxifen, Alone or in Combination trial, therapy with anastrozole was associated with more vaginal dryness, dyspareunia, and decreased libido compared with tamoxifen.¹²

Treatment requires a comprehensive history, a physical examination, and a discussion of relationship satisfaction with the patient.

Vaginal dryness and dyspareunia can be treated with vaginal lubricants and moisturizers. Moisturizers are effective if used multiple times per week, whereas lubricants can be used on demand. Low-dose vaginal estrogen preparations can be used in select patients with severe vaginal dryness; the goal should be discussed. Hormone replacement therapy is contraindicated in breast cancer survivors due to the risk of recurrence.¹¹

Prostate cancer survivors. Up to 70% of men felt their quality of life and sexual function were adversely affected after the diagnosis and treatment.^13,14 Erectile dysfunction following radical prostatectomy and radiation therapy remains one of the leading causes of sexual dysfunction.^14–15 Erectile dysfunction is multifactorial, with both psychogenic and organic causes. Comorbidities must be considered including hypertension, diabetes, hyperlipidemia, and smoking. Early penile rehabilitation is a proposed treatment strategy.¹⁴

First-line therapy for penile rehabilitation includes introduction of daily low-dose phosphodiesterase type 5 inhibitors as early as the time of catheter removal to within the first month after surgery. The need for daily dosing vs on-demand dosing has been controversial.¹⁵ Two large multicenter, double-blind studies had conflicting outcomes. The first reported that in men receiving nightly sildenafil (50 or 100 mg) after radical prostatectomy, 27% had increased return of spontaneous erectile function vs 4% with placebo¹⁶; the second study showed no difference between nightly and on-demand dosing.¹⁷ The consensus is that a phosphodiesterase type 5 inhibitor should be initiated early.

Second-line therapy includes intracavernosal injections and vacuum erection devices. Finally, a penile prosthesis implant can be offered to patients who have responded poorly to medical therapy.¹³

Colorectal cancer survivors suffer from sexually related problems similar to those stated above, including erectile dysfunction, ejaculation problems, dyspareunia, vaginal dryness, and decreased enjoyment.¹⁸ These patients should be provided treatments similar to those described above. In addition, they may suffer from body image issues, particularly those with a permanent ostomy.⁹

Sexual dysfunction is a multifaceted problem for patients. Encouraging couples to discuss sexual intimacy frequently helps to reveal and cope with the problems, whether physical or psychological. It is the primary care physician’s role to recognize any sexual concerns and refer to the appropriate specialist.

Osteoporosis is a metabolic bone disease characterized by low bone mineral density. As a result, bones become weak and fracture more easily from minor injuries.

Risk factors for osteoporosis include female sex, family history, advanced age, low body weight, low calcium and vitamin D levels, sedentary lifestyle, smoking, and low estrogen levels.¹⁹ Cancer treatment places patients at a greater risk for osteoporosis, particularly for those patients with chemotherapy-induced ovarian failure, those treated with aromatase inhibitors, men receiving androgen-deprivation therapy, and patients on glucocorticoid therapy. The morbidity and mortality associated with bone loss can be prevented with appropriate screening, lifestyle changes, and therapy.²

According to the National Osteoporosis Foundation Guideline for Preventing and Treating Osteoporosis, all men and postmenopausal women age 50 and older should be evaluated clinically for osteoporosis risk to determine the need for bone mineral density testing.^2,19 The US Preventive Services Task Force recommends bone mineral density testing in all women age 65 and older, and for women 60 to 64 who are at high risk for bone loss. ASCO agrees, and further suggests bone mineral density screening for women with breast cancer who have risk factors such as positive family history, body weight less than 70 kg, and prior nontraumatic fracture, as well as for postmenopausal women of any age receiving aromatase inhibitors and for premenopausal women with therapy-induced ovarian failure.¹¹

Androgen deprivation therapy is a mainstay of treatment in recurrent and metastatic prostate cancer. The effect is severe hypogonadism with reductions in serum testosterone levels. Androgen deprivation therapy accelerates bone turnover, decreases bone mineral density, and contributes to fracture risk. The National Comprehensive Cancer Network additionally suggests measuring bone mineral density at baseline for all men receiving androgen deprivation therapy or other medications associated with bone loss, repeating it 1 year after androgen deprivation therapy and then every 2 years, or as clinically indicated.²⁰

The gold standard for measuring bone mineral density is dual-energy x-ray absorptiometry. The World Health Organization FRAX tool uses bone mineral density and several clinical factors to estimate the risk of fracture in the next 10 years, which can help guide therapy. Cancer patients with elevated fracture risk should be evaluated every 2 years. Counseling should be provided to address modifiable risk factors such as smoking, alcohol consumption, physical inactivity, and low calcium and vitamin D intake. Therapy should be strongly considered in patients with a bone mineral density below a T-score of –2.0. ^2,19

Treatment begins with lifestyle modifications such as weight-bearing exercises to improve balance and muscle strength and to prevent falls, and adequate intake of calcium (≥ 1,200 mg daily) and vitamin D (800–1,000 IU daily) for adults age 50 and older. Treatment with bisphosphonates may be required.^2,11,20

NEUROPATHY

Many chemotherapeutic agents can lead to neuropathy and can result in long-term disability in patients. Patients treated with taxane- and platinum-based chemotherapy are at particular risk.

Paclitaxel, used in the treatment of breast, ovarian, and lung cancer, can lead to distal neuropathy. This neuropathy commonly has a stocking-and-glove distribution and is primarily sensory; however, it may have motor and autonomic components. The neuropathy typically lessens when the medication is stopped, although in some patients it can persist and lead to long-term disability.

Treatment can include massage. Medications such as gabapentin and pregabalin can also be used, but randomized controlled trials do not support them, as they predominantly treat the tingling rather than the numbness.¹¹

BLADDER AND BOWEL DYSFUNCTION

Urinary incontinence and dysfunction are frequent complications in prostate cancer survivors. Urinary function should be discussed regularly with patients, addressing quality of the urinary stream, difficulty emptying the bladder, timing, and incontinence.⁴ Urinary incontinence is frequently seen in postprostatectomy patients.

The cornerstone of treating urinary incontinence is determining the cause of the incontinence, whether it is stress or urge incontinence, or both.²¹ For those patients with urge incontinence alone, practitioners can address the problem with a combination of behavior modification, pelvic floor exercises, and anticholinergic medications such as oxybutynin. If the problem stems from difficulty initiating or a slow stream, physicians may consider alpha-blockers.^4,21 If the incontinence is persistent, bothersome, and has components of stress incontinence, the patient should be referred to a urologist for urodynamic testing, cystoscopy, and surgical evaluation for possible placement of a male urethral sling or artificial urinary sphincter.²¹

Colorectal cancer survivors, particularly those who received radiation therapy, are at high risk of bowel dysfunction such as chronic diarrhea and stool incontinence. Patients should be educated about this possible side effect. Symptoms of bowel dysfunction can affect body image and interfere with social functioning and overall quality of life. Patients should be provided with coping tools such as antidiarrheal medication, stool bulking agents, changes in diet, and protective underwear.

CARDIOVASCULAR DISEASE

Evidence suggests that certain types of chemotherapy and radiation therapy increase the risk of cardiovascular disease. Prostate cancer survivors treated with androgen deprivation therapy, particularly those more than 75 years old, are at increased risk of cardiovascular disease and diabetes.²²

It is recommended that men be screened with fasting plasma glucose at baseline and yearly thereafter while receiving androgen deprivation therapy. Lipid panel testing should be done 1 year from initiation of androgen deprivation therapy and then, if results are normal, every 5 years or as clinically warranted. The focus should be on primary prevention with emphasis on smoking cessation, treating hypertension per guidelines, lifestyle modifications, and treatment with aspirin and statins when clinically appropriate.²⁰

Radiation therapy, chemotherapy, and endocrine therapy have all been suggested to lead to cardiotoxicity in breast cancer patients. Anthracycline-based chemotherapies have a well-recognized association with cardiomyopathy. Factors associated with increased risk of anthracycline-induced cardiomyopathy include older age, hypertension, pre-existing coronary artery disease, and previous mediastinal radiation.

Early detection of cardiomyopathy may lead to avoidance of irreversible cardiotoxicity, but there are currently no clear guidelines for cardiac screening in breast cancer survivors. If cardiomyopathy is detected, treatment should include beta-blockers and angiotensin-converting enzyme inhibitors as well as modification of other cardiovascular risk factors.¹¹

A SURVIVORSHIP CARE PLAN

There is life beyond the diagnosis of cancer. As patients are living longer, with an estimated 5-year survival rate of 66.5% of all cancers in the United States, there must be a transition of care from the oncologist to the primary care physician.¹ While the oncologist will remain involved in the initial years of follow-up care, these visits will go from twice a year to once a year, and eventually the patient will make a full transition to care by the primary care physician. The timing of this changeover varies from physician to physician, but the primary care physician is ultimately responsible for the follow-up.

A tool to ease this transition is a survivorship care plan. The goal of a survivorship care plan is to individualize a follow-up plan while keeping in mind the necessary surveillance as outlined. These care plans are created with the patient and oncologist and then brought to the primary care physician. While there is an abundance of literature regarding the creation and initiation of survivorship care plans, the success of these plans is uncertain. Ultimately, the goal of a survivorship care plan is to create open dialogue among the oncologist, the primary care physician, and the patient. This unique patient population requires close follow-up by a multidisciplinary team with the primary care physician serving as the steward.

Patients should undergo biopsy to guide management and prognosis if suspected of having steatohepatitis or fibrosis.

WHAT IS NAFLD?

Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in the United States and is the second most common reason for liver transplant.¹ It is thought to be the hepatic consequence of systemic insulin resistance and the metabolic syndrome characterized by obesity, dyslipidemia, and type 2 diabetes mellitus.

WHAT IS THE RELATIONSHIP BETWEEN NAFLD AND NASH?

NAFLD is defined by the accumulation of hepatic fat as evidenced by imaging or histologic study and without a coexisting cause of chronic liver disease or a secondary cause of hepatic steatosis, including significant alcohol use, medications, or an inherited or acquired metabolic state.

NAFLD has two subtypes: nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). NAFL is characterized by steatosis, including inflammation, in at least 5% of hepatocytes. NASH is defined by a constellation of features that include steatosis, lobular and portal inflammation, and liver cell injury in the form of hepatocyte ballooning.²

Clinically, it is especially important to distinguish patients with the NASH subtype, as most NAFLD patients have steatosis without necroinflammation or fibrosis and do not require medical therapy.

CLINICAL SIGNIFICANCE OF NAFLD: NASH IS WORSE THAN NAFL

NAFL carries an excellent prognosis in terms of histologic progression of liver disease, whereas NASH can histologically progress to fibrosis and, in up to 15% of patients, to cirrhosis.³

Progression of fibrosis poses secondary risks, including complications associated with portal hypertension (ascites, variceal hemorrhage, hepatic encephalopathy), end-stage liver disease, and hepatocellular carcinoma. In Western countries, 4% to 22% of cases of hepatocellular carcinoma are attributed to NAFLD.⁴

In a 2015 meta-analysis, patients with NAFL and stage 0 fibrosis at baseline progressed 1 stage of fibrosis over 14.3 years, whereas patients with NASH and stage 0 fibrosis experienced an accelerated rate of progression, advancing 1 stage of fibrosis over 7.1 years.⁵ A systematic review of patients with NASH identified age and inflammation on initial liver biopsy as independent predictors of progression to advanced fibrosis.⁶

Patients with NAFLD have a higher all-cause mortality rate than patients of the same age and sex without NAFLD.⁷

HOW SHOULD PATIENTS WITH NAFLD BE EVALUATED?

Initial evaluation of a patient with suspected NAFLD should include a thorough serologic evaluation to exclude coexisting causes of chronic liver disease. Tests include:

• A viral hepatitis panel
• Antinuclear antibody (ANA)
• Antismooth muscle antibody (ASMA)
• Antimitochondrial antibody (AMA)
• Iron studies
• Alpha-1 antitrypsin level
• Ceruloplasmin level.

Aminotransferase levels and imaging studies (ultrasonography, computed tomography, and magnetic resonance imaging) do not reliably convey the degree of NASH and fibrosis.

Biopsy. Whereas sensitive serologic tests have been introduced to detect and diagnose many causes of liver disease, liver biopsy (trans­jugular or percutaneous) with histologic examination remains the only way to accurately assess the degree of steatosis and, thus, to distinguish NAFL from NASH.²

The Pathology Committee of the NASH Clinical Research Network designed and validated a NAFLD scoring system,^8,9 with points allocated for degrees of:

• Steatosis (0–3)
• Lobular inflammation (0–2)
• Hepatocellular ballooning (0–2)
• Fibrosis (0–4).

A NAFLD Activity Score of less than 3 is consistent with “not NASH,” a score of 3 or 4 with borderline NASH, and a score of 5 or more with NASH.⁸ However, the diagnosis of NASH is not based on the NAFLD scoring system, but rather on the pathologist’s overall evaluation of the liver biopsy.⁹

The metabolic syndrome is an established risk factor for steatohepatitis in patients with NAFLD, and its presence in patients with persistently elevated liver biochemical tests may help identify those who would benefit from further diagnostic and prognostic evaluation, including liver biopsy.^2,10 In addition, a 2008 study that used a decision-tree modeling system demonstrated that early liver biopsy could provide a survival benefit.¹¹

Since liver biopsy is associated with procedure-related morbidity, mortality, and cost, researchers have been developing noninvasive markers of steatohepatitis and fibrosis.¹²

The NAFLD fibrosis score—based on patient age, body mass index, hyperglycemia, platelet count, albumin, and ratio of aspartate aminotransferase to alanine aminotransferase—has been shown to have an area under the receiver operating curve of 0.85 for predicting advanced fibrosis, with a negative predictive value of 88% to 93% and a positive predictive value of 82% to 90%.¹³ The NAFLD fibrosis score can be used to identify patients who may have fibrosis or cirrhosis and can help direct the use of liver biopsy in patients who would benefit from prognostication and potential treatment.

Of note, the NAFLD fibrosis score is only slightly less accurate than the imaging techniques of magnetic resonance elastography and transient elastography, particularly when the relative costs are considered.¹⁴

INDICATIONS FOR LIVER BIOPSY

There are two clear indications for liver biopsy in NAFLD.

Before starting any pharmacologic therapy for NAFLD. Most NAFLD patients have steatosis without NASH or fibrosis and do not require medical therapy. Importantly, the available treatments have significant adverse effects—prostate cancer with vitamin E, bladder cancer and weight gain with pioglitazone, and nausea with pentoxifylline.

Diagnosis. Up to 30% of patients have elevated serum ferritin and autoantibodies, including ANA, ASMA, and AMA. Liver biopsy is often needed to exclude hemochromatosis or autoimmune hepatitis.¹⁵ Occasionally, a possible confounding drug-induced liver injury may necessitate a liver biopsy.

LIFESTYLE MODIFICATION

The first step in managing patients who have NAFLD is to treat components of the metabolic syndrome, including obesity, dyslipidemia, and type 2 diabetes.

In a randomized controlled trial in 31 obese patients with biopsy-proven NASH,¹⁶ intensive lifestyle modification (consisting of diet, behavior modification, and 200 minutes of exercise weekly for 48 weeks) was shown to improve histologic NAFLD Activity Scores, including degrees of steatosis, necrosis, and inflammation. As a result, weight loss of 7% to 9% is generally recommended for patients with NAFLD.

DRUG THERAPIES

Much research has been directed toward identifying risk factors for progression of fibrosis and toward developing new therapies for patients with NAFLD. A 2015 meta-analysis concluded that pentoxifylline and obeticholic acid improve fibrosis, while vitamin E, thiazolidinediones, and obeticholic acid improve necroinflammation associated with NASH.¹⁷

Long-term studies are needed to determine the impact of these drugs on NASH-related morbidity, mortality, and need for liver transplant.

TAKE-AWAY POINTS

• NAFLD is the leading cause of chronic liver disease in the United States and is increasing as a reason for liver transplant.
• NASH is associated with the metabolic syndrome and can progress to fibrosis, cirrhosis, and end-stage liver disease. Noninvasive markers such as the NAFLD Activity Score can be useful in identifying patients who may have advanced fibrosis and can select patients who should be directed to liver biopsy for definitive diagnosis.^8,9
• Liver biopsy is the gold standard for diagnosing steatohepatitis and fibrosis and is the only diagnostic tool used in clinical trials to direct pharmacotherapy for NASH.
• Liver biopsy should be reserved for patients suspected of having NASH or fibrosis and who might benefit from therapy.
• Liver biopsy is also indicated for those NAFLD patients who have confounding laboratory findings such as an elevated ferritin level and autoantibodies including ANA, ASMA, and AMA.

Patients should undergo biopsy to guide management and prognosis if suspected of having steatohepatitis or fibrosis.

WHAT IS NAFLD?

Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in the United States and is the second most common reason for liver transplant.¹ It is thought to be the hepatic consequence of systemic insulin resistance and the metabolic syndrome characterized by obesity, dyslipidemia, and type 2 diabetes mellitus.

WHAT IS THE RELATIONSHIP BETWEEN NAFLD AND NASH?

NAFLD is defined by the accumulation of hepatic fat as evidenced by imaging or histologic study and without a coexisting cause of chronic liver disease or a secondary cause of hepatic steatosis, including significant alcohol use, medications, or an inherited or acquired metabolic state.

NAFLD has two subtypes: nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). NAFL is characterized by steatosis, including inflammation, in at least 5% of hepatocytes. NASH is defined by a constellation of features that include steatosis, lobular and portal inflammation, and liver cell injury in the form of hepatocyte ballooning.²

Clinically, it is especially important to distinguish patients with the NASH subtype, as most NAFLD patients have steatosis without necroinflammation or fibrosis and do not require medical therapy.

CLINICAL SIGNIFICANCE OF NAFLD: NASH IS WORSE THAN NAFL

NAFL carries an excellent prognosis in terms of histologic progression of liver disease, whereas NASH can histologically progress to fibrosis and, in up to 15% of patients, to cirrhosis.³

Progression of fibrosis poses secondary risks, including complications associated with portal hypertension (ascites, variceal hemorrhage, hepatic encephalopathy), end-stage liver disease, and hepatocellular carcinoma. In Western countries, 4% to 22% of cases of hepatocellular carcinoma are attributed to NAFLD.⁴

In a 2015 meta-analysis, patients with NAFL and stage 0 fibrosis at baseline progressed 1 stage of fibrosis over 14.3 years, whereas patients with NASH and stage 0 fibrosis experienced an accelerated rate of progression, advancing 1 stage of fibrosis over 7.1 years.⁵ A systematic review of patients with NASH identified age and inflammation on initial liver biopsy as independent predictors of progression to advanced fibrosis.⁶

Patients with NAFLD have a higher all-cause mortality rate than patients of the same age and sex without NAFLD.⁷

HOW SHOULD PATIENTS WITH NAFLD BE EVALUATED?

Initial evaluation of a patient with suspected NAFLD should include a thorough serologic evaluation to exclude coexisting causes of chronic liver disease. Tests include:

• A viral hepatitis panel
• Antinuclear antibody (ANA)
• Antismooth muscle antibody (ASMA)
• Antimitochondrial antibody (AMA)
• Iron studies
• Alpha-1 antitrypsin level
• Ceruloplasmin level.

Aminotransferase levels and imaging studies (ultrasonography, computed tomography, and magnetic resonance imaging) do not reliably convey the degree of NASH and fibrosis.

Biopsy. Whereas sensitive serologic tests have been introduced to detect and diagnose many causes of liver disease, liver biopsy (trans­jugular or percutaneous) with histologic examination remains the only way to accurately assess the degree of steatosis and, thus, to distinguish NAFL from NASH.²

The Pathology Committee of the NASH Clinical Research Network designed and validated a NAFLD scoring system,^8,9 with points allocated for degrees of:

• Steatosis (0–3)
• Lobular inflammation (0–2)
• Hepatocellular ballooning (0–2)
• Fibrosis (0–4).

A NAFLD Activity Score of less than 3 is consistent with “not NASH,” a score of 3 or 4 with borderline NASH, and a score of 5 or more with NASH.⁸ However, the diagnosis of NASH is not based on the NAFLD scoring system, but rather on the pathologist’s overall evaluation of the liver biopsy.⁹

The metabolic syndrome is an established risk factor for steatohepatitis in patients with NAFLD, and its presence in patients with persistently elevated liver biochemical tests may help identify those who would benefit from further diagnostic and prognostic evaluation, including liver biopsy.^2,10 In addition, a 2008 study that used a decision-tree modeling system demonstrated that early liver biopsy could provide a survival benefit.¹¹

Since liver biopsy is associated with procedure-related morbidity, mortality, and cost, researchers have been developing noninvasive markers of steatohepatitis and fibrosis.¹²

The NAFLD fibrosis score—based on patient age, body mass index, hyperglycemia, platelet count, albumin, and ratio of aspartate aminotransferase to alanine aminotransferase—has been shown to have an area under the receiver operating curve of 0.85 for predicting advanced fibrosis, with a negative predictive value of 88% to 93% and a positive predictive value of 82% to 90%.¹³ The NAFLD fibrosis score can be used to identify patients who may have fibrosis or cirrhosis and can help direct the use of liver biopsy in patients who would benefit from prognostication and potential treatment.

Of note, the NAFLD fibrosis score is only slightly less accurate than the imaging techniques of magnetic resonance elastography and transient elastography, particularly when the relative costs are considered.¹⁴

INDICATIONS FOR LIVER BIOPSY

There are two clear indications for liver biopsy in NAFLD.

Before starting any pharmacologic therapy for NAFLD. Most NAFLD patients have steatosis without NASH or fibrosis and do not require medical therapy. Importantly, the available treatments have significant adverse effects—prostate cancer with vitamin E, bladder cancer and weight gain with pioglitazone, and nausea with pentoxifylline.

Diagnosis. Up to 30% of patients have elevated serum ferritin and autoantibodies, including ANA, ASMA, and AMA. Liver biopsy is often needed to exclude hemochromatosis or autoimmune hepatitis.¹⁵ Occasionally, a possible confounding drug-induced liver injury may necessitate a liver biopsy.

LIFESTYLE MODIFICATION

The first step in managing patients who have NAFLD is to treat components of the metabolic syndrome, including obesity, dyslipidemia, and type 2 diabetes.

In a randomized controlled trial in 31 obese patients with biopsy-proven NASH,¹⁶ intensive lifestyle modification (consisting of diet, behavior modification, and 200 minutes of exercise weekly for 48 weeks) was shown to improve histologic NAFLD Activity Scores, including degrees of steatosis, necrosis, and inflammation. As a result, weight loss of 7% to 9% is generally recommended for patients with NAFLD.

DRUG THERAPIES

Much research has been directed toward identifying risk factors for progression of fibrosis and toward developing new therapies for patients with NAFLD. A 2015 meta-analysis concluded that pentoxifylline and obeticholic acid improve fibrosis, while vitamin E, thiazolidinediones, and obeticholic acid improve necroinflammation associated with NASH.¹⁷

Long-term studies are needed to determine the impact of these drugs on NASH-related morbidity, mortality, and need for liver transplant.

TAKE-AWAY POINTS

• NAFLD is the leading cause of chronic liver disease in the United States and is increasing as a reason for liver transplant.
• NASH is associated with the metabolic syndrome and can progress to fibrosis, cirrhosis, and end-stage liver disease. Noninvasive markers such as the NAFLD Activity Score can be useful in identifying patients who may have advanced fibrosis and can select patients who should be directed to liver biopsy for definitive diagnosis.^8,9
• Liver biopsy is the gold standard for diagnosing steatohepatitis and fibrosis and is the only diagnostic tool used in clinical trials to direct pharmacotherapy for NASH.
• Liver biopsy should be reserved for patients suspected of having NASH or fibrosis and who might benefit from therapy.
• Liver biopsy is also indicated for those NAFLD patients who have confounding laboratory findings such as an elevated ferritin level and autoantibodies including ANA, ASMA, and AMA.

Patients should undergo biopsy to guide management and prognosis if suspected of having steatohepatitis or fibrosis.

WHAT IS NAFLD?

Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in the United States and is the second most common reason for liver transplant.¹ It is thought to be the hepatic consequence of systemic insulin resistance and the metabolic syndrome characterized by obesity, dyslipidemia, and type 2 diabetes mellitus.

WHAT IS THE RELATIONSHIP BETWEEN NAFLD AND NASH?

NAFLD is defined by the accumulation of hepatic fat as evidenced by imaging or histologic study and without a coexisting cause of chronic liver disease or a secondary cause of hepatic steatosis, including significant alcohol use, medications, or an inherited or acquired metabolic state.

NAFLD has two subtypes: nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). NAFL is characterized by steatosis, including inflammation, in at least 5% of hepatocytes. NASH is defined by a constellation of features that include steatosis, lobular and portal inflammation, and liver cell injury in the form of hepatocyte ballooning.²

Clinically, it is especially important to distinguish patients with the NASH subtype, as most NAFLD patients have steatosis without necroinflammation or fibrosis and do not require medical therapy.

CLINICAL SIGNIFICANCE OF NAFLD: NASH IS WORSE THAN NAFL

NAFL carries an excellent prognosis in terms of histologic progression of liver disease, whereas NASH can histologically progress to fibrosis and, in up to 15% of patients, to cirrhosis.³

Progression of fibrosis poses secondary risks, including complications associated with portal hypertension (ascites, variceal hemorrhage, hepatic encephalopathy), end-stage liver disease, and hepatocellular carcinoma. In Western countries, 4% to 22% of cases of hepatocellular carcinoma are attributed to NAFLD.⁴

In a 2015 meta-analysis, patients with NAFL and stage 0 fibrosis at baseline progressed 1 stage of fibrosis over 14.3 years, whereas patients with NASH and stage 0 fibrosis experienced an accelerated rate of progression, advancing 1 stage of fibrosis over 7.1 years.⁵ A systematic review of patients with NASH identified age and inflammation on initial liver biopsy as independent predictors of progression to advanced fibrosis.⁶

Patients with NAFLD have a higher all-cause mortality rate than patients of the same age and sex without NAFLD.⁷

HOW SHOULD PATIENTS WITH NAFLD BE EVALUATED?

Initial evaluation of a patient with suspected NAFLD should include a thorough serologic evaluation to exclude coexisting causes of chronic liver disease. Tests include:

• A viral hepatitis panel
• Antinuclear antibody (ANA)
• Antismooth muscle antibody (ASMA)
• Antimitochondrial antibody (AMA)
• Iron studies
• Alpha-1 antitrypsin level
• Ceruloplasmin level.

Aminotransferase levels and imaging studies (ultrasonography, computed tomography, and magnetic resonance imaging) do not reliably convey the degree of NASH and fibrosis.

Biopsy. Whereas sensitive serologic tests have been introduced to detect and diagnose many causes of liver disease, liver biopsy (trans­jugular or percutaneous) with histologic examination remains the only way to accurately assess the degree of steatosis and, thus, to distinguish NAFL from NASH.²

The Pathology Committee of the NASH Clinical Research Network designed and validated a NAFLD scoring system,^8,9 with points allocated for degrees of:

• Steatosis (0–3)
• Lobular inflammation (0–2)
• Hepatocellular ballooning (0–2)
• Fibrosis (0–4).

A NAFLD Activity Score of less than 3 is consistent with “not NASH,” a score of 3 or 4 with borderline NASH, and a score of 5 or more with NASH.⁸ However, the diagnosis of NASH is not based on the NAFLD scoring system, but rather on the pathologist’s overall evaluation of the liver biopsy.⁹

The metabolic syndrome is an established risk factor for steatohepatitis in patients with NAFLD, and its presence in patients with persistently elevated liver biochemical tests may help identify those who would benefit from further diagnostic and prognostic evaluation, including liver biopsy.^2,10 In addition, a 2008 study that used a decision-tree modeling system demonstrated that early liver biopsy could provide a survival benefit.¹¹

Since liver biopsy is associated with procedure-related morbidity, mortality, and cost, researchers have been developing noninvasive markers of steatohepatitis and fibrosis.¹²

The NAFLD fibrosis score—based on patient age, body mass index, hyperglycemia, platelet count, albumin, and ratio of aspartate aminotransferase to alanine aminotransferase—has been shown to have an area under the receiver operating curve of 0.85 for predicting advanced fibrosis, with a negative predictive value of 88% to 93% and a positive predictive value of 82% to 90%.¹³ The NAFLD fibrosis score can be used to identify patients who may have fibrosis or cirrhosis and can help direct the use of liver biopsy in patients who would benefit from prognostication and potential treatment.

Of note, the NAFLD fibrosis score is only slightly less accurate than the imaging techniques of magnetic resonance elastography and transient elastography, particularly when the relative costs are considered.¹⁴

INDICATIONS FOR LIVER BIOPSY

There are two clear indications for liver biopsy in NAFLD.

Before starting any pharmacologic therapy for NAFLD. Most NAFLD patients have steatosis without NASH or fibrosis and do not require medical therapy. Importantly, the available treatments have significant adverse effects—prostate cancer with vitamin E, bladder cancer and weight gain with pioglitazone, and nausea with pentoxifylline.

Diagnosis. Up to 30% of patients have elevated serum ferritin and autoantibodies, including ANA, ASMA, and AMA. Liver biopsy is often needed to exclude hemochromatosis or autoimmune hepatitis.¹⁵ Occasionally, a possible confounding drug-induced liver injury may necessitate a liver biopsy.

LIFESTYLE MODIFICATION

The first step in managing patients who have NAFLD is to treat components of the metabolic syndrome, including obesity, dyslipidemia, and type 2 diabetes.

In a randomized controlled trial in 31 obese patients with biopsy-proven NASH,¹⁶ intensive lifestyle modification (consisting of diet, behavior modification, and 200 minutes of exercise weekly for 48 weeks) was shown to improve histologic NAFLD Activity Scores, including degrees of steatosis, necrosis, and inflammation. As a result, weight loss of 7% to 9% is generally recommended for patients with NAFLD.

DRUG THERAPIES

Much research has been directed toward identifying risk factors for progression of fibrosis and toward developing new therapies for patients with NAFLD. A 2015 meta-analysis concluded that pentoxifylline and obeticholic acid improve fibrosis, while vitamin E, thiazolidinediones, and obeticholic acid improve necroinflammation associated with NASH.¹⁷

Long-term studies are needed to determine the impact of these drugs on NASH-related morbidity, mortality, and need for liver transplant.

TAKE-AWAY POINTS

• NAFLD is the leading cause of chronic liver disease in the United States and is increasing as a reason for liver transplant.
• NASH is associated with the metabolic syndrome and can progress to fibrosis, cirrhosis, and end-stage liver disease. Noninvasive markers such as the NAFLD Activity Score can be useful in identifying patients who may have advanced fibrosis and can select patients who should be directed to liver biopsy for definitive diagnosis.^8,9
• Liver biopsy is the gold standard for diagnosing steatohepatitis and fibrosis and is the only diagnostic tool used in clinical trials to direct pharmacotherapy for NASH.
• Liver biopsy should be reserved for patients suspected of having NASH or fibrosis and who might benefit from therapy.
• Liver biopsy is also indicated for those NAFLD patients who have confounding laboratory findings such as an elevated ferritin level and autoantibodies including ANA, ASMA, and AMA.

The incidence of maternal asthma is rising. Based on US national health surveys, the prevalence of asthma during pregnancy is between 3.7% and 8.4%.¹ It is the most common respiratory illness of pregnancy.² Hence, clinicians need to know how asthma affects the mother and the fetus. Appropriate care of asthma during pregnancy is based on several management principles, as reviewed here, and is key to ensuring good outcomes for the mother and the baby.

EFFECT OF PREGNANCY ON ASTHMA CONTROL

Asthma control can vary in pregnancy. About a third of asthmatic women experience a worsening of asthma control with pregnancy, a third remain unchanged, and another third have improvement in asthma symptoms.³ The peak worsening of asthma tends to occur in the sixth month.⁴ Asthma control also tends to be better in the last month of pregnancy.³

The peak expiratory flow rate was noted to increase with each trimester in a small study of 43 women.⁵ The authors speculated that a rising progesterone level stimulates cyclic adenosine monophosphate to cause bronchodilation, thereby improving the expiratory flow rate and asthma control. Asthma control tends to follow the pattern experienced in the previous pregnancy: ie, if asthma worsened during the previous pregnancy, the same will be likely in the subsequent pregnancy.³

Two maternal factors that adversely affect asthma severity during pregnancy are the use of asthma medications contrary to guidelines such as those of the Global Initiative for Asthma (http://ginasthma.org/2017-gina-report-global-strategy-for-asthma-management-and-prevention) and inadquate control of asthma before becoming pregnant.⁶ Pregnancy can bring on stress, and stress is known to worsen asthma. In addition, when patients themselves were interviewed to elucidate the reasons for poor adherence to asthma medications during pregnancy, concerns about medication use, especially corticosteroids, stood out.⁷ A study based on prescription claims data showed that in the first trimester, there was a significant decline in asthma prescription medications (a 23% decline in inhaled corticosteroids, a 13% decline in short-acting bronchodilator agents, and a 54% decline in rescue corticosteroids).⁸ Lack of physician education about management of asthma in pregnancy and discomfort with prescribing to pregnant women also affect asthma control.

EFFECT OF ASTHMA ON MATERNAL AND FETAL OUTCOMES

Studies of the effects of asthma on fetal and maternal outcomes have yielded mixed and conflicting results.⁹ Adverse outcomes that have been shown to be associated with maternal asthma are listed in Table 1. Other studies have not demonstrated an association between asthma in pregnancy and maternal or fetal adverse events.⁹ Such discrepant findings are due to differences in study population characteristics that make comparisons difficult. A meta-analysis involving more than 1.6 million asthmatic women showed maternal asthma was associated with a 40% greater risk of low birth weight and preterm delivery, a 50% greater risk of preeclampsia, and a 20% greater risk of the baby being small for its gestational age.¹⁰

The association of maternal asthma and preterm birth may pose short-term and long-term health risks to the child associated with prematurity.⁹ Short-term risks with prematurity include infection, respiratory distress syndrome, brain injury, and necrotizing enterocolitis. Long-term risks include neuro­developmental and behavioral sequelae. Furthermore, asthma exacerbations during pregnancy are associated with a twofold higher risk of low birth weight.¹¹ The benefits of good adherence to asthma regimens during pregnancy outweigh the risks associated with frequent symptoms and exacerbations caused by untreated asthma.¹²

OUTPATIENT MANAGEMENT OF MATERNAL ASTHMA

Goals

In the 2004 update of the National Asthma Education and Prevention Program (NAEPP) Working Group Report on Managing Asthma During Pregnancy, goals focused mainly on adequate asthma control for maternal health and quality of life, as well as normal fetal maturation (Table 2),¹² goals similar to those in nonpregnant asthmatic women.

Assessment and monitoring

Monthly physician visits during pregnancy are recommended for assessment of symptoms and pulmonary function. If symptoms are uncontrolled, therapy must be stepped up, and any trigger for exacerbation, such as gastroesophageal reflux disease (GERD), exposure, or rhinitis, must be treated and eliminated. NAEPP guidelines recommend baseline spirometry at the time of initial assessment.¹² At follow-up visits, spirometry is preferred, but measurement of the peak expiratory flow rate usually suffices. Such objective data can help differentiate dyspnea from asthma and from dyspnea that usually accompanies the physiologic changes of pregnancy. In addition, patients should be advised to monitor for adequate fetal activity. If asthma is uncontrolled or poorly controlled, serial fetal ultrasonography should be considered from 32 weeks of gestation, as well as after recovery from an asthma exacerbation. Regular monitoring of the pregnant asthmatic patient by a multidisciplinary team can improve outcomes.¹³

Avoiding triggers

Patients should be advised to avoid asthma triggers such as pet dander, dust mites, pollen, smoke, mold, and perfumes, as this can decrease symptoms and allow for use of lower doses of medications.¹² Additionally, smoking cessation must be strongly encouraged, not only to control maternal asthma, but also to prevent harm to the fetus.

MANAGEMENT OF SPECIFIC TRIGGERS

GERD

Reflux disease often worsens during pregnancy, and it can coexist with asthma and can also exacerbate it.¹⁴ Optimal control of GERD helps maintain adequate asthma control. For mild reflux symptoms, lifestyle modifications such as elevating the head of bed, avoiding eating too close to bedtime, and avoiding foods that cause heartburn may be adequate.^15,16 If medications are needed, antacids (but not sodium bicarbonate, for fear of metabolic alkalosis) and sucralfate should be considered before using a histamine 2 receptor antagonist such as ranitidine. Proton pump inhibitors should be considered only if reflux symptoms are refractory to other therapies.

Allergic rhinitis

Intranasal corticosteroids are effective against allergic rhinitis in pregnancy (Table 3).¹² Montelukast, a leukotriene receptor antagonist, can be used, but data to support its use for allergic rhinitis in pregnancy are limited.

Among antihistamines, second-generation drugs such as cetirizine or loratadine can be considered.¹² Oral decongestants such as pseudoephedrine in early pregnancy are associated with a rare congenital fetal abnormality called gastroschisis, caused by vascular disruption.¹⁷ Hence, if a nasal decongestant is required in early pregnancy, a local therapy such as an intranasal corticosteroid, short-term oxymetazoline, or an external nasal dilator may be considered.¹² These therapies must be combined with avoidance of allergens whenever possible.

Allergies

Diagnostic allergy and skin tests during pregnancy pose a risk of anaphylaxis and thus should be avoided. Instead, the focus should be on obtaining a thorough medical history about exposures and eliminating specific asthma triggers. It is also inadvisable to start allergen immunotherapy during pregnancy because of the risk of anaphylaxis and the effect of treatment on the mother and fetus.¹⁸ However, maintenance doses of allergen immunotherapy can be continued during pregnancy.¹⁸

Patient education

Because of concern about the risks of taking medications during pregnancy, many women with asthma stop using their inhalers during pregnancy, thus compromising asthma control.^8,13 The physician and multidisciplinary team must use every opportunity to emphasize the importance of good asthma control during pregnancy. Inhaler technique should also be reviewed and, if defective, corrected. Again, trigger avoidance and tobacco cessation should be addressed.

Drugs

The NAEPP recommendations state that asthma therapy should be continued during pregnancy, as it is safer both for mother and fetus to avoid exacerbations and uncontrolled asthma.¹² Despite this, 25% of primary care physicians instruct their patients to decrease or discontinue their inhaled corticosteroid during pregnancy.¹⁹ As with asthma in general, treatment should involve using the lowest dose of drugs that achieves adequate control of symptoms.

In 2015, the US Food and Drug Administration (FDA) amended the labeling rule for medications used in pregnancy and lactation. The previous risk categories A (safest), B, C, D, and X (highest risk) are in the process of being removed from labels for all human prescription drugs and biologic products, to be replaced with a summary of the risks of taking the drug during pregnancy and lactation, a discussion of the data supporting the use, and relevant information to help healthcare providers make prescribing decisions and counsel women about the use of drugs during pregnancy and lactation (www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/ucm093307.htm).

ROLES OF CONTROLLER THERAPY AND RESCUE THERAPY

Inhaled corticosteroids

Inhaled corticosteroids are the mainstay of asthma controller therapy during pregnancy. A meta-analysis of 16 studies showed no increased risk of congenital malformations, cesarean delivery, or stillbirth among mothers who used these agents during pregnancy.²⁰ Because there are more safety data for budesonide, it is currently the preferred inhaled corticosteroid during pregnancy.⁹ However, if a patient’s asthma is controlled with a different corticosteroid before pregnancy, that agent may be continued during pregnancy, especially if it is thought that switching formulations could adversely affect asthma control.¹² This is mainly because current data do not prove that other inhaled corticosteroids are unsafe.

Inhaled beta-agonists

Inhaled beta-agonists, both short-acting and long-acting, are used for rescue therapy. Al­buterol is the preferred short-acting agent for rescue therapy in pregnant women with asthma.¹² Meta-analysis has shown no increased risk of major or minor congenital malformations in pregnant patients who use bronchodilators.²⁰ Long-acting beta-agonists typically are used as add-on therapy when asthma cannot be controlled by an inhaled corticosteroid. They should not be used without a controller medication (ie, an inhaled corticosteroid).

Guidelines for rescue therapy are similar to those for nonpregnant asthmatic patients. Although data are limited as to the gestational effects of long-acting beta-agonists (ie, formoterol, salmeterol), it can be assumed that the toxicologic and pharmacologic profiles are similar to those of the short-acting bronchodilators. Thus, the safety of albuterol can be extended potentially to the long-acting beta-agonists.¹²

Combining controller and rescue therapy

When asthma is not adequately controlled on inhaled corticosteroids, a long-acting beta-agonist can be added or the dose of corticosteroid can be increased. The 2004 NAEPP guidelines stated that based on available literature, there was no clear advantage of one option over the other.¹² A study that compared the 2 approaches found no difference in rates of congenital malformations.²¹

Leukotriene receptor antagonists

There is little in the literature regarding the use of leukotriene receptor antagonists during pregnancy. However, animal safety data are reassuring,¹² and human studies have not found a higher risk of major congenital malformations.^22,23 Thus, they are an alternative for patients whose asthma has been well controlled on these agents before pregnancy. Montelukast and zafirlukast are in former FDA pregnancy risk factor category B (probably safe) (Table 3). However, 5-lipoxygenase inhibitors such as zileuton are contraindicated based on animal studies showing teratogenicity.²⁴

Omalizumab

Omalizumab, a recombinant anti-immunoglobulin E antibody, can be used for allergic asthma not controlled with inhaled corticosteroids (Table 3). An analysis of the omalizumab pregnancy registry²⁵ found no significant increase in the rate of major congenital malformations, prematurity, or babies small for gestational age in asthmatic women taking omalizumab 8 weeks before conception or during pregnancy vs pregnant asthmatic women not taking omalizumab. However, this drug carries a risk of anaphylaxis and so should not be started during pregnancy.²⁵

Theophylline

Because of potential toxicity, use of theophylline during pregnancy requires careful monitoring to ensure the serum concentration remains between 5 and 12 µg/mL.¹² Drug interactions are also common: for example, alcohol may increase the serum concentration of theophylline, and theophylline may increase the toxic effect of formoterol.

Systemic corticosteroids

Pregnant women with asthma that is not well controlled despite the therapies described above may require a daily oral corticosteroid such as prednisone to achieve adequate control. Oral steroids are also a mainstay of treatment of asthma exacerbation.

Although use of corticosteroids in the first trimester was associated with orofacial cleft in infants,¹² these studies did not include many women with asthma. In 2011, a nationwide cohort study from Denmark showed no increase in the risk of orofacial cleft with the use of corticosteroids during pregnancy.²⁶

Preeclampsia, low birth weight, and preterm delivery have been described with corticosteroid use in pregnancy. It is not known whether these problems were a result of corticosteroid use or were due to the uncontrolled nature of the underlying condition that led to the steroid use. Since the risk of uncontrolled asthma to mother and fetus outweighs the risk of systemic corticosteroids, these drugs are recommended when indicated for management of maternal asthma.¹²

ACUTE EXACERBATIONS REQUIRE AGGRESSIVE MANAGEMENT

Based on a systematic review, 20% of pregnant women with asthma require some intervention for an asthma exacerbation during pregnancy, and 5.8% are admitted to the hospital for an exacerbation.¹¹ Exacerbations were associated with a higher risk of low birth weight compared with rates in women without asthma.

Exacerbations are more common late in the second trimester and are unlikely to occur during labor and delivery.²  The incidence of exacerbations increases with the severity of asthma, from 8% in mild asthma, to 47% in moderate asthma, to 65% in severe asthma.²⁷ Risk factors for exacerbations include poor prenatal care, obesity, and lack of appropriate treatment with inhaled corticosteroids.² The main triggers are viral respiratory infections and noncompliance with inhaled corticosteroid therapy.¹¹

Asthma exacerbations during pregnancy should be managed aggressively (Table 4),¹² as the risk to the fetus of hypoxia far outweighs any risk from asthma medications. Close collaboration between the primary care physician and the obstetrician allows closer monitoring of mother and fetus.

The goal oxygen saturation must be above 95%.¹² Signs of acute respiratory failure in a pregnant patient include a partial pressure of arterial oxygen less than 70 mm Hg or a partial pressure of carbon dioxide greater than 35 mm Hg.

In a multicenter study comparing nonpregnant and pregnant women visiting the emergency room for asthma exacerbations,²⁸ pregnant women were less likely to be prescribed systemic corticosteroids either in the emergency room or at the time of hospital discharge, and they were also more likely to describe an ongoing exacerbation at 2-week follow-up. However, a recent study showed a significant increase in systemic corticosteroid treatment in the emergency room (51% to 78% across the time periods, odds ratio 3.11, 95% confidence interval 1.27–7.60, P = .01). There was also an increase in steroid treatment at discharge (42% to 63%, odds ratio 2.49, 95% confidence interval 0.97–6.37, P = .054), though the increase was not statistically significant.²⁹ Although emergency room care for pregnant asthmatic women has improved, this group concluded that further improvement is still warranted, as 1 in 3 women is discharged without corticosteroid treatment.

The incidence of maternal asthma is rising. Based on US national health surveys, the prevalence of asthma during pregnancy is between 3.7% and 8.4%.¹ It is the most common respiratory illness of pregnancy.² Hence, clinicians need to know how asthma affects the mother and the fetus. Appropriate care of asthma during pregnancy is based on several management principles, as reviewed here, and is key to ensuring good outcomes for the mother and the baby.

EFFECT OF PREGNANCY ON ASTHMA CONTROL

Asthma control can vary in pregnancy. About a third of asthmatic women experience a worsening of asthma control with pregnancy, a third remain unchanged, and another third have improvement in asthma symptoms.³ The peak worsening of asthma tends to occur in the sixth month.⁴ Asthma control also tends to be better in the last month of pregnancy.³

The peak expiratory flow rate was noted to increase with each trimester in a small study of 43 women.⁵ The authors speculated that a rising progesterone level stimulates cyclic adenosine monophosphate to cause bronchodilation, thereby improving the expiratory flow rate and asthma control. Asthma control tends to follow the pattern experienced in the previous pregnancy: ie, if asthma worsened during the previous pregnancy, the same will be likely in the subsequent pregnancy.³

Two maternal factors that adversely affect asthma severity during pregnancy are the use of asthma medications contrary to guidelines such as those of the Global Initiative for Asthma (http://ginasthma.org/2017-gina-report-global-strategy-for-asthma-management-and-prevention) and inadquate control of asthma before becoming pregnant.⁶ Pregnancy can bring on stress, and stress is known to worsen asthma. In addition, when patients themselves were interviewed to elucidate the reasons for poor adherence to asthma medications during pregnancy, concerns about medication use, especially corticosteroids, stood out.⁷ A study based on prescription claims data showed that in the first trimester, there was a significant decline in asthma prescription medications (a 23% decline in inhaled corticosteroids, a 13% decline in short-acting bronchodilator agents, and a 54% decline in rescue corticosteroids).⁸ Lack of physician education about management of asthma in pregnancy and discomfort with prescribing to pregnant women also affect asthma control.

EFFECT OF ASTHMA ON MATERNAL AND FETAL OUTCOMES

Studies of the effects of asthma on fetal and maternal outcomes have yielded mixed and conflicting results.⁹ Adverse outcomes that have been shown to be associated with maternal asthma are listed in Table 1. Other studies have not demonstrated an association between asthma in pregnancy and maternal or fetal adverse events.⁹ Such discrepant findings are due to differences in study population characteristics that make comparisons difficult. A meta-analysis involving more than 1.6 million asthmatic women showed maternal asthma was associated with a 40% greater risk of low birth weight and preterm delivery, a 50% greater risk of preeclampsia, and a 20% greater risk of the baby being small for its gestational age.¹⁰

The association of maternal asthma and preterm birth may pose short-term and long-term health risks to the child associated with prematurity.⁹ Short-term risks with prematurity include infection, respiratory distress syndrome, brain injury, and necrotizing enterocolitis. Long-term risks include neuro­developmental and behavioral sequelae. Furthermore, asthma exacerbations during pregnancy are associated with a twofold higher risk of low birth weight.¹¹ The benefits of good adherence to asthma regimens during pregnancy outweigh the risks associated with frequent symptoms and exacerbations caused by untreated asthma.¹²

OUTPATIENT MANAGEMENT OF MATERNAL ASTHMA

Goals

In the 2004 update of the National Asthma Education and Prevention Program (NAEPP) Working Group Report on Managing Asthma During Pregnancy, goals focused mainly on adequate asthma control for maternal health and quality of life, as well as normal fetal maturation (Table 2),¹² goals similar to those in nonpregnant asthmatic women.

Assessment and monitoring

Monthly physician visits during pregnancy are recommended for assessment of symptoms and pulmonary function. If symptoms are uncontrolled, therapy must be stepped up, and any trigger for exacerbation, such as gastroesophageal reflux disease (GERD), exposure, or rhinitis, must be treated and eliminated. NAEPP guidelines recommend baseline spirometry at the time of initial assessment.¹² At follow-up visits, spirometry is preferred, but measurement of the peak expiratory flow rate usually suffices. Such objective data can help differentiate dyspnea from asthma and from dyspnea that usually accompanies the physiologic changes of pregnancy. In addition, patients should be advised to monitor for adequate fetal activity. If asthma is uncontrolled or poorly controlled, serial fetal ultrasonography should be considered from 32 weeks of gestation, as well as after recovery from an asthma exacerbation. Regular monitoring of the pregnant asthmatic patient by a multidisciplinary team can improve outcomes.¹³

Avoiding triggers

Patients should be advised to avoid asthma triggers such as pet dander, dust mites, pollen, smoke, mold, and perfumes, as this can decrease symptoms and allow for use of lower doses of medications.¹² Additionally, smoking cessation must be strongly encouraged, not only to control maternal asthma, but also to prevent harm to the fetus.

MANAGEMENT OF SPECIFIC TRIGGERS

GERD

Reflux disease often worsens during pregnancy, and it can coexist with asthma and can also exacerbate it.¹⁴ Optimal control of GERD helps maintain adequate asthma control. For mild reflux symptoms, lifestyle modifications such as elevating the head of bed, avoiding eating too close to bedtime, and avoiding foods that cause heartburn may be adequate.^15,16 If medications are needed, antacids (but not sodium bicarbonate, for fear of metabolic alkalosis) and sucralfate should be considered before using a histamine 2 receptor antagonist such as ranitidine. Proton pump inhibitors should be considered only if reflux symptoms are refractory to other therapies.

Allergic rhinitis

Intranasal corticosteroids are effective against allergic rhinitis in pregnancy (Table 3).¹² Montelukast, a leukotriene receptor antagonist, can be used, but data to support its use for allergic rhinitis in pregnancy are limited.

Among antihistamines, second-generation drugs such as cetirizine or loratadine can be considered.¹² Oral decongestants such as pseudoephedrine in early pregnancy are associated with a rare congenital fetal abnormality called gastroschisis, caused by vascular disruption.¹⁷ Hence, if a nasal decongestant is required in early pregnancy, a local therapy such as an intranasal corticosteroid, short-term oxymetazoline, or an external nasal dilator may be considered.¹² These therapies must be combined with avoidance of allergens whenever possible.

Allergies

Diagnostic allergy and skin tests during pregnancy pose a risk of anaphylaxis and thus should be avoided. Instead, the focus should be on obtaining a thorough medical history about exposures and eliminating specific asthma triggers. It is also inadvisable to start allergen immunotherapy during pregnancy because of the risk of anaphylaxis and the effect of treatment on the mother and fetus.¹⁸ However, maintenance doses of allergen immunotherapy can be continued during pregnancy.¹⁸

Patient education

Because of concern about the risks of taking medications during pregnancy, many women with asthma stop using their inhalers during pregnancy, thus compromising asthma control.^8,13 The physician and multidisciplinary team must use every opportunity to emphasize the importance of good asthma control during pregnancy. Inhaler technique should also be reviewed and, if defective, corrected. Again, trigger avoidance and tobacco cessation should be addressed.

Drugs

The NAEPP recommendations state that asthma therapy should be continued during pregnancy, as it is safer both for mother and fetus to avoid exacerbations and uncontrolled asthma.¹² Despite this, 25% of primary care physicians instruct their patients to decrease or discontinue their inhaled corticosteroid during pregnancy.¹⁹ As with asthma in general, treatment should involve using the lowest dose of drugs that achieves adequate control of symptoms.

In 2015, the US Food and Drug Administration (FDA) amended the labeling rule for medications used in pregnancy and lactation. The previous risk categories A (safest), B, C, D, and X (highest risk) are in the process of being removed from labels for all human prescription drugs and biologic products, to be replaced with a summary of the risks of taking the drug during pregnancy and lactation, a discussion of the data supporting the use, and relevant information to help healthcare providers make prescribing decisions and counsel women about the use of drugs during pregnancy and lactation (www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/ucm093307.htm).

ROLES OF CONTROLLER THERAPY AND RESCUE THERAPY

Inhaled corticosteroids

Inhaled corticosteroids are the mainstay of asthma controller therapy during pregnancy. A meta-analysis of 16 studies showed no increased risk of congenital malformations, cesarean delivery, or stillbirth among mothers who used these agents during pregnancy.²⁰ Because there are more safety data for budesonide, it is currently the preferred inhaled corticosteroid during pregnancy.⁹ However, if a patient’s asthma is controlled with a different corticosteroid before pregnancy, that agent may be continued during pregnancy, especially if it is thought that switching formulations could adversely affect asthma control.¹² This is mainly because current data do not prove that other inhaled corticosteroids are unsafe.

Inhaled beta-agonists

Inhaled beta-agonists, both short-acting and long-acting, are used for rescue therapy. Al­buterol is the preferred short-acting agent for rescue therapy in pregnant women with asthma.¹² Meta-analysis has shown no increased risk of major or minor congenital malformations in pregnant patients who use bronchodilators.²⁰ Long-acting beta-agonists typically are used as add-on therapy when asthma cannot be controlled by an inhaled corticosteroid. They should not be used without a controller medication (ie, an inhaled corticosteroid).

Guidelines for rescue therapy are similar to those for nonpregnant asthmatic patients. Although data are limited as to the gestational effects of long-acting beta-agonists (ie, formoterol, salmeterol), it can be assumed that the toxicologic and pharmacologic profiles are similar to those of the short-acting bronchodilators. Thus, the safety of albuterol can be extended potentially to the long-acting beta-agonists.¹²

Combining controller and rescue therapy

When asthma is not adequately controlled on inhaled corticosteroids, a long-acting beta-agonist can be added or the dose of corticosteroid can be increased. The 2004 NAEPP guidelines stated that based on available literature, there was no clear advantage of one option over the other.¹² A study that compared the 2 approaches found no difference in rates of congenital malformations.²¹

Leukotriene receptor antagonists

There is little in the literature regarding the use of leukotriene receptor antagonists during pregnancy. However, animal safety data are reassuring,¹² and human studies have not found a higher risk of major congenital malformations.^22,23 Thus, they are an alternative for patients whose asthma has been well controlled on these agents before pregnancy. Montelukast and zafirlukast are in former FDA pregnancy risk factor category B (probably safe) (Table 3). However, 5-lipoxygenase inhibitors such as zileuton are contraindicated based on animal studies showing teratogenicity.²⁴

Omalizumab

Omalizumab, a recombinant anti-immunoglobulin E antibody, can be used for allergic asthma not controlled with inhaled corticosteroids (Table 3). An analysis of the omalizumab pregnancy registry²⁵ found no significant increase in the rate of major congenital malformations, prematurity, or babies small for gestational age in asthmatic women taking omalizumab 8 weeks before conception or during pregnancy vs pregnant asthmatic women not taking omalizumab. However, this drug carries a risk of anaphylaxis and so should not be started during pregnancy.²⁵

Theophylline

Because of potential toxicity, use of theophylline during pregnancy requires careful monitoring to ensure the serum concentration remains between 5 and 12 µg/mL.¹² Drug interactions are also common: for example, alcohol may increase the serum concentration of theophylline, and theophylline may increase the toxic effect of formoterol.

Systemic corticosteroids

Pregnant women with asthma that is not well controlled despite the therapies described above may require a daily oral corticosteroid such as prednisone to achieve adequate control. Oral steroids are also a mainstay of treatment of asthma exacerbation.

Although use of corticosteroids in the first trimester was associated with orofacial cleft in infants,¹² these studies did not include many women with asthma. In 2011, a nationwide cohort study from Denmark showed no increase in the risk of orofacial cleft with the use of corticosteroids during pregnancy.²⁶

Preeclampsia, low birth weight, and preterm delivery have been described with corticosteroid use in pregnancy. It is not known whether these problems were a result of corticosteroid use or were due to the uncontrolled nature of the underlying condition that led to the steroid use. Since the risk of uncontrolled asthma to mother and fetus outweighs the risk of systemic corticosteroids, these drugs are recommended when indicated for management of maternal asthma.¹²

ACUTE EXACERBATIONS REQUIRE AGGRESSIVE MANAGEMENT

Based on a systematic review, 20% of pregnant women with asthma require some intervention for an asthma exacerbation during pregnancy, and 5.8% are admitted to the hospital for an exacerbation.¹¹ Exacerbations were associated with a higher risk of low birth weight compared with rates in women without asthma.

Exacerbations are more common late in the second trimester and are unlikely to occur during labor and delivery.²  The incidence of exacerbations increases with the severity of asthma, from 8% in mild asthma, to 47% in moderate asthma, to 65% in severe asthma.²⁷ Risk factors for exacerbations include poor prenatal care, obesity, and lack of appropriate treatment with inhaled corticosteroids.² The main triggers are viral respiratory infections and noncompliance with inhaled corticosteroid therapy.¹¹

Asthma exacerbations during pregnancy should be managed aggressively (Table 4),¹² as the risk to the fetus of hypoxia far outweighs any risk from asthma medications. Close collaboration between the primary care physician and the obstetrician allows closer monitoring of mother and fetus.

The goal oxygen saturation must be above 95%.¹² Signs of acute respiratory failure in a pregnant patient include a partial pressure of arterial oxygen less than 70 mm Hg or a partial pressure of carbon dioxide greater than 35 mm Hg.

In a multicenter study comparing nonpregnant and pregnant women visiting the emergency room for asthma exacerbations,²⁸ pregnant women were less likely to be prescribed systemic corticosteroids either in the emergency room or at the time of hospital discharge, and they were also more likely to describe an ongoing exacerbation at 2-week follow-up. However, a recent study showed a significant increase in systemic corticosteroid treatment in the emergency room (51% to 78% across the time periods, odds ratio 3.11, 95% confidence interval 1.27–7.60, P = .01). There was also an increase in steroid treatment at discharge (42% to 63%, odds ratio 2.49, 95% confidence interval 0.97–6.37, P = .054), though the increase was not statistically significant.²⁹ Although emergency room care for pregnant asthmatic women has improved, this group concluded that further improvement is still warranted, as 1 in 3 women is discharged without corticosteroid treatment.

The incidence of maternal asthma is rising. Based on US national health surveys, the prevalence of asthma during pregnancy is between 3.7% and 8.4%.¹ It is the most common respiratory illness of pregnancy.² Hence, clinicians need to know how asthma affects the mother and the fetus. Appropriate care of asthma during pregnancy is based on several management principles, as reviewed here, and is key to ensuring good outcomes for the mother and the baby.

EFFECT OF PREGNANCY ON ASTHMA CONTROL

Asthma control can vary in pregnancy. About a third of asthmatic women experience a worsening of asthma control with pregnancy, a third remain unchanged, and another third have improvement in asthma symptoms.³ The peak worsening of asthma tends to occur in the sixth month.⁴ Asthma control also tends to be better in the last month of pregnancy.³

The peak expiratory flow rate was noted to increase with each trimester in a small study of 43 women.⁵ The authors speculated that a rising progesterone level stimulates cyclic adenosine monophosphate to cause bronchodilation, thereby improving the expiratory flow rate and asthma control. Asthma control tends to follow the pattern experienced in the previous pregnancy: ie, if asthma worsened during the previous pregnancy, the same will be likely in the subsequent pregnancy.³

Two maternal factors that adversely affect asthma severity during pregnancy are the use of asthma medications contrary to guidelines such as those of the Global Initiative for Asthma (http://ginasthma.org/2017-gina-report-global-strategy-for-asthma-management-and-prevention) and inadquate control of asthma before becoming pregnant.⁶ Pregnancy can bring on stress, and stress is known to worsen asthma. In addition, when patients themselves were interviewed to elucidate the reasons for poor adherence to asthma medications during pregnancy, concerns about medication use, especially corticosteroids, stood out.⁷ A study based on prescription claims data showed that in the first trimester, there was a significant decline in asthma prescription medications (a 23% decline in inhaled corticosteroids, a 13% decline in short-acting bronchodilator agents, and a 54% decline in rescue corticosteroids).⁸ Lack of physician education about management of asthma in pregnancy and discomfort with prescribing to pregnant women also affect asthma control.

EFFECT OF ASTHMA ON MATERNAL AND FETAL OUTCOMES

Studies of the effects of asthma on fetal and maternal outcomes have yielded mixed and conflicting results.⁹ Adverse outcomes that have been shown to be associated with maternal asthma are listed in Table 1. Other studies have not demonstrated an association between asthma in pregnancy and maternal or fetal adverse events.⁹ Such discrepant findings are due to differences in study population characteristics that make comparisons difficult. A meta-analysis involving more than 1.6 million asthmatic women showed maternal asthma was associated with a 40% greater risk of low birth weight and preterm delivery, a 50% greater risk of preeclampsia, and a 20% greater risk of the baby being small for its gestational age.¹⁰

The association of maternal asthma and preterm birth may pose short-term and long-term health risks to the child associated with prematurity.⁹ Short-term risks with prematurity include infection, respiratory distress syndrome, brain injury, and necrotizing enterocolitis. Long-term risks include neuro­developmental and behavioral sequelae. Furthermore, asthma exacerbations during pregnancy are associated with a twofold higher risk of low birth weight.¹¹ The benefits of good adherence to asthma regimens during pregnancy outweigh the risks associated with frequent symptoms and exacerbations caused by untreated asthma.¹²

OUTPATIENT MANAGEMENT OF MATERNAL ASTHMA

Goals

In the 2004 update of the National Asthma Education and Prevention Program (NAEPP) Working Group Report on Managing Asthma During Pregnancy, goals focused mainly on adequate asthma control for maternal health and quality of life, as well as normal fetal maturation (Table 2),¹² goals similar to those in nonpregnant asthmatic women.

Assessment and monitoring

Monthly physician visits during pregnancy are recommended for assessment of symptoms and pulmonary function. If symptoms are uncontrolled, therapy must be stepped up, and any trigger for exacerbation, such as gastroesophageal reflux disease (GERD), exposure, or rhinitis, must be treated and eliminated. NAEPP guidelines recommend baseline spirometry at the time of initial assessment.¹² At follow-up visits, spirometry is preferred, but measurement of the peak expiratory flow rate usually suffices. Such objective data can help differentiate dyspnea from asthma and from dyspnea that usually accompanies the physiologic changes of pregnancy. In addition, patients should be advised to monitor for adequate fetal activity. If asthma is uncontrolled or poorly controlled, serial fetal ultrasonography should be considered from 32 weeks of gestation, as well as after recovery from an asthma exacerbation. Regular monitoring of the pregnant asthmatic patient by a multidisciplinary team can improve outcomes.¹³

Avoiding triggers

Patients should be advised to avoid asthma triggers such as pet dander, dust mites, pollen, smoke, mold, and perfumes, as this can decrease symptoms and allow for use of lower doses of medications.¹² Additionally, smoking cessation must be strongly encouraged, not only to control maternal asthma, but also to prevent harm to the fetus.

MANAGEMENT OF SPECIFIC TRIGGERS

GERD

Reflux disease often worsens during pregnancy, and it can coexist with asthma and can also exacerbate it.¹⁴ Optimal control of GERD helps maintain adequate asthma control. For mild reflux symptoms, lifestyle modifications such as elevating the head of bed, avoiding eating too close to bedtime, and avoiding foods that cause heartburn may be adequate.^15,16 If medications are needed, antacids (but not sodium bicarbonate, for fear of metabolic alkalosis) and sucralfate should be considered before using a histamine 2 receptor antagonist such as ranitidine. Proton pump inhibitors should be considered only if reflux symptoms are refractory to other therapies.

Allergic rhinitis

Intranasal corticosteroids are effective against allergic rhinitis in pregnancy (Table 3).¹² Montelukast, a leukotriene receptor antagonist, can be used, but data to support its use for allergic rhinitis in pregnancy are limited.

Among antihistamines, second-generation drugs such as cetirizine or loratadine can be considered.¹² Oral decongestants such as pseudoephedrine in early pregnancy are associated with a rare congenital fetal abnormality called gastroschisis, caused by vascular disruption.¹⁷ Hence, if a nasal decongestant is required in early pregnancy, a local therapy such as an intranasal corticosteroid, short-term oxymetazoline, or an external nasal dilator may be considered.¹² These therapies must be combined with avoidance of allergens whenever possible.

Allergies

Diagnostic allergy and skin tests during pregnancy pose a risk of anaphylaxis and thus should be avoided. Instead, the focus should be on obtaining a thorough medical history about exposures and eliminating specific asthma triggers. It is also inadvisable to start allergen immunotherapy during pregnancy because of the risk of anaphylaxis and the effect of treatment on the mother and fetus.¹⁸ However, maintenance doses of allergen immunotherapy can be continued during pregnancy.¹⁸

Patient education

Because of concern about the risks of taking medications during pregnancy, many women with asthma stop using their inhalers during pregnancy, thus compromising asthma control.^8,13 The physician and multidisciplinary team must use every opportunity to emphasize the importance of good asthma control during pregnancy. Inhaler technique should also be reviewed and, if defective, corrected. Again, trigger avoidance and tobacco cessation should be addressed.

Drugs

The NAEPP recommendations state that asthma therapy should be continued during pregnancy, as it is safer both for mother and fetus to avoid exacerbations and uncontrolled asthma.¹² Despite this, 25% of primary care physicians instruct their patients to decrease or discontinue their inhaled corticosteroid during pregnancy.¹⁹ As with asthma in general, treatment should involve using the lowest dose of drugs that achieves adequate control of symptoms.

In 2015, the US Food and Drug Administration (FDA) amended the labeling rule for medications used in pregnancy and lactation. The previous risk categories A (safest), B, C, D, and X (highest risk) are in the process of being removed from labels for all human prescription drugs and biologic products, to be replaced with a summary of the risks of taking the drug during pregnancy and lactation, a discussion of the data supporting the use, and relevant information to help healthcare providers make prescribing decisions and counsel women about the use of drugs during pregnancy and lactation (www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/ucm093307.htm).

ROLES OF CONTROLLER THERAPY AND RESCUE THERAPY

Inhaled corticosteroids

Inhaled corticosteroids are the mainstay of asthma controller therapy during pregnancy. A meta-analysis of 16 studies showed no increased risk of congenital malformations, cesarean delivery, or stillbirth among mothers who used these agents during pregnancy.²⁰ Because there are more safety data for budesonide, it is currently the preferred inhaled corticosteroid during pregnancy.⁹ However, if a patient’s asthma is controlled with a different corticosteroid before pregnancy, that agent may be continued during pregnancy, especially if it is thought that switching formulations could adversely affect asthma control.¹² This is mainly because current data do not prove that other inhaled corticosteroids are unsafe.

Inhaled beta-agonists

Inhaled beta-agonists, both short-acting and long-acting, are used for rescue therapy. Al­buterol is the preferred short-acting agent for rescue therapy in pregnant women with asthma.¹² Meta-analysis has shown no increased risk of major or minor congenital malformations in pregnant patients who use bronchodilators.²⁰ Long-acting beta-agonists typically are used as add-on therapy when asthma cannot be controlled by an inhaled corticosteroid. They should not be used without a controller medication (ie, an inhaled corticosteroid).

Guidelines for rescue therapy are similar to those for nonpregnant asthmatic patients. Although data are limited as to the gestational effects of long-acting beta-agonists (ie, formoterol, salmeterol), it can be assumed that the toxicologic and pharmacologic profiles are similar to those of the short-acting bronchodilators. Thus, the safety of albuterol can be extended potentially to the long-acting beta-agonists.¹²

Combining controller and rescue therapy

When asthma is not adequately controlled on inhaled corticosteroids, a long-acting beta-agonist can be added or the dose of corticosteroid can be increased. The 2004 NAEPP guidelines stated that based on available literature, there was no clear advantage of one option over the other.¹² A study that compared the 2 approaches found no difference in rates of congenital malformations.²¹

Leukotriene receptor antagonists

There is little in the literature regarding the use of leukotriene receptor antagonists during pregnancy. However, animal safety data are reassuring,¹² and human studies have not found a higher risk of major congenital malformations.^22,23 Thus, they are an alternative for patients whose asthma has been well controlled on these agents before pregnancy. Montelukast and zafirlukast are in former FDA pregnancy risk factor category B (probably safe) (Table 3). However, 5-lipoxygenase inhibitors such as zileuton are contraindicated based on animal studies showing teratogenicity.²⁴

Omalizumab

Omalizumab, a recombinant anti-immunoglobulin E antibody, can be used for allergic asthma not controlled with inhaled corticosteroids (Table 3). An analysis of the omalizumab pregnancy registry²⁵ found no significant increase in the rate of major congenital malformations, prematurity, or babies small for gestational age in asthmatic women taking omalizumab 8 weeks before conception or during pregnancy vs pregnant asthmatic women not taking omalizumab. However, this drug carries a risk of anaphylaxis and so should not be started during pregnancy.²⁵

Theophylline

Because of potential toxicity, use of theophylline during pregnancy requires careful monitoring to ensure the serum concentration remains between 5 and 12 µg/mL.¹² Drug interactions are also common: for example, alcohol may increase the serum concentration of theophylline, and theophylline may increase the toxic effect of formoterol.

Systemic corticosteroids

Pregnant women with asthma that is not well controlled despite the therapies described above may require a daily oral corticosteroid such as prednisone to achieve adequate control. Oral steroids are also a mainstay of treatment of asthma exacerbation.

Although use of corticosteroids in the first trimester was associated with orofacial cleft in infants,¹² these studies did not include many women with asthma. In 2011, a nationwide cohort study from Denmark showed no increase in the risk of orofacial cleft with the use of corticosteroids during pregnancy.²⁶

Preeclampsia, low birth weight, and preterm delivery have been described with corticosteroid use in pregnancy. It is not known whether these problems were a result of corticosteroid use or were due to the uncontrolled nature of the underlying condition that led to the steroid use. Since the risk of uncontrolled asthma to mother and fetus outweighs the risk of systemic corticosteroids, these drugs are recommended when indicated for management of maternal asthma.¹²

ACUTE EXACERBATIONS REQUIRE AGGRESSIVE MANAGEMENT

Based on a systematic review, 20% of pregnant women with asthma require some intervention for an asthma exacerbation during pregnancy, and 5.8% are admitted to the hospital for an exacerbation.¹¹ Exacerbations were associated with a higher risk of low birth weight compared with rates in women without asthma.

Exacerbations are more common late in the second trimester and are unlikely to occur during labor and delivery.²  The incidence of exacerbations increases with the severity of asthma, from 8% in mild asthma, to 47% in moderate asthma, to 65% in severe asthma.²⁷ Risk factors for exacerbations include poor prenatal care, obesity, and lack of appropriate treatment with inhaled corticosteroids.² The main triggers are viral respiratory infections and noncompliance with inhaled corticosteroid therapy.¹¹

Asthma exacerbations during pregnancy should be managed aggressively (Table 4),¹² as the risk to the fetus of hypoxia far outweighs any risk from asthma medications. Close collaboration between the primary care physician and the obstetrician allows closer monitoring of mother and fetus.

The goal oxygen saturation must be above 95%.¹² Signs of acute respiratory failure in a pregnant patient include a partial pressure of arterial oxygen less than 70 mm Hg or a partial pressure of carbon dioxide greater than 35 mm Hg.

In a multicenter study comparing nonpregnant and pregnant women visiting the emergency room for asthma exacerbations,²⁸ pregnant women were less likely to be prescribed systemic corticosteroids either in the emergency room or at the time of hospital discharge, and they were also more likely to describe an ongoing exacerbation at 2-week follow-up. However, a recent study showed a significant increase in systemic corticosteroid treatment in the emergency room (51% to 78% across the time periods, odds ratio 3.11, 95% confidence interval 1.27–7.60, P = .01). There was also an increase in steroid treatment at discharge (42% to 63%, odds ratio 2.49, 95% confidence interval 0.97–6.37, P = .054), though the increase was not statistically significant.²⁹ Although emergency room care for pregnant asthmatic women has improved, this group concluded that further improvement is still warranted, as 1 in 3 women is discharged without corticosteroid treatment.

Helicobacter pylori infection is an infectious disease and should be treated like one, with due consideration of antibiotic resistance and stewardship.^1–4

This was the consensus of the 2015 Kyoto H pylori conference,² and it signaled a fundamental shift in thinking. Up to now, H pylori treatment has not been based on infectious disease principles, leading to suboptimal results and antibiotic resistance. In addition, the conference recommended that H pylori infection be treated whenever it is found unless there are compelling reasons not to.

Here we review current and possible future regimens for eradicating H pylori that we hope will be more effective and will lead to less resistance than in the past.

H PYLORI AS AN INFECTIOUS DISEASE

Not until the late 1980s was H pylori recognized as the cause of peptic ulcer disease, which until then accounted for hundreds of thousands of hospitalizations and more than 100,000 surgical procedures each year.⁵ Now, peptic ulcer disease is routinely treated by eradicating H pylori. In addition, the World Health Organization has recommended considering H pylori eradication to reduce the risk of gastric cancer,⁶ which causes 738,000 deaths worldwide per year.⁷

The problems of how to diagnose and treat H pylori infection were taken on by gastroenterologists, and not by specialists in infectious disease.¹ Even now, almost all the major reviews and consensus statements on H pylori come from gastroenterologists and are published in gastroenterology journals.^2,8,9

But infectious diseases differ from most gastrointestinal diseases. In gastrointestinal problems such as constipation or inflammatory bowel disease,¹⁰ the causes are generally unknown, and there is a large placebo response to therapy. In contrast, in infectious diseases, the cause is generally known, there is no placebo response, and treatment success depends on susceptibility of the organism. Failure of proven regimens is generally due to resistant organisms, poor adherence, or, in the case of H pylori, poorly designed regimens in terms of doses, frequency of administration, or duration of therapy.

The differences extend to clinical trials of treatment.³ In other infectious diseases, treatment is based on susceptibility. The usual comparative approach in infectious diseases is a noninferiority trial in which the new treatment is compared with standard care, ie, a regimen that reliably achieves nearly 100% cure rates. Not so with H pylori. Most trials of H pylori therapy compared regimens in populations with high but unknown prevalences of resistance and therefore are of limited or no help to the clinician in choosing the best regimen for an individual patient.³

Many thousands of H pylori-infected patients participated in clinical trials in which the results would have been predictable if the researchers had assessed susceptibility before giving the drugs.^11–13 Worse, many patients were also randomized to receive regimens that the investigators knew provided poor cure rates in the population being studied. This knowledge was generally not shared with the patients. This approach was used to demonstrate that a new regimen was superior to an old one, even though the new one was already known to be less affected by resistance to the key element in the comparator.

Clinicians generally do not test for susceptibility when treating H pylori, one reason being that such testing is often unavailable.³ However, almost every hospital, clinic, and major laboratory in the world provides susceptibility testing for other common local pathogens. H pylori is easy to grow, and laboratories could test for susceptibility if we asked them to.

Current H pylori recommendations may also contribute to the global increase in antimicrobal resistance.

As discussed below, all recent guidelines have recommended 4-drug non-bismuth-containing concomitant therapy as first-line therapy. An infectious disease colleague described it as a “hope therapy” because the prescriber hoped that the infection would be susceptible to either metronidazole or clarithromycin. All who receive this combination receive an antibiotic they do not need. This is an expedient rather than a medically rational choice resulting from failure to deal with H pylori as an infectious disease.

H PYLORI THERAPIES

Conceptually, treating infectious disease is straightforward: one should prescribe antimicrobial drugs to which the organism is susceptible³ (Table 1). However, clinical success lies in the details, which include the doses, frequency of doses, duration of therapy, timing of doses in relation to meals, and use of adjuvants such as antisecretory drugs, antacids, and probiotics. A number of regimens reliably yield high cure rates—95% or higher—if the organism is susceptible and the patients are adherent.

The effectiveness of any regimen may vary depending on the population it is used in, due to polymorphisms in drug-metabolizing enzymes such as CYP2C19.

Sequential therapy is obsolete

Sequential therapy for H pylori infection consisted of amoxicillin plus a proton pump inhibitor for 7 days, followed by clarithromycin, tinidazole, or metronidazole plus a proton pump inhibitor for a further 7 days. This regimen should not be used any more because concomitant therapy will always be superior (see below).

H pylori occupies a number of different niches in the body ranging from gastric mucus (which is technically outside the body) to inside gastric epithelial cells. As a general rule, 14-day therapy provides the best results, in part because the longer duration helps kill the organisms that persist in different niches.^14,15

In addition, proton pump inhibitors, which are part of all the currently recommended regimens, require 3 or more days to reach their full antisecretory effectiveness, which further limits the effectiveness of short-duration therapies.

Shorter regimens should be used only if they are proved to be as good as 14-day regimens and if both achieve 95% or greater cure rates with susceptible infections.

How to choose a therapy

Since rational infectious-disease therapy is based on susceptibility, one should start by considering the susceptibility pattern in the local population and, therefore, the likely susceptibility in the patient in front of us.

Unfortunately, we do not yet have local or regional susceptibility data on H pylori for most locales. Until those data are available, we must use the indirect information that is available, such as the patient’s history of antibiotic use.

Triple therapy should not be used empirically

Triple therapy (Table 1) consists of the combination of:

• Clarithromycin or metronidazole or a fluoroquinolone
• Amoxicillin
• A proton pump inhibitor.

However, prior use of a macrolide (eg, erythromycin, clarithromycin, or azithromycin), metronidazole, or a fluoroquinolone (eg, ciprofloxacin, levofloxacin) almost guarantees resistance to those drugs. In the United States, resistance to clarithromycin, metronidazole, levofloxacin, and related drugs is already widespread, and none should be used empirically in triple therapies. In contrast, amoxicillin, tetracycline, and furazolidone can often be used again, as resistance to them is rare even with prior use.

For example, 14 days of clarithromycin triple therapy (clarithromycin, amoxicillin, and a proton pump inhibitor) can be expected to cure more than 95% of patients who have susceptible infections and about 20% of those with resistant infections.¹⁶ This 20% is due to the proton pump inhibitor and amoxicillin, as the contribution to the cure rate from clarithromycin is close to zero.

If the prevalence of resistance to clarithromycin is 25%, the cure rate in the entire population will be a little more than 75%—97% in the 75% of the population with susceptible infections and 20% in patients who previously received clarithromycin (Figure 1).

Based on Graham DY. Hp-normogram (normo-graham) for assessing the outcome of H. pylori therapy: effect of resistance, duration, and CYP2C19 genotype. Helicobacter 2015; 21:85–90.

If we know that our patient has an infection that is susceptible to clarithromycin, metronidazole, or levofloxacin, good results could be achieved with triple therapy that includes a proton pump inhibitor, for 14 days. Fluoroquinolones have a number of black-box warnings from the US Food and Drug Administration (www.fda.gov/Drugs/DrugSafety/ucm500143.htm) and should always be a last choice. However, in the United States, lacking definite data about susceptibility to clarithromycin, metronidazole, and levofloxacin, we should assume resistance is present and use a 4-drug regimen (eg, concomitant therapy or bismuth quadruple therapy).

Concomitant therapy is preferred

Concomitant therapy is the combination of:

• Amoxicillin
• Metronidazole
• Clarithromycin
• A proton pump inhibitor.

Functionally, this is a combination of clarithromycin and metronidazole triple therapies, given simultaneously.¹⁷ The premise is that even though the prevalence of metronidazole resistance in the United States is high (20%–40%), and so is the prevalence of clarithromycin resistance (about 20%), the prevalence of resistance to both drugs at the same time is expected to be low (eg, 0.4 × 0.2 = 0.08, or 8%) unless the drugs had previously been used together, as in some older regimens that contained both. Thus, the metronidazole will kill the clarithromycin-resistant but metronidazole-susceptible strains, and the clarithromycin will kill the clarithromycin-susceptible, metronidazole-resistant strains. Only with dual resistant strains will this regimen fail (with a 20% cure rate due to the proton pump inhibitor and amoxicillin and a population cure rate of slightly more than 90%).

The downside of this highly recommended therapy is that all who receive it are getting an antibiotic that they don’t need, which is, in a global sense, inappropriate. In other words, all those who are cured by clarithromycin also receive metronidazole, which plays no role in treatment success, and those cured by metronidazole receive unneeded clarithromycin (Figure 2). Had susceptibility testing been available, those with susceptible strains would have received appropriate triple therapies, and those with dual resistance would not have received either antibiotic.

Thus, while we recommend concomitant therapy as an empiric regimen in populations that do not have high levels of resistance to metronidazole or clarithromycin (as those would also have a high prevalence of dual resistance), one must be aware of the “dirty little secret” of inappropriate antibiotic use that accompanies it and some other H pylori therapies (eg, vonoprazan triple therapy in Japan).^18–20

Bismuth quadruple therapy (Table 1) consists of:

• Bismuth
• Tetracycline
• Metronidazole
• A proton pump inhibitor.

This was the first truly effective regimen for H pylori. Its advantage is that it can partially or completely overcome metronidazole resistance.^21,22 As such, it is potentially ideal, as it should be effective despite resistance to clarithromycin, metronidazole, or levofloxacin, and it can be used in patients allergic to penicillin.

The major downside is a high frequency of side effects, particularly abdominal pain, nausea, and vomiting, often resulting in poor adherence. Most regimens that contain antibiotics have side effects, but adherence seems to be more of a problem with bismuth quadruple therapy, probably because of the combination of the high doses of metronidazole and tetracycline.²² In our experience, this regimen can be effective if the physician takes the time to explain to the patient that side effects are common but treatment success depends on completing the full course of 14 days.

Another problem is that tetracycline has become difficult to obtain in many areas, and doxycycline cannot be substituted in those with metronidazole resistance. To date, it has been difficult or impossible to obtain the same excellent results with doxycycline as can be obtained with tetracycline. It is not clear why.²¹

To use bismuth quadruple therapy one must often use a name-brand product, Pylera. Pylera is packaged as a 10-day course, which is effective against metronidazole-susceptible infections. However, 14 days are generally required to achieve a high cure rate with metronidazole-resistant infections, which are the main indication for use of this product. Moreover, Pylera does not include a proton pump inhibitor, which must be prescribed separately.

In the United States, Pylera is expensive, costing $740 to $790 with a coupon for a 10-day supply and proportionally more for the required 14-day supply (www.goodrx.com/pylera?drug-name=pylera), whereas in Europe it costs less than 70 Euros ($73).²¹ If generic tetracycline is available, the US cost for 14 days of generic bismuth quadruple therapy is less than $50.

An alternate and simpler approach is to substitute amoxicillin for tetracycline.²³ This regimen has been used successfully in China and was shown to be noninferior to the tetracycline-containing regimen in a head-to-head comparison.²⁴

Recent studies have confirmed earlier Italian studies suggesting that twice-a-day bismuth and tetracycline is effective, which would further simplify therapy and possibly reduce side effects.^21,23,24 These variations on bismuth quadruple therapy have not yet been optimized to where one can reliably achieve 95% or greater cure rates, and further studies are needed.

Why include more than 1 antibiotic?

The H pylori load in the stomach is typically large, which increases the odds that a subpopulation of resistant organisms is present. Resistance may be due to a relatively high rate of mutation in certain bacterial genes.²⁵ This is particularly a problem with clarithromycin, metronidazole, and fluoroquinolones and is reflected in a high rate of resistance among patients for whom single-drug regimens have failed. These drugs are always given with a second antimicrobial to which H pylori rarely becomes resistant, such as amoxicillin or tetracycline.

Why include a proton pump inhibitor?

An antisecretory drug is needed to increase the gastric pH, which makes antimicrobial therapy more effective. It also decreases antibiotic washout from the stomach and likely protects and increases the gastric concentration of some antibiotics.

The activities of amoxicillin, fluoroquinolones, and to a lesser degree clarithromycin are pH-dependent. For example, keeping the gastric pH above 6.0 promotes H pylori replication,^26,27 making it is more susceptible to amoxicillin (reviewed in detail by Dore et al²¹). A gastric pH of 6.0 or more is very difficult to achieve with proton pump inhibitors, and has been accomplished regularly only in people who metabolize these drugs slowly (“slow metabolizers”) who received both the proton pump inhibitor and amoxicillin every 6 hours for 14 days.²¹

With standard clarithromycin, metronidazole, or fluoroquinolone triple therapy, proton pump inhibitors appear to provide satisfactory cure rates when given for 14 days in standard doses. However, double doses (eg, 40 mg of omeprazole or an equivalent) may be slightly better, especially in the presence of resistance.

The cure rate reflects the sum of the 2 populations of organisms: the susceptible and the resistant. In triple therapy, increasing the gastric pH with a proton pump inhibitor makes the amoxicillin component of the regimen more effective against resistant organisms and thus increases the cure rate. For example, in Western countries, esomeprazole  40 mg (approximately equivalent to rabeprazole 40 mg, omeprazole or lansoprazole 60 mg, or pantoprazole 240 mg)²⁸ given twice a day in a 14-day triple therapy regimen cures about 40% to 50% of resistant infections. This benefit will be evident in an improvement in cure rates in populations in which resistance has reduced the average cure rate. This is also why meta-analyses have shown better results with second-generation proton pump inhibitors and with longer duration of therapy.^29,30

Generally, we recommend omeprazole 40 mg twice a day or an equivalent (Tables 1–3).

Would a potassium-competitive acid blocker be better than a proton pump inhibitor?

Vonoprazan is a potassium-competitive acid blocker. It does not require intermediate complex formation and is stable at low pH. It has a longer half-life than proton pump inhibitors, and its bioavailability is unaffected by food.³¹ It was recently approved in Japan for H pylori eradication in combination with clarithromycin or metronidazole plus amoxicillin.¹⁸

Vonoprazan is more effective than current proton pump inhibitors for keeping the gastric pH high. There are no published studies of vonoprazan dual therapy in Western countries, but given twice a day for 7 days along with twice-daily amoxicillin it cured only approximately 80% of clarithromycin-resistant strains. Further studies are needed to identify the optimum proton pump inhibitor or potassium-competitive acid blocker, dose, and duration.

In triple therapy, the second antimicrobial drug (eg, amoxicillin) is given in part to prevent resistance from developing. It is not clear whether the combination is additive or synergistic, but until we can reliably maintain the intragastric pH above 6.0, which would increase the effectiveness of the amoxicillin component of the regimen, this practice cannot be considered as misuse of antibiotics.

In contrast, in the 4-drug nonbismuth combinations (concomitant, sequential, and hybrid therapies) and the new vonoprazan, clarithromycin, and metronidazole triple therapies, 1 of the antibiotics provides no benefit to some, often most, of the patients.^18–20,32 This practice should end when susceptibility data become more widely available and when vonoprazan becomes available, so that we can deliver effective vonoprazan-amoxicillin dual therapy.

First-, second-, and third-line therapies

Many recommendations give advice in terms of first-, second-, and third-line therapies. In practice, a physician should have at least 2 first-line regimens (a first and a second choice). Both should be proven highly successful as empiric therapies in one’s patient population but differ in terms of primary antibiotics. This approach allows the clinician to tailor therapy depending on whether he or she suspects antibiotic resistance (eg, if the patient has taken clarithromycin before) or the patient is allergic or cannot take 1 or more drugs.

Two treatment failures with 2 different regimens known to be effective suggest poor compliance (a difficult patient) or a multiple-drug-resistant infection (a difficult infection). That patient would require salvage therapy (Table 2), which logically should be based on antimicrobial testing or, at a minimum, consultation with someone who frequently deals with this problem.

Test of cure

Monitoring the outcome of therapy (testing for cure) is essential, as it provides a reliable measure of the local effectiveness of particular therapies and also serves as an early warning of development of resistance in one’s patient population.¹⁴

Unless there are compelling reasons, testing for cure should use noninvasive testing with the urea breath test or stool antigen test. It is recommended that this be delayed at least 4 weeks to allow the organisms if still present to repopulate the stomach sufficiently for the tests to become positive. Because antibiotics, bismuth, and proton pump inhibitors reduce the bacterial load, they should be withheld at least 2 weeks before testing. Histamine-2 receptor antagonists can be substituted for proton pump inhibitors if antisecretory therapy is needed for symptoms, and continued up to the day before testing. The urea breath test should contain citric acid to overcome any residual pH effects. Physician groups should share their experience so as to alert the community about which therapies should likely be avoided.³³

Salvage therapy

Salvage therapy is given after 2 or more treatment failures with different antibiotics. Ideally, the regimen should be based on the results of antimicrobial testing. Current regimens include rifabutin triple therapy, dual therapy (a protein pump inhibitor or vonoprazan and amoxicillin), or furazolidone quadruple therapy (Table 2).

Furazolidone is a synthetic nitrofuran derivative that is effective against many enteric organisms, including gram-negative bacteria and protozoa. It is not available in most Western countries but is available in many other parts of the world.^34,35 It is also a monoamine oxidase inhibitor and thus interacts with many drugs and foods (eg, soy sauce, aged cheeses), leading to a relatively high rate of side effects such as fever, palpitations, and skin rash.

Rifabutin-containing regimens, generally, a proton pump inhibitor, amoxicillin 1 g, and rifabutin 150 mg, all twice a day (Table 3) provide average cure rates of less than 80% (typically in the mid-70% range).³⁶ Borody et al³⁷ reported greater than 95% success with a 12-day regimen consisting of rifabutin 150 mg once daily (half-dose), amoxicillin 1.5 g 3 times a day, and pantoprazole 80 mg (approximately equivalent to omeprazole 20 mg) 3 times a day. Ciccaglione et al,³⁸ in a small study, used a 10-day quadruple regimen containing a proton pump inhibitor, amoxicillin, rifabutin, and bismuth (all twice a day), with high cure rates. The results of these studies are yet to be confirmed, and the optimal rifabutin-containing regimen remains to be determined.

PROBIOTICS

There is considerable interest in using probiotics to enhance the effectiveness of antimicrobial therapy for H pylori by increasing tolerability, reducing side effects, and therefore improving compliance.^39,40

In a meta-analysis of 14 randomized trials (N = 1,671), when probiotics were added, pooled H pylori eradication rates were only slightly improved: 83.6% (95% CI 80.5%–86.7%) with probiotics and 74.8% (95% CI 71.1%–78.5%) without probiotics by intent-to-treat analysis.⁴¹

Another meta-analysis of probiotics suggested that those containing Saccharomyces boulardii, Lactobacillus, and Bifidobacterium significantly increased the eradication rate of triple therapy in populations with high rates of antimicrobial resistance and reduced the risk of overall H pylori therapy-related adverse effects, especially diarrhea.^42,43

At present, we recommend that probiotics be considered only for patients who are likely not to comply with treatment (eg, those with irritable bowel syndrome or difficulty taking antibiotics), to try to take advantage of their ability to improve antibiotic tolerability.

Helicobacter pylori infection is an infectious disease and should be treated like one, with due consideration of antibiotic resistance and stewardship.^1–4

This was the consensus of the 2015 Kyoto H pylori conference,² and it signaled a fundamental shift in thinking. Up to now, H pylori treatment has not been based on infectious disease principles, leading to suboptimal results and antibiotic resistance. In addition, the conference recommended that H pylori infection be treated whenever it is found unless there are compelling reasons not to.

Here we review current and possible future regimens for eradicating H pylori that we hope will be more effective and will lead to less resistance than in the past.

H PYLORI AS AN INFECTIOUS DISEASE

Not until the late 1980s was H pylori recognized as the cause of peptic ulcer disease, which until then accounted for hundreds of thousands of hospitalizations and more than 100,000 surgical procedures each year.⁵ Now, peptic ulcer disease is routinely treated by eradicating H pylori. In addition, the World Health Organization has recommended considering H pylori eradication to reduce the risk of gastric cancer,⁶ which causes 738,000 deaths worldwide per year.⁷

The problems of how to diagnose and treat H pylori infection were taken on by gastroenterologists, and not by specialists in infectious disease.¹ Even now, almost all the major reviews and consensus statements on H pylori come from gastroenterologists and are published in gastroenterology journals.^2,8,9

But infectious diseases differ from most gastrointestinal diseases. In gastrointestinal problems such as constipation or inflammatory bowel disease,¹⁰ the causes are generally unknown, and there is a large placebo response to therapy. In contrast, in infectious diseases, the cause is generally known, there is no placebo response, and treatment success depends on susceptibility of the organism. Failure of proven regimens is generally due to resistant organisms, poor adherence, or, in the case of H pylori, poorly designed regimens in terms of doses, frequency of administration, or duration of therapy.

The differences extend to clinical trials of treatment.³ In other infectious diseases, treatment is based on susceptibility. The usual comparative approach in infectious diseases is a noninferiority trial in which the new treatment is compared with standard care, ie, a regimen that reliably achieves nearly 100% cure rates. Not so with H pylori. Most trials of H pylori therapy compared regimens in populations with high but unknown prevalences of resistance and therefore are of limited or no help to the clinician in choosing the best regimen for an individual patient.³

Many thousands of H pylori-infected patients participated in clinical trials in which the results would have been predictable if the researchers had assessed susceptibility before giving the drugs.^11–13 Worse, many patients were also randomized to receive regimens that the investigators knew provided poor cure rates in the population being studied. This knowledge was generally not shared with the patients. This approach was used to demonstrate that a new regimen was superior to an old one, even though the new one was already known to be less affected by resistance to the key element in the comparator.

Clinicians generally do not test for susceptibility when treating H pylori, one reason being that such testing is often unavailable.³ However, almost every hospital, clinic, and major laboratory in the world provides susceptibility testing for other common local pathogens. H pylori is easy to grow, and laboratories could test for susceptibility if we asked them to.

Current H pylori recommendations may also contribute to the global increase in antimicrobal resistance.

As discussed below, all recent guidelines have recommended 4-drug non-bismuth-containing concomitant therapy as first-line therapy. An infectious disease colleague described it as a “hope therapy” because the prescriber hoped that the infection would be susceptible to either metronidazole or clarithromycin. All who receive this combination receive an antibiotic they do not need. This is an expedient rather than a medically rational choice resulting from failure to deal with H pylori as an infectious disease.

H PYLORI THERAPIES

Conceptually, treating infectious disease is straightforward: one should prescribe antimicrobial drugs to which the organism is susceptible³ (Table 1). However, clinical success lies in the details, which include the doses, frequency of doses, duration of therapy, timing of doses in relation to meals, and use of adjuvants such as antisecretory drugs, antacids, and probiotics. A number of regimens reliably yield high cure rates—95% or higher—if the organism is susceptible and the patients are adherent.

The effectiveness of any regimen may vary depending on the population it is used in, due to polymorphisms in drug-metabolizing enzymes such as CYP2C19.

Sequential therapy is obsolete

Sequential therapy for H pylori infection consisted of amoxicillin plus a proton pump inhibitor for 7 days, followed by clarithromycin, tinidazole, or metronidazole plus a proton pump inhibitor for a further 7 days. This regimen should not be used any more because concomitant therapy will always be superior (see below).

H pylori occupies a number of different niches in the body ranging from gastric mucus (which is technically outside the body) to inside gastric epithelial cells. As a general rule, 14-day therapy provides the best results, in part because the longer duration helps kill the organisms that persist in different niches.^14,15

In addition, proton pump inhibitors, which are part of all the currently recommended regimens, require 3 or more days to reach their full antisecretory effectiveness, which further limits the effectiveness of short-duration therapies.

Shorter regimens should be used only if they are proved to be as good as 14-day regimens and if both achieve 95% or greater cure rates with susceptible infections.

How to choose a therapy

Since rational infectious-disease therapy is based on susceptibility, one should start by considering the susceptibility pattern in the local population and, therefore, the likely susceptibility in the patient in front of us.

Unfortunately, we do not yet have local or regional susceptibility data on H pylori for most locales. Until those data are available, we must use the indirect information that is available, such as the patient’s history of antibiotic use.

Triple therapy should not be used empirically

Triple therapy (Table 1) consists of the combination of:

• Clarithromycin or metronidazole or a fluoroquinolone
• Amoxicillin
• A proton pump inhibitor.

However, prior use of a macrolide (eg, erythromycin, clarithromycin, or azithromycin), metronidazole, or a fluoroquinolone (eg, ciprofloxacin, levofloxacin) almost guarantees resistance to those drugs. In the United States, resistance to clarithromycin, metronidazole, levofloxacin, and related drugs is already widespread, and none should be used empirically in triple therapies. In contrast, amoxicillin, tetracycline, and furazolidone can often be used again, as resistance to them is rare even with prior use.

For example, 14 days of clarithromycin triple therapy (clarithromycin, amoxicillin, and a proton pump inhibitor) can be expected to cure more than 95% of patients who have susceptible infections and about 20% of those with resistant infections.¹⁶ This 20% is due to the proton pump inhibitor and amoxicillin, as the contribution to the cure rate from clarithromycin is close to zero.

If the prevalence of resistance to clarithromycin is 25%, the cure rate in the entire population will be a little more than 75%—97% in the 75% of the population with susceptible infections and 20% in patients who previously received clarithromycin (Figure 1).

Based on Graham DY. Hp-normogram (normo-graham) for assessing the outcome of H. pylori therapy: effect of resistance, duration, and CYP2C19 genotype. Helicobacter 2015; 21:85–90.

If we know that our patient has an infection that is susceptible to clarithromycin, metronidazole, or levofloxacin, good results could be achieved with triple therapy that includes a proton pump inhibitor, for 14 days. Fluoroquinolones have a number of black-box warnings from the US Food and Drug Administration (www.fda.gov/Drugs/DrugSafety/ucm500143.htm) and should always be a last choice. However, in the United States, lacking definite data about susceptibility to clarithromycin, metronidazole, and levofloxacin, we should assume resistance is present and use a 4-drug regimen (eg, concomitant therapy or bismuth quadruple therapy).

Concomitant therapy is preferred

Concomitant therapy is the combination of:

• Amoxicillin
• Metronidazole
• Clarithromycin
• A proton pump inhibitor.

Functionally, this is a combination of clarithromycin and metronidazole triple therapies, given simultaneously.¹⁷ The premise is that even though the prevalence of metronidazole resistance in the United States is high (20%–40%), and so is the prevalence of clarithromycin resistance (about 20%), the prevalence of resistance to both drugs at the same time is expected to be low (eg, 0.4 × 0.2 = 0.08, or 8%) unless the drugs had previously been used together, as in some older regimens that contained both. Thus, the metronidazole will kill the clarithromycin-resistant but metronidazole-susceptible strains, and the clarithromycin will kill the clarithromycin-susceptible, metronidazole-resistant strains. Only with dual resistant strains will this regimen fail (with a 20% cure rate due to the proton pump inhibitor and amoxicillin and a population cure rate of slightly more than 90%).

The downside of this highly recommended therapy is that all who receive it are getting an antibiotic that they don’t need, which is, in a global sense, inappropriate. In other words, all those who are cured by clarithromycin also receive metronidazole, which plays no role in treatment success, and those cured by metronidazole receive unneeded clarithromycin (Figure 2). Had susceptibility testing been available, those with susceptible strains would have received appropriate triple therapies, and those with dual resistance would not have received either antibiotic.

Thus, while we recommend concomitant therapy as an empiric regimen in populations that do not have high levels of resistance to metronidazole or clarithromycin (as those would also have a high prevalence of dual resistance), one must be aware of the “dirty little secret” of inappropriate antibiotic use that accompanies it and some other H pylori therapies (eg, vonoprazan triple therapy in Japan).^18–20

Bismuth quadruple therapy (Table 1) consists of:

• Bismuth
• Tetracycline
• Metronidazole
• A proton pump inhibitor.

This was the first truly effective regimen for H pylori. Its advantage is that it can partially or completely overcome metronidazole resistance.^21,22 As such, it is potentially ideal, as it should be effective despite resistance to clarithromycin, metronidazole, or levofloxacin, and it can be used in patients allergic to penicillin.

The major downside is a high frequency of side effects, particularly abdominal pain, nausea, and vomiting, often resulting in poor adherence. Most regimens that contain antibiotics have side effects, but adherence seems to be more of a problem with bismuth quadruple therapy, probably because of the combination of the high doses of metronidazole and tetracycline.²² In our experience, this regimen can be effective if the physician takes the time to explain to the patient that side effects are common but treatment success depends on completing the full course of 14 days.

Another problem is that tetracycline has become difficult to obtain in many areas, and doxycycline cannot be substituted in those with metronidazole resistance. To date, it has been difficult or impossible to obtain the same excellent results with doxycycline as can be obtained with tetracycline. It is not clear why.²¹

To use bismuth quadruple therapy one must often use a name-brand product, Pylera. Pylera is packaged as a 10-day course, which is effective against metronidazole-susceptible infections. However, 14 days are generally required to achieve a high cure rate with metronidazole-resistant infections, which are the main indication for use of this product. Moreover, Pylera does not include a proton pump inhibitor, which must be prescribed separately.

In the United States, Pylera is expensive, costing $740 to $790 with a coupon for a 10-day supply and proportionally more for the required 14-day supply (www.goodrx.com/pylera?drug-name=pylera), whereas in Europe it costs less than 70 Euros ($73).²¹ If generic tetracycline is available, the US cost for 14 days of generic bismuth quadruple therapy is less than $50.

An alternate and simpler approach is to substitute amoxicillin for tetracycline.²³ This regimen has been used successfully in China and was shown to be noninferior to the tetracycline-containing regimen in a head-to-head comparison.²⁴

Recent studies have confirmed earlier Italian studies suggesting that twice-a-day bismuth and tetracycline is effective, which would further simplify therapy and possibly reduce side effects.^21,23,24 These variations on bismuth quadruple therapy have not yet been optimized to where one can reliably achieve 95% or greater cure rates, and further studies are needed.

Why include more than 1 antibiotic?

The H pylori load in the stomach is typically large, which increases the odds that a subpopulation of resistant organisms is present. Resistance may be due to a relatively high rate of mutation in certain bacterial genes.²⁵ This is particularly a problem with clarithromycin, metronidazole, and fluoroquinolones and is reflected in a high rate of resistance among patients for whom single-drug regimens have failed. These drugs are always given with a second antimicrobial to which H pylori rarely becomes resistant, such as amoxicillin or tetracycline.

Why include a proton pump inhibitor?

An antisecretory drug is needed to increase the gastric pH, which makes antimicrobial therapy more effective. It also decreases antibiotic washout from the stomach and likely protects and increases the gastric concentration of some antibiotics.

The activities of amoxicillin, fluoroquinolones, and to a lesser degree clarithromycin are pH-dependent. For example, keeping the gastric pH above 6.0 promotes H pylori replication,^26,27 making it is more susceptible to amoxicillin (reviewed in detail by Dore et al²¹). A gastric pH of 6.0 or more is very difficult to achieve with proton pump inhibitors, and has been accomplished regularly only in people who metabolize these drugs slowly (“slow metabolizers”) who received both the proton pump inhibitor and amoxicillin every 6 hours for 14 days.²¹

With standard clarithromycin, metronidazole, or fluoroquinolone triple therapy, proton pump inhibitors appear to provide satisfactory cure rates when given for 14 days in standard doses. However, double doses (eg, 40 mg of omeprazole or an equivalent) may be slightly better, especially in the presence of resistance.

The cure rate reflects the sum of the 2 populations of organisms: the susceptible and the resistant. In triple therapy, increasing the gastric pH with a proton pump inhibitor makes the amoxicillin component of the regimen more effective against resistant organisms and thus increases the cure rate. For example, in Western countries, esomeprazole  40 mg (approximately equivalent to rabeprazole 40 mg, omeprazole or lansoprazole 60 mg, or pantoprazole 240 mg)²⁸ given twice a day in a 14-day triple therapy regimen cures about 40% to 50% of resistant infections. This benefit will be evident in an improvement in cure rates in populations in which resistance has reduced the average cure rate. This is also why meta-analyses have shown better results with second-generation proton pump inhibitors and with longer duration of therapy.^29,30

Generally, we recommend omeprazole 40 mg twice a day or an equivalent (Tables 1–3).

Would a potassium-competitive acid blocker be better than a proton pump inhibitor?

Vonoprazan is a potassium-competitive acid blocker. It does not require intermediate complex formation and is stable at low pH. It has a longer half-life than proton pump inhibitors, and its bioavailability is unaffected by food.³¹ It was recently approved in Japan for H pylori eradication in combination with clarithromycin or metronidazole plus amoxicillin.¹⁸

Vonoprazan is more effective than current proton pump inhibitors for keeping the gastric pH high. There are no published studies of vonoprazan dual therapy in Western countries, but given twice a day for 7 days along with twice-daily amoxicillin it cured only approximately 80% of clarithromycin-resistant strains. Further studies are needed to identify the optimum proton pump inhibitor or potassium-competitive acid blocker, dose, and duration.

In triple therapy, the second antimicrobial drug (eg, amoxicillin) is given in part to prevent resistance from developing. It is not clear whether the combination is additive or synergistic, but until we can reliably maintain the intragastric pH above 6.0, which would increase the effectiveness of the amoxicillin component of the regimen, this practice cannot be considered as misuse of antibiotics.

In contrast, in the 4-drug nonbismuth combinations (concomitant, sequential, and hybrid therapies) and the new vonoprazan, clarithromycin, and metronidazole triple therapies, 1 of the antibiotics provides no benefit to some, often most, of the patients.^18–20,32 This practice should end when susceptibility data become more widely available and when vonoprazan becomes available, so that we can deliver effective vonoprazan-amoxicillin dual therapy.

First-, second-, and third-line therapies

Many recommendations give advice in terms of first-, second-, and third-line therapies. In practice, a physician should have at least 2 first-line regimens (a first and a second choice). Both should be proven highly successful as empiric therapies in one’s patient population but differ in terms of primary antibiotics. This approach allows the clinician to tailor therapy depending on whether he or she suspects antibiotic resistance (eg, if the patient has taken clarithromycin before) or the patient is allergic or cannot take 1 or more drugs.

Two treatment failures with 2 different regimens known to be effective suggest poor compliance (a difficult patient) or a multiple-drug-resistant infection (a difficult infection). That patient would require salvage therapy (Table 2), which logically should be based on antimicrobial testing or, at a minimum, consultation with someone who frequently deals with this problem.

Test of cure

Monitoring the outcome of therapy (testing for cure) is essential, as it provides a reliable measure of the local effectiveness of particular therapies and also serves as an early warning of development of resistance in one’s patient population.¹⁴

Unless there are compelling reasons, testing for cure should use noninvasive testing with the urea breath test or stool antigen test. It is recommended that this be delayed at least 4 weeks to allow the organisms if still present to repopulate the stomach sufficiently for the tests to become positive. Because antibiotics, bismuth, and proton pump inhibitors reduce the bacterial load, they should be withheld at least 2 weeks before testing. Histamine-2 receptor antagonists can be substituted for proton pump inhibitors if antisecretory therapy is needed for symptoms, and continued up to the day before testing. The urea breath test should contain citric acid to overcome any residual pH effects. Physician groups should share their experience so as to alert the community about which therapies should likely be avoided.³³

Salvage therapy

Salvage therapy is given after 2 or more treatment failures with different antibiotics. Ideally, the regimen should be based on the results of antimicrobial testing. Current regimens include rifabutin triple therapy, dual therapy (a protein pump inhibitor or vonoprazan and amoxicillin), or furazolidone quadruple therapy (Table 2).

Furazolidone is a synthetic nitrofuran derivative that is effective against many enteric organisms, including gram-negative bacteria and protozoa. It is not available in most Western countries but is available in many other parts of the world.^34,35 It is also a monoamine oxidase inhibitor and thus interacts with many drugs and foods (eg, soy sauce, aged cheeses), leading to a relatively high rate of side effects such as fever, palpitations, and skin rash.

Rifabutin-containing regimens, generally, a proton pump inhibitor, amoxicillin 1 g, and rifabutin 150 mg, all twice a day (Table 3) provide average cure rates of less than 80% (typically in the mid-70% range).³⁶ Borody et al³⁷ reported greater than 95% success with a 12-day regimen consisting of rifabutin 150 mg once daily (half-dose), amoxicillin 1.5 g 3 times a day, and pantoprazole 80 mg (approximately equivalent to omeprazole 20 mg) 3 times a day. Ciccaglione et al,³⁸ in a small study, used a 10-day quadruple regimen containing a proton pump inhibitor, amoxicillin, rifabutin, and bismuth (all twice a day), with high cure rates. The results of these studies are yet to be confirmed, and the optimal rifabutin-containing regimen remains to be determined.

PROBIOTICS

There is considerable interest in using probiotics to enhance the effectiveness of antimicrobial therapy for H pylori by increasing tolerability, reducing side effects, and therefore improving compliance.^39,40

In a meta-analysis of 14 randomized trials (N = 1,671), when probiotics were added, pooled H pylori eradication rates were only slightly improved: 83.6% (95% CI 80.5%–86.7%) with probiotics and 74.8% (95% CI 71.1%–78.5%) without probiotics by intent-to-treat analysis.⁴¹

Another meta-analysis of probiotics suggested that those containing Saccharomyces boulardii, Lactobacillus, and Bifidobacterium significantly increased the eradication rate of triple therapy in populations with high rates of antimicrobial resistance and reduced the risk of overall H pylori therapy-related adverse effects, especially diarrhea.^42,43

At present, we recommend that probiotics be considered only for patients who are likely not to comply with treatment (eg, those with irritable bowel syndrome or difficulty taking antibiotics), to try to take advantage of their ability to improve antibiotic tolerability.

Helicobacter pylori infection is an infectious disease and should be treated like one, with due consideration of antibiotic resistance and stewardship.^1–4

This was the consensus of the 2015 Kyoto H pylori conference,² and it signaled a fundamental shift in thinking. Up to now, H pylori treatment has not been based on infectious disease principles, leading to suboptimal results and antibiotic resistance. In addition, the conference recommended that H pylori infection be treated whenever it is found unless there are compelling reasons not to.

Here we review current and possible future regimens for eradicating H pylori that we hope will be more effective and will lead to less resistance than in the past.

H PYLORI AS AN INFECTIOUS DISEASE

Not until the late 1980s was H pylori recognized as the cause of peptic ulcer disease, which until then accounted for hundreds of thousands of hospitalizations and more than 100,000 surgical procedures each year.⁵ Now, peptic ulcer disease is routinely treated by eradicating H pylori. In addition, the World Health Organization has recommended considering H pylori eradication to reduce the risk of gastric cancer,⁶ which causes 738,000 deaths worldwide per year.⁷

The problems of how to diagnose and treat H pylori infection were taken on by gastroenterologists, and not by specialists in infectious disease.¹ Even now, almost all the major reviews and consensus statements on H pylori come from gastroenterologists and are published in gastroenterology journals.^2,8,9

But infectious diseases differ from most gastrointestinal diseases. In gastrointestinal problems such as constipation or inflammatory bowel disease,¹⁰ the causes are generally unknown, and there is a large placebo response to therapy. In contrast, in infectious diseases, the cause is generally known, there is no placebo response, and treatment success depends on susceptibility of the organism. Failure of proven regimens is generally due to resistant organisms, poor adherence, or, in the case of H pylori, poorly designed regimens in terms of doses, frequency of administration, or duration of therapy.

The differences extend to clinical trials of treatment.³ In other infectious diseases, treatment is based on susceptibility. The usual comparative approach in infectious diseases is a noninferiority trial in which the new treatment is compared with standard care, ie, a regimen that reliably achieves nearly 100% cure rates. Not so with H pylori. Most trials of H pylori therapy compared regimens in populations with high but unknown prevalences of resistance and therefore are of limited or no help to the clinician in choosing the best regimen for an individual patient.³

Many thousands of H pylori-infected patients participated in clinical trials in which the results would have been predictable if the researchers had assessed susceptibility before giving the drugs.^11–13 Worse, many patients were also randomized to receive regimens that the investigators knew provided poor cure rates in the population being studied. This knowledge was generally not shared with the patients. This approach was used to demonstrate that a new regimen was superior to an old one, even though the new one was already known to be less affected by resistance to the key element in the comparator.

Clinicians generally do not test for susceptibility when treating H pylori, one reason being that such testing is often unavailable.³ However, almost every hospital, clinic, and major laboratory in the world provides susceptibility testing for other common local pathogens. H pylori is easy to grow, and laboratories could test for susceptibility if we asked them to.

Current H pylori recommendations may also contribute to the global increase in antimicrobal resistance.

As discussed below, all recent guidelines have recommended 4-drug non-bismuth-containing concomitant therapy as first-line therapy. An infectious disease colleague described it as a “hope therapy” because the prescriber hoped that the infection would be susceptible to either metronidazole or clarithromycin. All who receive this combination receive an antibiotic they do not need. This is an expedient rather than a medically rational choice resulting from failure to deal with H pylori as an infectious disease.

H PYLORI THERAPIES

Conceptually, treating infectious disease is straightforward: one should prescribe antimicrobial drugs to which the organism is susceptible³ (Table 1). However, clinical success lies in the details, which include the doses, frequency of doses, duration of therapy, timing of doses in relation to meals, and use of adjuvants such as antisecretory drugs, antacids, and probiotics. A number of regimens reliably yield high cure rates—95% or higher—if the organism is susceptible and the patients are adherent.

The effectiveness of any regimen may vary depending on the population it is used in, due to polymorphisms in drug-metabolizing enzymes such as CYP2C19.

Sequential therapy is obsolete

Sequential therapy for H pylori infection consisted of amoxicillin plus a proton pump inhibitor for 7 days, followed by clarithromycin, tinidazole, or metronidazole plus a proton pump inhibitor for a further 7 days. This regimen should not be used any more because concomitant therapy will always be superior (see below).

H pylori occupies a number of different niches in the body ranging from gastric mucus (which is technically outside the body) to inside gastric epithelial cells. As a general rule, 14-day therapy provides the best results, in part because the longer duration helps kill the organisms that persist in different niches.^14,15

In addition, proton pump inhibitors, which are part of all the currently recommended regimens, require 3 or more days to reach their full antisecretory effectiveness, which further limits the effectiveness of short-duration therapies.

Shorter regimens should be used only if they are proved to be as good as 14-day regimens and if both achieve 95% or greater cure rates with susceptible infections.

How to choose a therapy

Since rational infectious-disease therapy is based on susceptibility, one should start by considering the susceptibility pattern in the local population and, therefore, the likely susceptibility in the patient in front of us.

Unfortunately, we do not yet have local or regional susceptibility data on H pylori for most locales. Until those data are available, we must use the indirect information that is available, such as the patient’s history of antibiotic use.

Triple therapy should not be used empirically

Triple therapy (Table 1) consists of the combination of:

• Clarithromycin or metronidazole or a fluoroquinolone
• Amoxicillin
• A proton pump inhibitor.

However, prior use of a macrolide (eg, erythromycin, clarithromycin, or azithromycin), metronidazole, or a fluoroquinolone (eg, ciprofloxacin, levofloxacin) almost guarantees resistance to those drugs. In the United States, resistance to clarithromycin, metronidazole, levofloxacin, and related drugs is already widespread, and none should be used empirically in triple therapies. In contrast, amoxicillin, tetracycline, and furazolidone can often be used again, as resistance to them is rare even with prior use.

For example, 14 days of clarithromycin triple therapy (clarithromycin, amoxicillin, and a proton pump inhibitor) can be expected to cure more than 95% of patients who have susceptible infections and about 20% of those with resistant infections.¹⁶ This 20% is due to the proton pump inhibitor and amoxicillin, as the contribution to the cure rate from clarithromycin is close to zero.

If the prevalence of resistance to clarithromycin is 25%, the cure rate in the entire population will be a little more than 75%—97% in the 75% of the population with susceptible infections and 20% in patients who previously received clarithromycin (Figure 1).

Based on Graham DY. Hp-normogram (normo-graham) for assessing the outcome of H. pylori therapy: effect of resistance, duration, and CYP2C19 genotype. Helicobacter 2015; 21:85–90.

If we know that our patient has an infection that is susceptible to clarithromycin, metronidazole, or levofloxacin, good results could be achieved with triple therapy that includes a proton pump inhibitor, for 14 days. Fluoroquinolones have a number of black-box warnings from the US Food and Drug Administration (www.fda.gov/Drugs/DrugSafety/ucm500143.htm) and should always be a last choice. However, in the United States, lacking definite data about susceptibility to clarithromycin, metronidazole, and levofloxacin, we should assume resistance is present and use a 4-drug regimen (eg, concomitant therapy or bismuth quadruple therapy).

Concomitant therapy is preferred

Concomitant therapy is the combination of:

• Amoxicillin
• Metronidazole
• Clarithromycin
• A proton pump inhibitor.

Functionally, this is a combination of clarithromycin and metronidazole triple therapies, given simultaneously.¹⁷ The premise is that even though the prevalence of metronidazole resistance in the United States is high (20%–40%), and so is the prevalence of clarithromycin resistance (about 20%), the prevalence of resistance to both drugs at the same time is expected to be low (eg, 0.4 × 0.2 = 0.08, or 8%) unless the drugs had previously been used together, as in some older regimens that contained both. Thus, the metronidazole will kill the clarithromycin-resistant but metronidazole-susceptible strains, and the clarithromycin will kill the clarithromycin-susceptible, metronidazole-resistant strains. Only with dual resistant strains will this regimen fail (with a 20% cure rate due to the proton pump inhibitor and amoxicillin and a population cure rate of slightly more than 90%).

The downside of this highly recommended therapy is that all who receive it are getting an antibiotic that they don’t need, which is, in a global sense, inappropriate. In other words, all those who are cured by clarithromycin also receive metronidazole, which plays no role in treatment success, and those cured by metronidazole receive unneeded clarithromycin (Figure 2). Had susceptibility testing been available, those with susceptible strains would have received appropriate triple therapies, and those with dual resistance would not have received either antibiotic.

Thus, while we recommend concomitant therapy as an empiric regimen in populations that do not have high levels of resistance to metronidazole or clarithromycin (as those would also have a high prevalence of dual resistance), one must be aware of the “dirty little secret” of inappropriate antibiotic use that accompanies it and some other H pylori therapies (eg, vonoprazan triple therapy in Japan).^18–20

Bismuth quadruple therapy (Table 1) consists of:

• Bismuth
• Tetracycline
• Metronidazole
• A proton pump inhibitor.

This was the first truly effective regimen for H pylori. Its advantage is that it can partially or completely overcome metronidazole resistance.^21,22 As such, it is potentially ideal, as it should be effective despite resistance to clarithromycin, metronidazole, or levofloxacin, and it can be used in patients allergic to penicillin.

The major downside is a high frequency of side effects, particularly abdominal pain, nausea, and vomiting, often resulting in poor adherence. Most regimens that contain antibiotics have side effects, but adherence seems to be more of a problem with bismuth quadruple therapy, probably because of the combination of the high doses of metronidazole and tetracycline.²² In our experience, this regimen can be effective if the physician takes the time to explain to the patient that side effects are common but treatment success depends on completing the full course of 14 days.

Another problem is that tetracycline has become difficult to obtain in many areas, and doxycycline cannot be substituted in those with metronidazole resistance. To date, it has been difficult or impossible to obtain the same excellent results with doxycycline as can be obtained with tetracycline. It is not clear why.²¹

To use bismuth quadruple therapy one must often use a name-brand product, Pylera. Pylera is packaged as a 10-day course, which is effective against metronidazole-susceptible infections. However, 14 days are generally required to achieve a high cure rate with metronidazole-resistant infections, which are the main indication for use of this product. Moreover, Pylera does not include a proton pump inhibitor, which must be prescribed separately.

In the United States, Pylera is expensive, costing $740 to $790 with a coupon for a 10-day supply and proportionally more for the required 14-day supply (www.goodrx.com/pylera?drug-name=pylera), whereas in Europe it costs less than 70 Euros ($73).²¹ If generic tetracycline is available, the US cost for 14 days of generic bismuth quadruple therapy is less than $50.

An alternate and simpler approach is to substitute amoxicillin for tetracycline.²³ This regimen has been used successfully in China and was shown to be noninferior to the tetracycline-containing regimen in a head-to-head comparison.²⁴

Recent studies have confirmed earlier Italian studies suggesting that twice-a-day bismuth and tetracycline is effective, which would further simplify therapy and possibly reduce side effects.^21,23,24 These variations on bismuth quadruple therapy have not yet been optimized to where one can reliably achieve 95% or greater cure rates, and further studies are needed.

Why include more than 1 antibiotic?

The H pylori load in the stomach is typically large, which increases the odds that a subpopulation of resistant organisms is present. Resistance may be due to a relatively high rate of mutation in certain bacterial genes.²⁵ This is particularly a problem with clarithromycin, metronidazole, and fluoroquinolones and is reflected in a high rate of resistance among patients for whom single-drug regimens have failed. These drugs are always given with a second antimicrobial to which H pylori rarely becomes resistant, such as amoxicillin or tetracycline.

Why include a proton pump inhibitor?

An antisecretory drug is needed to increase the gastric pH, which makes antimicrobial therapy more effective. It also decreases antibiotic washout from the stomach and likely protects and increases the gastric concentration of some antibiotics.

The activities of amoxicillin, fluoroquinolones, and to a lesser degree clarithromycin are pH-dependent. For example, keeping the gastric pH above 6.0 promotes H pylori replication,^26,27 making it is more susceptible to amoxicillin (reviewed in detail by Dore et al²¹). A gastric pH of 6.0 or more is very difficult to achieve with proton pump inhibitors, and has been accomplished regularly only in people who metabolize these drugs slowly (“slow metabolizers”) who received both the proton pump inhibitor and amoxicillin every 6 hours for 14 days.²¹

With standard clarithromycin, metronidazole, or fluoroquinolone triple therapy, proton pump inhibitors appear to provide satisfactory cure rates when given for 14 days in standard doses. However, double doses (eg, 40 mg of omeprazole or an equivalent) may be slightly better, especially in the presence of resistance.

The cure rate reflects the sum of the 2 populations of organisms: the susceptible and the resistant. In triple therapy, increasing the gastric pH with a proton pump inhibitor makes the amoxicillin component of the regimen more effective against resistant organisms and thus increases the cure rate. For example, in Western countries, esomeprazole  40 mg (approximately equivalent to rabeprazole 40 mg, omeprazole or lansoprazole 60 mg, or pantoprazole 240 mg)²⁸ given twice a day in a 14-day triple therapy regimen cures about 40% to 50% of resistant infections. This benefit will be evident in an improvement in cure rates in populations in which resistance has reduced the average cure rate. This is also why meta-analyses have shown better results with second-generation proton pump inhibitors and with longer duration of therapy.^29,30

Generally, we recommend omeprazole 40 mg twice a day or an equivalent (Tables 1–3).

Would a potassium-competitive acid blocker be better than a proton pump inhibitor?

Vonoprazan is a potassium-competitive acid blocker. It does not require intermediate complex formation and is stable at low pH. It has a longer half-life than proton pump inhibitors, and its bioavailability is unaffected by food.³¹ It was recently approved in Japan for H pylori eradication in combination with clarithromycin or metronidazole plus amoxicillin.¹⁸

Vonoprazan is more effective than current proton pump inhibitors for keeping the gastric pH high. There are no published studies of vonoprazan dual therapy in Western countries, but given twice a day for 7 days along with twice-daily amoxicillin it cured only approximately 80% of clarithromycin-resistant strains. Further studies are needed to identify the optimum proton pump inhibitor or potassium-competitive acid blocker, dose, and duration.

In triple therapy, the second antimicrobial drug (eg, amoxicillin) is given in part to prevent resistance from developing. It is not clear whether the combination is additive or synergistic, but until we can reliably maintain the intragastric pH above 6.0, which would increase the effectiveness of the amoxicillin component of the regimen, this practice cannot be considered as misuse of antibiotics.

In contrast, in the 4-drug nonbismuth combinations (concomitant, sequential, and hybrid therapies) and the new vonoprazan, clarithromycin, and metronidazole triple therapies, 1 of the antibiotics provides no benefit to some, often most, of the patients.^18–20,32 This practice should end when susceptibility data become more widely available and when vonoprazan becomes available, so that we can deliver effective vonoprazan-amoxicillin dual therapy.

First-, second-, and third-line therapies

Many recommendations give advice in terms of first-, second-, and third-line therapies. In practice, a physician should have at least 2 first-line regimens (a first and a second choice). Both should be proven highly successful as empiric therapies in one’s patient population but differ in terms of primary antibiotics. This approach allows the clinician to tailor therapy depending on whether he or she suspects antibiotic resistance (eg, if the patient has taken clarithromycin before) or the patient is allergic or cannot take 1 or more drugs.

Two treatment failures with 2 different regimens known to be effective suggest poor compliance (a difficult patient) or a multiple-drug-resistant infection (a difficult infection). That patient would require salvage therapy (Table 2), which logically should be based on antimicrobial testing or, at a minimum, consultation with someone who frequently deals with this problem.

Test of cure

Monitoring the outcome of therapy (testing for cure) is essential, as it provides a reliable measure of the local effectiveness of particular therapies and also serves as an early warning of development of resistance in one’s patient population.¹⁴

Unless there are compelling reasons, testing for cure should use noninvasive testing with the urea breath test or stool antigen test. It is recommended that this be delayed at least 4 weeks to allow the organisms if still present to repopulate the stomach sufficiently for the tests to become positive. Because antibiotics, bismuth, and proton pump inhibitors reduce the bacterial load, they should be withheld at least 2 weeks before testing. Histamine-2 receptor antagonists can be substituted for proton pump inhibitors if antisecretory therapy is needed for symptoms, and continued up to the day before testing. The urea breath test should contain citric acid to overcome any residual pH effects. Physician groups should share their experience so as to alert the community about which therapies should likely be avoided.³³

Salvage therapy

Salvage therapy is given after 2 or more treatment failures with different antibiotics. Ideally, the regimen should be based on the results of antimicrobial testing. Current regimens include rifabutin triple therapy, dual therapy (a protein pump inhibitor or vonoprazan and amoxicillin), or furazolidone quadruple therapy (Table 2).

Furazolidone is a synthetic nitrofuran derivative that is effective against many enteric organisms, including gram-negative bacteria and protozoa. It is not available in most Western countries but is available in many other parts of the world.^34,35 It is also a monoamine oxidase inhibitor and thus interacts with many drugs and foods (eg, soy sauce, aged cheeses), leading to a relatively high rate of side effects such as fever, palpitations, and skin rash.

Rifabutin-containing regimens, generally, a proton pump inhibitor, amoxicillin 1 g, and rifabutin 150 mg, all twice a day (Table 3) provide average cure rates of less than 80% (typically in the mid-70% range).³⁶ Borody et al³⁷ reported greater than 95% success with a 12-day regimen consisting of rifabutin 150 mg once daily (half-dose), amoxicillin 1.5 g 3 times a day, and pantoprazole 80 mg (approximately equivalent to omeprazole 20 mg) 3 times a day. Ciccaglione et al,³⁸ in a small study, used a 10-day quadruple regimen containing a proton pump inhibitor, amoxicillin, rifabutin, and bismuth (all twice a day), with high cure rates. The results of these studies are yet to be confirmed, and the optimal rifabutin-containing regimen remains to be determined.

PROBIOTICS

There is considerable interest in using probiotics to enhance the effectiveness of antimicrobial therapy for H pylori by increasing tolerability, reducing side effects, and therefore improving compliance.^39,40

In a meta-analysis of 14 randomized trials (N = 1,671), when probiotics were added, pooled H pylori eradication rates were only slightly improved: 83.6% (95% CI 80.5%–86.7%) with probiotics and 74.8% (95% CI 71.1%–78.5%) without probiotics by intent-to-treat analysis.⁴¹

Another meta-analysis of probiotics suggested that those containing Saccharomyces boulardii, Lactobacillus, and Bifidobacterium significantly increased the eradication rate of triple therapy in populations with high rates of antimicrobial resistance and reduced the risk of overall H pylori therapy-related adverse effects, especially diarrhea.^42,43

At present, we recommend that probiotics be considered only for patients who are likely not to comply with treatment (eg, those with irritable bowel syndrome or difficulty taking antibiotics), to try to take advantage of their ability to improve antibiotic tolerability.

Bariatric surgery, though beneficial, is associated with complications, one of which is post-gastric bypass hypoglycemia (PGBH).¹ The mean time from gastric bypass to documented hypoglycemia is about 28 months.²

PGBH is probably more common than initially thought. In older reports, the prevalence was only 0.1% to 0.36%.^1,3 In contrast, in a mail survey in 2015,⁴ one-third of bariatric surgery patients reported symptoms that raised the suspicion of hypoglycemia. Those with suspicious symptoms were more likely to have undergone Roux-en-Y surgery, to have had no preoperative diabetes, to have had a longer interval since surgery, and to be female. Restricting the suspicion of postprandial hypoglycemia to those who reported more serious symptoms, including needing third-party assistance, the prevalence was 11.6%.

Kefurt et al⁵ followed Roux-en-Y patients who wore a continuous glucose monitor for 86 months after surgery and found that 38% had hypoglycemia; however, symptoms of hypoglycemia were not discussed.

Thus, the exact prevalence is currently unknown. But as time goes by and more procedures are performed, the incidence will likely rise.

OBESITY IS ON THE RISE, AND SO IS WEIGHT-LOSS SURGERY

Obesity is rampant, and its prevalence continues to rise. In 2011–2012, more than two-thirds of adults in the United States were reported as obese.⁶ Complications of obesity such as cardiac disease, diabetes, and cancer lead to increased mortality risk.⁷ Obesity is difficult to reverse, as many people fail to lose weight with diet, exercise, and pharmacotherapy.

Given the difficulty of losing weight and the complications that arise from obesity, bariatric surgery has become increasingly popular. Not only do patients lose significantly more weight with bariatric surgery than with conventional measures, but surgery also reduces and often cures conditions associated with obesity.⁸

Nguyen et al⁹ reported that 671,959 patients underwent gastric bypass procedures in the United States from 2003 to 2008. In a registry maintained by the American Society for Metabolic and Bariatric Surgery¹⁰ from June 2007 to May 2009, the most common bariatric procedure in the United States was Roux-en-Y gastric bypass, followed by sleeve gastrectomy.

DIFFERENTIAL DIAGNOSIS AND DEFINITIONS

The differential diagnosis for hyperinsulinemic hypoglycemia after gastric bypass surgery includes exogenous and endogenous causes (Table 1). Exogenous causes include abuse of insulin secretagogues such as sulfonylureas or meglitinides and abuse of insulin, which may occur in patients with Munchausen syndrome, Munchausen syndrome by proxy, or malingering. Endogenous causes include insulinoma, early and late dumping syndromes, and PGBH.

When differentiating endogenous from exogenous hypoglycemia, insulin and C-peptide levels are useful (Table 2). The pancreas produces proinsulin, which is broken down into insulin and C-peptide. Since exogenous insulin does not have a C-peptide component, people abusing insulin have elevated insulin levels with a low C-peptide level.¹¹ Insulin secretagogues cause endogenous insulin secretion, resulting in elevated levels of both insulin and C-peptide. Thus, a screen for these medications is necessary to determine this as the cause.

Differentiating endogenous causes of hypoglycemia

Differentiating the endogenous causes (insulinoma, early or late dumping syndrome, and PGBH) can be challenging, as all 3 have similar biochemical profiles (Table 2).

Insulinoma is a tumor of pancreatic beta cells that produces excessive amounts of insulin. Unlike dumping syndrome, which only occurs postprandially, insulinoma primarily causes fasting hypoglycemia, although postprandial hypoglycemia can occur less commonly. Insulinoma after Roux-en-Y is rare. Only 7 cases have been reported.¹²

Dumping syndrome is classified as either early or late.

Early dumping syndrome usually occurs within 20 minutes of eating. The rapid transit of carbohydrates into the small intestine results in a fluid shift and a sympathetic response characterized by tachycardia, nausea, and diarrhea. Hypoglycemia is not present. Early dumping syndrome usually arises during the first few months after surgery.¹³

Late dumping syndrome usually occurs 1 to 4 hours after ingestion of a carbohydrate load, with symptoms of diaphoresis, dizziness, and fatigue caused by hypoglycemia from an excessive insulin release in response to the carbohydrates.¹³ It does not tend to cause neuroglycopenic symptoms.¹⁴ We define late dumping syndrome as postprandial hypoglycemic symptoms that occur after eating simple sugars and that resolve with dietary changes alone.

Differentiating late dumping syndrome from PGBH is difficult, as the line between the 2 processes is blurred.¹³

PGBH is defined as postprandial hypoglycemia (although it can be fasting in severe cases), often with neuroglycopenic symptoms, that occurs despite adherence to an acceptable bariatric diet (outlined in Table 3). We categorize PGBH as mild, moderate, or severe. Mild PGBH resolves with dietary changes with or without an alpha-glucosidase inhibitor. Moderate PGBH does not respond to an alpha-glucosidase inhibitor and dietary changes, and alternative or additional medication or medications are needed for resolution. Severe PGBH does not respond to dietary or medical interventions, and patients experience persistent episodes of neuroglycopenia.

THE EXACT MECHANISM IS UNCERTAIN

Patients with PGBH have a significant postprandial rise in glucose (often with levels > 200 mg/dL), leading to a robust insulin response and a subsequent drop in blood glucose.¹⁵

The exact mechanisms causing hypoglycemia are unknown, but excessive release of the incretin hormones glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) are thought to contribute. GLP-1 is primarily secreted in the gut in response to nutrients, causing a glucose-dependent release of insulin and suppression of glucagon, as well as a delay in gastric emptying and motility. Salehi et al¹⁶ demonstrated excessive GLP-1 and insulin release after glucose administration in postbypass patients, with a more exaggerated response in those experiencing postprandial hypoglycemia.

Excessive incretin hormones may also contribute to pancreatic islet cell hyperplasia, leading to hyperinsulinism.¹⁷ Other proposed mechanisms of PGBH are the lack of a decrease in beta cell mass after gastric bypass, a postoperative increase in insulin sensitivity, a decrease in ghrelin (an insulin counterregulatory hormone), and an abnormal glucagon response.^13,17

Pathologic changes vary widely

PGBH is a challenging diagnosis to make pathologically. On review of pancreatic tissue from 36 patients undergoing partial pancreatectomy for PGBH, the pancreatic islet cells of the PGBH group were larger and more irregular compared with controls.^18,19 This histologic condition with islet-cell hypertrophy, hyperplasia, and other changes has been termed nesidioblastosis.^11,14,20 However, the pancreatic tissue appears grossly normal. The histopathologic findings can vary greatly in individual cases and in one-third of cases the pancreatic changes can be minimal, so that “normal” and PGBH cells can be nearly impossible to distinguish from each other.²¹

DIAGNOSIS AND TREATMENT

We recommend a stepwise approach to evaluating and treating PGBH (Figures 1 and 2).

Step 1: Evaluate blood glucose and Whipple triad

The first step is a thorough history, including food consumption and timing of hypoglycemic symptoms. Give the patient a glucometer to take home, with instructions to check blood glucose levels when hypoglycemic symptoms occur. The patient should keep a log documenting time tested, food consumed, symptoms, and blood glucose data.

Hypoglycemic symptoms are categorized as autonomic and neuroglycopenic. Autonomic symptoms include anxiety, palpitations, tremulousness, and diaphoresis. Neuroglycopenic symptoms include confusion, falls, seizures, and loss of consciousness.¹²

There are degrees of hypoglycemia and hypoglycemic symptoms. Clinical hypoglycemia—a blood glucose level low enough to cause signs or symptoms—can be confirmed by the Whipple triad:

• Measured low blood glucose
• Symptoms of low blood glucose
• Relief of symptoms when low blood glucose is corrected.

Hypoglycemic symptoms can occur when the blood glucose level falls to less than 55 mg/dL in healthy people, but this cutoff can shift lower in someone who has recurrent hypoglycemia.

When the Whipple triad is documented, rule out nonhyperinsulinemic causes of hypoglycemia such as hypothyroidism, adrenal insufficiency, underlying organ dysfunction (ie, liver disease), and medications that cause hypoglycemia.

Step 2: Modify the diet

If postprandial hypoglycemia is occurring, the next step is dietary modification. Two studies showed that a low-carbohydrate diet prevented hypoglycemia; however, these diets contained nearly no carbohydrates (with meals consisting of eggs, sausage, cheese, and black coffee or tea).^15,22

Instruct patients to never eat pure carbohydrates without fat or protein, as this can result in a more severe hypoglycemic response.²² In addition, foods with a high glycemic index (a measure of how a carbohydrate-containing food raises blood sugar) should be avoided, and a low glycemic index diet is recommended.²³ High glycemic index foods include white bread, bagels, pretzels, and pineapple. Low glycemic index foods include 100% stone-ground whole wheat or pumpernickel bread, lima beans, butter beans, peas, legumes, lentils, and nonstarchy vegetables.

Our bariatric surgeons provide all postbariatric surgery patients with the dietary guidelines shown in Table 3.²⁴ We also ask our patients with PGBH to limit carbohydrates to 15 to 30 g per meal and to limit added sugars to less than 4 g per meal, including regular and sugar alcohols (polyols). Snacks should contain only protein and fat. In severe cases, we further limit the diet to 15 g of carbohydrate per meal, with no added sugars.

The hypoglycemia occurring with PGBH is treated differently than the hypoglycemia that occurs in diabetic patients. Advise patients with PGBH to treat their hypoglycemic episodes with a simple sugar combined with a protein or fat (eg, a small handful of candy with a spoonful of peanut butter), as they will often have recurrent hypoglycemia if a simple sugar is used alone. If patients regain weight, ask them about frequent eating, which would be related to self-treatment of hypoglycemia.

Step 3: Start an alpha-glucosidase inhibitor

If postprandial hypoglycemia persists despite dietary modification, then start an alpha-glucosidase inhibitor such as acarbose. Acarbose inhibits carbohydrate absorption, resulting in a decreased insulin response; thus, it blunts the decline in postprandial blood glucose.

Unfortunately, gastrointestinal side effects such as flatulence, diarrhea, and abdominal pain occur in up to 20% of patients who take acarbose, often leading to its discontinuation.²⁵ To minimize gastrointestinal side effects, we usually start with 25 mg of acarbose with 1 meal daily for 1 week, then increase the dosage weekly to 25 mg with the other 2 meals. If tolerated, acarbose can be increased to 50 to 100 mg with 3 meals daily.

Step 4: Obtain a mixed meal tolerance test or a provocation meal test

If dietary changes and an alpha-glucosidase inhibitor do not prevent postprandial hypoglycemia from recurring, then confirmation of PGBH is needed, using a mixed meal tolerance test or a provocation meal test.

In a mixed meal tolerance test, the meal consists of 55% carbohydrate, 30% fat, and 15% protein. Patients with hyperinsulinemic hypoglycemia have a rapid rise in blood glucose (> 200 mg/dL) with a robust insulin response that is often followed by hypoglycemia after ingesting a meal containing carbohydrates in this test. Insulin levels that remain elevated after the plasma glucose level falls to less than 55 mg/dL indicate hyperinsulinism.¹¹

Nevertheless, a mixed meal tolerance test will not always induce hypoglycemia. In a study of 51 patients with PGBH, all wore a continuous glucose monitor, were instructed to follow their normal diet for 5 days, and then underwent a mixed meal tolerance test on day 6. The glucose monitor revealed hypoglycemia in 75% of patients, while the mixed meal tolerance test was positive in only 29%.⁵

Moreover, to date, there is no standardized mixed meal.^5,15 This might also explain the difference in prevalence of hypoglycemia detected by this test.

Based on these conflicting findings, we recommend a provocation meal test—ie, the patient is given foods that have induced hypoglycemia earlier.

Of note, the Endocrine Society guidelines on hypoglycemia state that an oral glucose tolerance test should never be used to document postprandial hypoglycemia.²⁶ Lev-Ran and Anderson²⁷ found that an oral glucose tolerance test could be positive in at least 10% of normal people.

Step 5: Consider other pharmacotherapy

For moderate to severe PGBH in which dietary modification and acarbose have failed, additional medical therapy is the next step. Medical therapies include calcium channel blockers, somatostatin analogues (eg, octreotide), and diazoxide.

Calcium channel blockers inhibit insulin release from beta cells²⁸ but at the risk of hypotension. Mordes and Alonso²⁹ treated 6 PGBH patients with nifedipine or verapamil with or without acarbose, and symptoms resolved in 5 of the 6 patients.

When we treat PGBH, we often add a calcium channel blocker as the next step in therapy if the patient has hypertension or if the blood pressure can tolerate this. If the patient’s blood pressure is low, then avoiding calcium channel blocker therapy may be necessary. The next step would be octreotide and then diazoxide.

Somatostatin analogues such as octreotide inhibit GLP-1 and insulin release.³⁰ The most common side effects of octreotide are diarrhea and abdominal pain. Bile stone formation can also occur, but this is not common.

Diazoxide opens adenosine triphosphate-sensitive potassium channels and reduces the opening of calcium channels, inhibiting insulin release and raising blood glucose. In a study of 6 Japanese patients with inoperable insulinoma, diazoxide was used to treat hypoglycemia.³¹ Unfortunately, the doses required to control the low blood sugars also led to adverse reactions, most of which involved edema secondary to volume overload and other heart failure symptoms. Diazoxide also commonly causes hypotension and hirsutism.

Step 6: 72-hour fast

A 72-hour fast is recommended in severe cases of PGBH in patients for whom dietary modification and the additional pharmacotherapy outlined in step 5 have failed. A 72-hour fast is always indicated in evaluating confirmed fasting hypoglycemia. People with insulinoma usually have fasting hypoglycemia, while patients with dumping syndrome do not. Patients with PGBH usually do not have fasting hypoglycemia, but they can in severe cases.¹¹

For safety, this test should be done in the hospital. Baseline plasma levels of insulin, C-peptide, proinsulin, beta-hydroxybutyrate, and glucose should be obtained. The patient then fasts, consuming only noncaloric and noncaffeinated beverages for 72 hours. During this time, capillary glucose checks are performed every 6 hours. If the capillary glucose level falls below 55 mg/dL,^11,26 then the baseline tests are redrawn along with a sulfonylurea screen. To reduce costs and unnecessary testing, the tests are not sent for laboratory processing unless the plasma glucose is less than 55 mg/dL.

When the plasma glucose is less than 55 mg/dL, insulin production should cease. Elevated insulin levels and insulin byproducts raise concern for hyperinsulinism. These values confirm hyperinsulinemic hypoglycemia²⁶:

• Glucose < 55 mg/dL
• Insulin ≥ 3 µU/mL
• C-peptide ≥ 0.2 nmol/L
• Proinsulin ≥ 5.0 pmol/L.

After hypoglycemia is confirmed, 1 mg of glucagon is given intravenously, and plasma glucose levels are obtained at 10, 20, and 30 minutes.^11,26 A rise in plasma glucose of at least 25 mg/dL after intravenous glucagon injection indicates hypoglycemia due to hyperinsulinemia. Two-thirds of patients with insulinoma experience hypoglycemia within the first 24 hours, and nearly all experience hypoglycemia within 48 hours.²⁶

Step 7: Obtain pancreatic imaging

If fasting hypoglycemia is present and hyperinsulinemic hypoglycemia is confirmed during a 72-hour fast, then pancreatic imaging should be obtained to evaluate for an insulinoma. We also recommend pancreatic imaging to rule out insulinoma when severe PGBH has not responded to dietary modification or pharmacotherapy.

Imaging is not recommended in PGBH that has been successfully treated with dietary modification with or without pharmacotherapy.

Endoscopic ultrasonography alone has 80% to 92% sensitivity for localizing a pancreatic mass as small as 5 mm. However, when coupled with computed tomography or magnetic resonance imaging, the sensitivity increases to nearly 100%.¹²

Step 8: Selective arterial calcium stimulation test

If a patient is found to have hyperinsulinemic hypoglycemia during a 72-hour fast but pancreatic imaging is negative, then selective arterial calcium stimulation testing (SACST) and hepatic vein sampling should be performed. Also, for severe PGBH, in which hypoglycemia has persisted despite dietary modification and pharmacotherapy, SACST can be performed to evaluate for possible localization of hyperinsulinism in patients considering surgery. For mild and moderate cases of PGBH, in which the hypoglycemia has been successfully treated with dietary changes with or without pharmacotherapy, SACST is not necessary.

This test can localize the area of excess insulin production in the pancreas in patients with an insulinoma. Patients with severe PGBH usually have diffuse hyperinsulinism without localization on SACST.^32,33

When SACST is performed, a sampling catheter is placed in the femoral vein. Calcium gluconate is injected into the major arteries of the pancreas (superior mesenteric, gastroduodenal, and splenic arteries). Calcium stimulates release of insulin from an insulinoma or hyperplastic beta cells. Resultant insulin levels are measured in the hepatic vein. If there is a greater than twofold increase in insulin release from 2 segments, then the test is considered positive.

Thompson et al³⁴ documented that insulin release from insulinoma is almost 4 times higher than in diffuse nesidioblastosis. SACST has a sensitivity of 96% for detecting insulinomas.³⁵

Step 9: Other alternatives and surgery

In patients with severe PGBH for whom dietary modification and all pharmacotherapy have failed and who continue to have debilitating neuroglycopenia, there are options before proceeding with surgery, the last resort in this condition.

Continuous glucose monitoring is helpful in many patients with severe PGBH. Many of them have hypoglycemia unawareness, and the monitor alerts them when their blood sugar is low. In addition, the monitor indicates when the blood sugar is dropping, so that intervention can occur before hypoglycemia occurs.

Unfortunately, insurance coverage for continuous monitors in this patient population is limited. We argue that insurance should cover the cost for these severe cases.

Pasireotide, a somatostatin analogue that is longer-acting than octreotide, is approved for use in Cushing disease and acromegaly and actually causes hyperglycemia. In a case report of a 50-year-old woman, pasireotide resulted in less hypoglycemia and higher glucagon levels then octreotide.³⁶ Pasireotide is available from Novartis for compassionate use in patients with severe PGBH.

Glucocorticoids are another off-label option. However, in excess, they can lead to iatrogenic Cushing syndrome, which has its own complications. Prednisone and diazoxide have been used together to help prevent hypoglycemia in a patients with inoperable insulinoma.³¹

Tube feeding. Some researchers have studied altering nutrition access through surgical means. McLaughlin et al³⁷ discussed a case of gastric tube insertion into the remnant stomach of a patient with PGBH, with resolution of hypoglycemic symptoms and hypoglycemia; however, this does not always provide complete resolution of symptoms.^37,38 If gastric bypass reversal is being considered, a trial of solely remnant stomach tube feeds (with no oral intake) should be pursued first. If this ameliorates the hypoglycemia, then gastric bypass reversal may be of benefit.

Surgery is the last resort if all of the above treatments have failed and severe debilitating neuroglycopenia persists. However, surgery poses risks, and the success rate in correcting hypoglycemia is not ideal. Surgical options include Roux-en-Y reversal, gastric pouch resection, and pancreatic resection.

In a review by Mala,² 75 patients with documented PGBH underwent surgical therapy. Hypoglycemic symptoms resolved in 34 of 51 pancreatic resections, 13 of 17 Roux-en-Y reversals, and 9 of 11 gastric pouch resections. However, the follow-up period was short.

As noted above, we recommend calcium stimulation testing only for severe cases of PGBH when surgery is being considered to evaluate for possible localization of hyperinsulinism for which partial pancreatectomy would be of benefit. Since there is no localization in many PGBH cases and the success rates are slightly higher in gastric bypass reversal, bypass reversal is usually preferred over partial or complete pancreatectomy.^2,32,33

POTENTIAL FUTURE THERAPIES

Given the elevated GLP-1 levels and robust insulin response to glucose observed in PGBH, blocking GLP-1 may provide clinical benefit. Salehi et al¹⁶ found that a GLP-1 antagonist prevented surges in GLP-1 and reduced hypoglycemic episodes in patients with PGBH. Unfortunately, the medication they used was given as a continuous infusion and is not currently available.

Conversely, a GLP-1 agonist showed benefit in a series of 5 cases of PGBH.³⁹ In addition, an insulin receptor antibody is undergoing phase 2 trials and has been shown to reverse insulin-induced hypoglycemia in rodents and humans; it may be a novel therapy in the future for hyperinsulinemic hypoglycemia.⁴⁰

MORE STUDY NEEDED

As the prevalence of obesity continues to rise and more people opt for bariatric surgery for weight loss, we will likely continue to see an increase in PGBH, since the onset of PGBH can be delayed for many years after surgery.²⁸

Unfortunately, the disease process involved in PGBH is not well understood. For example, we do not know why GLP-1 elevations or a robust insulin response causing hypoglycemia occurs in some but not all gastric bypass patients. Study is needed to elucidate the pathophysiology to further understand why most patients have no hypoglycemia after gastric bypass, some have mild to moderate PGBH, and a small percentage have severe PGBH with debilitating neuroglycopenia unresponsive to dietary changes and medications.     

Bariatric surgery, though beneficial, is associated with complications, one of which is post-gastric bypass hypoglycemia (PGBH).¹ The mean time from gastric bypass to documented hypoglycemia is about 28 months.²

PGBH is probably more common than initially thought. In older reports, the prevalence was only 0.1% to 0.36%.^1,3 In contrast, in a mail survey in 2015,⁴ one-third of bariatric surgery patients reported symptoms that raised the suspicion of hypoglycemia. Those with suspicious symptoms were more likely to have undergone Roux-en-Y surgery, to have had no preoperative diabetes, to have had a longer interval since surgery, and to be female. Restricting the suspicion of postprandial hypoglycemia to those who reported more serious symptoms, including needing third-party assistance, the prevalence was 11.6%.

Kefurt et al⁵ followed Roux-en-Y patients who wore a continuous glucose monitor for 86 months after surgery and found that 38% had hypoglycemia; however, symptoms of hypoglycemia were not discussed.

Thus, the exact prevalence is currently unknown. But as time goes by and more procedures are performed, the incidence will likely rise.

OBESITY IS ON THE RISE, AND SO IS WEIGHT-LOSS SURGERY

Obesity is rampant, and its prevalence continues to rise. In 2011–2012, more than two-thirds of adults in the United States were reported as obese.⁶ Complications of obesity such as cardiac disease, diabetes, and cancer lead to increased mortality risk.⁷ Obesity is difficult to reverse, as many people fail to lose weight with diet, exercise, and pharmacotherapy.

Given the difficulty of losing weight and the complications that arise from obesity, bariatric surgery has become increasingly popular. Not only do patients lose significantly more weight with bariatric surgery than with conventional measures, but surgery also reduces and often cures conditions associated with obesity.⁸

Nguyen et al⁹ reported that 671,959 patients underwent gastric bypass procedures in the United States from 2003 to 2008. In a registry maintained by the American Society for Metabolic and Bariatric Surgery¹⁰ from June 2007 to May 2009, the most common bariatric procedure in the United States was Roux-en-Y gastric bypass, followed by sleeve gastrectomy.

DIFFERENTIAL DIAGNOSIS AND DEFINITIONS

The differential diagnosis for hyperinsulinemic hypoglycemia after gastric bypass surgery includes exogenous and endogenous causes (Table 1). Exogenous causes include abuse of insulin secretagogues such as sulfonylureas or meglitinides and abuse of insulin, which may occur in patients with Munchausen syndrome, Munchausen syndrome by proxy, or malingering. Endogenous causes include insulinoma, early and late dumping syndromes, and PGBH.

When differentiating endogenous from exogenous hypoglycemia, insulin and C-peptide levels are useful (Table 2). The pancreas produces proinsulin, which is broken down into insulin and C-peptide. Since exogenous insulin does not have a C-peptide component, people abusing insulin have elevated insulin levels with a low C-peptide level.¹¹ Insulin secretagogues cause endogenous insulin secretion, resulting in elevated levels of both insulin and C-peptide. Thus, a screen for these medications is necessary to determine this as the cause.

Differentiating endogenous causes of hypoglycemia

Differentiating the endogenous causes (insulinoma, early or late dumping syndrome, and PGBH) can be challenging, as all 3 have similar biochemical profiles (Table 2).

Insulinoma is a tumor of pancreatic beta cells that produces excessive amounts of insulin. Unlike dumping syndrome, which only occurs postprandially, insulinoma primarily causes fasting hypoglycemia, although postprandial hypoglycemia can occur less commonly. Insulinoma after Roux-en-Y is rare. Only 7 cases have been reported.¹²

Dumping syndrome is classified as either early or late.

Early dumping syndrome usually occurs within 20 minutes of eating. The rapid transit of carbohydrates into the small intestine results in a fluid shift and a sympathetic response characterized by tachycardia, nausea, and diarrhea. Hypoglycemia is not present. Early dumping syndrome usually arises during the first few months after surgery.¹³

Late dumping syndrome usually occurs 1 to 4 hours after ingestion of a carbohydrate load, with symptoms of diaphoresis, dizziness, and fatigue caused by hypoglycemia from an excessive insulin release in response to the carbohydrates.¹³ It does not tend to cause neuroglycopenic symptoms.¹⁴ We define late dumping syndrome as postprandial hypoglycemic symptoms that occur after eating simple sugars and that resolve with dietary changes alone.

Differentiating late dumping syndrome from PGBH is difficult, as the line between the 2 processes is blurred.¹³

PGBH is defined as postprandial hypoglycemia (although it can be fasting in severe cases), often with neuroglycopenic symptoms, that occurs despite adherence to an acceptable bariatric diet (outlined in Table 3). We categorize PGBH as mild, moderate, or severe. Mild PGBH resolves with dietary changes with or without an alpha-glucosidase inhibitor. Moderate PGBH does not respond to an alpha-glucosidase inhibitor and dietary changes, and alternative or additional medication or medications are needed for resolution. Severe PGBH does not respond to dietary or medical interventions, and patients experience persistent episodes of neuroglycopenia.

THE EXACT MECHANISM IS UNCERTAIN

Patients with PGBH have a significant postprandial rise in glucose (often with levels > 200 mg/dL), leading to a robust insulin response and a subsequent drop in blood glucose.¹⁵

The exact mechanisms causing hypoglycemia are unknown, but excessive release of the incretin hormones glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) are thought to contribute. GLP-1 is primarily secreted in the gut in response to nutrients, causing a glucose-dependent release of insulin and suppression of glucagon, as well as a delay in gastric emptying and motility. Salehi et al¹⁶ demonstrated excessive GLP-1 and insulin release after glucose administration in postbypass patients, with a more exaggerated response in those experiencing postprandial hypoglycemia.

Excessive incretin hormones may also contribute to pancreatic islet cell hyperplasia, leading to hyperinsulinism.¹⁷ Other proposed mechanisms of PGBH are the lack of a decrease in beta cell mass after gastric bypass, a postoperative increase in insulin sensitivity, a decrease in ghrelin (an insulin counterregulatory hormone), and an abnormal glucagon response.^13,17

Pathologic changes vary widely

PGBH is a challenging diagnosis to make pathologically. On review of pancreatic tissue from 36 patients undergoing partial pancreatectomy for PGBH, the pancreatic islet cells of the PGBH group were larger and more irregular compared with controls.^18,19 This histologic condition with islet-cell hypertrophy, hyperplasia, and other changes has been termed nesidioblastosis.^11,14,20 However, the pancreatic tissue appears grossly normal. The histopathologic findings can vary greatly in individual cases and in one-third of cases the pancreatic changes can be minimal, so that “normal” and PGBH cells can be nearly impossible to distinguish from each other.²¹

DIAGNOSIS AND TREATMENT

We recommend a stepwise approach to evaluating and treating PGBH (Figures 1 and 2).

Step 1: Evaluate blood glucose and Whipple triad

The first step is a thorough history, including food consumption and timing of hypoglycemic symptoms. Give the patient a glucometer to take home, with instructions to check blood glucose levels when hypoglycemic symptoms occur. The patient should keep a log documenting time tested, food consumed, symptoms, and blood glucose data.

Hypoglycemic symptoms are categorized as autonomic and neuroglycopenic. Autonomic symptoms include anxiety, palpitations, tremulousness, and diaphoresis. Neuroglycopenic symptoms include confusion, falls, seizures, and loss of consciousness.¹²

There are degrees of hypoglycemia and hypoglycemic symptoms. Clinical hypoglycemia—a blood glucose level low enough to cause signs or symptoms—can be confirmed by the Whipple triad:

• Measured low blood glucose
• Symptoms of low blood glucose
• Relief of symptoms when low blood glucose is corrected.

Hypoglycemic symptoms can occur when the blood glucose level falls to less than 55 mg/dL in healthy people, but this cutoff can shift lower in someone who has recurrent hypoglycemia.

When the Whipple triad is documented, rule out nonhyperinsulinemic causes of hypoglycemia such as hypothyroidism, adrenal insufficiency, underlying organ dysfunction (ie, liver disease), and medications that cause hypoglycemia.

Step 2: Modify the diet

If postprandial hypoglycemia is occurring, the next step is dietary modification. Two studies showed that a low-carbohydrate diet prevented hypoglycemia; however, these diets contained nearly no carbohydrates (with meals consisting of eggs, sausage, cheese, and black coffee or tea).^15,22

Instruct patients to never eat pure carbohydrates without fat or protein, as this can result in a more severe hypoglycemic response.²² In addition, foods with a high glycemic index (a measure of how a carbohydrate-containing food raises blood sugar) should be avoided, and a low glycemic index diet is recommended.²³ High glycemic index foods include white bread, bagels, pretzels, and pineapple. Low glycemic index foods include 100% stone-ground whole wheat or pumpernickel bread, lima beans, butter beans, peas, legumes, lentils, and nonstarchy vegetables.

Our bariatric surgeons provide all postbariatric surgery patients with the dietary guidelines shown in Table 3.²⁴ We also ask our patients with PGBH to limit carbohydrates to 15 to 30 g per meal and to limit added sugars to less than 4 g per meal, including regular and sugar alcohols (polyols). Snacks should contain only protein and fat. In severe cases, we further limit the diet to 15 g of carbohydrate per meal, with no added sugars.

The hypoglycemia occurring with PGBH is treated differently than the hypoglycemia that occurs in diabetic patients. Advise patients with PGBH to treat their hypoglycemic episodes with a simple sugar combined with a protein or fat (eg, a small handful of candy with a spoonful of peanut butter), as they will often have recurrent hypoglycemia if a simple sugar is used alone. If patients regain weight, ask them about frequent eating, which would be related to self-treatment of hypoglycemia.

Step 3: Start an alpha-glucosidase inhibitor

If postprandial hypoglycemia persists despite dietary modification, then start an alpha-glucosidase inhibitor such as acarbose. Acarbose inhibits carbohydrate absorption, resulting in a decreased insulin response; thus, it blunts the decline in postprandial blood glucose.

Unfortunately, gastrointestinal side effects such as flatulence, diarrhea, and abdominal pain occur in up to 20% of patients who take acarbose, often leading to its discontinuation.²⁵ To minimize gastrointestinal side effects, we usually start with 25 mg of acarbose with 1 meal daily for 1 week, then increase the dosage weekly to 25 mg with the other 2 meals. If tolerated, acarbose can be increased to 50 to 100 mg with 3 meals daily.

Step 4: Obtain a mixed meal tolerance test or a provocation meal test

If dietary changes and an alpha-glucosidase inhibitor do not prevent postprandial hypoglycemia from recurring, then confirmation of PGBH is needed, using a mixed meal tolerance test or a provocation meal test.

In a mixed meal tolerance test, the meal consists of 55% carbohydrate, 30% fat, and 15% protein. Patients with hyperinsulinemic hypoglycemia have a rapid rise in blood glucose (> 200 mg/dL) with a robust insulin response that is often followed by hypoglycemia after ingesting a meal containing carbohydrates in this test. Insulin levels that remain elevated after the plasma glucose level falls to less than 55 mg/dL indicate hyperinsulinism.¹¹

Nevertheless, a mixed meal tolerance test will not always induce hypoglycemia. In a study of 51 patients with PGBH, all wore a continuous glucose monitor, were instructed to follow their normal diet for 5 days, and then underwent a mixed meal tolerance test on day 6. The glucose monitor revealed hypoglycemia in 75% of patients, while the mixed meal tolerance test was positive in only 29%.⁵

Moreover, to date, there is no standardized mixed meal.^5,15 This might also explain the difference in prevalence of hypoglycemia detected by this test.

Based on these conflicting findings, we recommend a provocation meal test—ie, the patient is given foods that have induced hypoglycemia earlier.

Of note, the Endocrine Society guidelines on hypoglycemia state that an oral glucose tolerance test should never be used to document postprandial hypoglycemia.²⁶ Lev-Ran and Anderson²⁷ found that an oral glucose tolerance test could be positive in at least 10% of normal people.

Step 5: Consider other pharmacotherapy

For moderate to severe PGBH in which dietary modification and acarbose have failed, additional medical therapy is the next step. Medical therapies include calcium channel blockers, somatostatin analogues (eg, octreotide), and diazoxide.

Calcium channel blockers inhibit insulin release from beta cells²⁸ but at the risk of hypotension. Mordes and Alonso²⁹ treated 6 PGBH patients with nifedipine or verapamil with or without acarbose, and symptoms resolved in 5 of the 6 patients.

When we treat PGBH, we often add a calcium channel blocker as the next step in therapy if the patient has hypertension or if the blood pressure can tolerate this. If the patient’s blood pressure is low, then avoiding calcium channel blocker therapy may be necessary. The next step would be octreotide and then diazoxide.

Somatostatin analogues such as octreotide inhibit GLP-1 and insulin release.³⁰ The most common side effects of octreotide are diarrhea and abdominal pain. Bile stone formation can also occur, but this is not common.

Diazoxide opens adenosine triphosphate-sensitive potassium channels and reduces the opening of calcium channels, inhibiting insulin release and raising blood glucose. In a study of 6 Japanese patients with inoperable insulinoma, diazoxide was used to treat hypoglycemia.³¹ Unfortunately, the doses required to control the low blood sugars also led to adverse reactions, most of which involved edema secondary to volume overload and other heart failure symptoms. Diazoxide also commonly causes hypotension and hirsutism.

Step 6: 72-hour fast

A 72-hour fast is recommended in severe cases of PGBH in patients for whom dietary modification and the additional pharmacotherapy outlined in step 5 have failed. A 72-hour fast is always indicated in evaluating confirmed fasting hypoglycemia. People with insulinoma usually have fasting hypoglycemia, while patients with dumping syndrome do not. Patients with PGBH usually do not have fasting hypoglycemia, but they can in severe cases.¹¹

For safety, this test should be done in the hospital. Baseline plasma levels of insulin, C-peptide, proinsulin, beta-hydroxybutyrate, and glucose should be obtained. The patient then fasts, consuming only noncaloric and noncaffeinated beverages for 72 hours. During this time, capillary glucose checks are performed every 6 hours. If the capillary glucose level falls below 55 mg/dL,^11,26 then the baseline tests are redrawn along with a sulfonylurea screen. To reduce costs and unnecessary testing, the tests are not sent for laboratory processing unless the plasma glucose is less than 55 mg/dL.

When the plasma glucose is less than 55 mg/dL, insulin production should cease. Elevated insulin levels and insulin byproducts raise concern for hyperinsulinism. These values confirm hyperinsulinemic hypoglycemia²⁶:

• Glucose < 55 mg/dL
• Insulin ≥ 3 µU/mL
• C-peptide ≥ 0.2 nmol/L
• Proinsulin ≥ 5.0 pmol/L.

After hypoglycemia is confirmed, 1 mg of glucagon is given intravenously, and plasma glucose levels are obtained at 10, 20, and 30 minutes.^11,26 A rise in plasma glucose of at least 25 mg/dL after intravenous glucagon injection indicates hypoglycemia due to hyperinsulinemia. Two-thirds of patients with insulinoma experience hypoglycemia within the first 24 hours, and nearly all experience hypoglycemia within 48 hours.²⁶

Step 7: Obtain pancreatic imaging

If fasting hypoglycemia is present and hyperinsulinemic hypoglycemia is confirmed during a 72-hour fast, then pancreatic imaging should be obtained to evaluate for an insulinoma. We also recommend pancreatic imaging to rule out insulinoma when severe PGBH has not responded to dietary modification or pharmacotherapy.

Imaging is not recommended in PGBH that has been successfully treated with dietary modification with or without pharmacotherapy.

Endoscopic ultrasonography alone has 80% to 92% sensitivity for localizing a pancreatic mass as small as 5 mm. However, when coupled with computed tomography or magnetic resonance imaging, the sensitivity increases to nearly 100%.¹²

Step 8: Selective arterial calcium stimulation test

If a patient is found to have hyperinsulinemic hypoglycemia during a 72-hour fast but pancreatic imaging is negative, then selective arterial calcium stimulation testing (SACST) and hepatic vein sampling should be performed. Also, for severe PGBH, in which hypoglycemia has persisted despite dietary modification and pharmacotherapy, SACST can be performed to evaluate for possible localization of hyperinsulinism in patients considering surgery. For mild and moderate cases of PGBH, in which the hypoglycemia has been successfully treated with dietary changes with or without pharmacotherapy, SACST is not necessary.

This test can localize the area of excess insulin production in the pancreas in patients with an insulinoma. Patients with severe PGBH usually have diffuse hyperinsulinism without localization on SACST.^32,33

When SACST is performed, a sampling catheter is placed in the femoral vein. Calcium gluconate is injected into the major arteries of the pancreas (superior mesenteric, gastroduodenal, and splenic arteries). Calcium stimulates release of insulin from an insulinoma or hyperplastic beta cells. Resultant insulin levels are measured in the hepatic vein. If there is a greater than twofold increase in insulin release from 2 segments, then the test is considered positive.

Thompson et al³⁴ documented that insulin release from insulinoma is almost 4 times higher than in diffuse nesidioblastosis. SACST has a sensitivity of 96% for detecting insulinomas.³⁵

Step 9: Other alternatives and surgery

In patients with severe PGBH for whom dietary modification and all pharmacotherapy have failed and who continue to have debilitating neuroglycopenia, there are options before proceeding with surgery, the last resort in this condition.

Continuous glucose monitoring is helpful in many patients with severe PGBH. Many of them have hypoglycemia unawareness, and the monitor alerts them when their blood sugar is low. In addition, the monitor indicates when the blood sugar is dropping, so that intervention can occur before hypoglycemia occurs.

Unfortunately, insurance coverage for continuous monitors in this patient population is limited. We argue that insurance should cover the cost for these severe cases.

Pasireotide, a somatostatin analogue that is longer-acting than octreotide, is approved for use in Cushing disease and acromegaly and actually causes hyperglycemia. In a case report of a 50-year-old woman, pasireotide resulted in less hypoglycemia and higher glucagon levels then octreotide.³⁶ Pasireotide is available from Novartis for compassionate use in patients with severe PGBH.

Glucocorticoids are another off-label option. However, in excess, they can lead to iatrogenic Cushing syndrome, which has its own complications. Prednisone and diazoxide have been used together to help prevent hypoglycemia in a patients with inoperable insulinoma.³¹

Tube feeding. Some researchers have studied altering nutrition access through surgical means. McLaughlin et al³⁷ discussed a case of gastric tube insertion into the remnant stomach of a patient with PGBH, with resolution of hypoglycemic symptoms and hypoglycemia; however, this does not always provide complete resolution of symptoms.^37,38 If gastric bypass reversal is being considered, a trial of solely remnant stomach tube feeds (with no oral intake) should be pursued first. If this ameliorates the hypoglycemia, then gastric bypass reversal may be of benefit.

Surgery is the last resort if all of the above treatments have failed and severe debilitating neuroglycopenia persists. However, surgery poses risks, and the success rate in correcting hypoglycemia is not ideal. Surgical options include Roux-en-Y reversal, gastric pouch resection, and pancreatic resection.

In a review by Mala,² 75 patients with documented PGBH underwent surgical therapy. Hypoglycemic symptoms resolved in 34 of 51 pancreatic resections, 13 of 17 Roux-en-Y reversals, and 9 of 11 gastric pouch resections. However, the follow-up period was short.

As noted above, we recommend calcium stimulation testing only for severe cases of PGBH when surgery is being considered to evaluate for possible localization of hyperinsulinism for which partial pancreatectomy would be of benefit. Since there is no localization in many PGBH cases and the success rates are slightly higher in gastric bypass reversal, bypass reversal is usually preferred over partial or complete pancreatectomy.^2,32,33

POTENTIAL FUTURE THERAPIES

Given the elevated GLP-1 levels and robust insulin response to glucose observed in PGBH, blocking GLP-1 may provide clinical benefit. Salehi et al¹⁶ found that a GLP-1 antagonist prevented surges in GLP-1 and reduced hypoglycemic episodes in patients with PGBH. Unfortunately, the medication they used was given as a continuous infusion and is not currently available.

Conversely, a GLP-1 agonist showed benefit in a series of 5 cases of PGBH.³⁹ In addition, an insulin receptor antibody is undergoing phase 2 trials and has been shown to reverse insulin-induced hypoglycemia in rodents and humans; it may be a novel therapy in the future for hyperinsulinemic hypoglycemia.⁴⁰

MORE STUDY NEEDED

As the prevalence of obesity continues to rise and more people opt for bariatric surgery for weight loss, we will likely continue to see an increase in PGBH, since the onset of PGBH can be delayed for many years after surgery.²⁸

Unfortunately, the disease process involved in PGBH is not well understood. For example, we do not know why GLP-1 elevations or a robust insulin response causing hypoglycemia occurs in some but not all gastric bypass patients. Study is needed to elucidate the pathophysiology to further understand why most patients have no hypoglycemia after gastric bypass, some have mild to moderate PGBH, and a small percentage have severe PGBH with debilitating neuroglycopenia unresponsive to dietary changes and medications.     

Bariatric surgery, though beneficial, is associated with complications, one of which is post-gastric bypass hypoglycemia (PGBH).¹ The mean time from gastric bypass to documented hypoglycemia is about 28 months.²

PGBH is probably more common than initially thought. In older reports, the prevalence was only 0.1% to 0.36%.^1,3 In contrast, in a mail survey in 2015,⁴ one-third of bariatric surgery patients reported symptoms that raised the suspicion of hypoglycemia. Those with suspicious symptoms were more likely to have undergone Roux-en-Y surgery, to have had no preoperative diabetes, to have had a longer interval since surgery, and to be female. Restricting the suspicion of postprandial hypoglycemia to those who reported more serious symptoms, including needing third-party assistance, the prevalence was 11.6%.

Kefurt et al⁵ followed Roux-en-Y patients who wore a continuous glucose monitor for 86 months after surgery and found that 38% had hypoglycemia; however, symptoms of hypoglycemia were not discussed.

Thus, the exact prevalence is currently unknown. But as time goes by and more procedures are performed, the incidence will likely rise.

OBESITY IS ON THE RISE, AND SO IS WEIGHT-LOSS SURGERY

Obesity is rampant, and its prevalence continues to rise. In 2011–2012, more than two-thirds of adults in the United States were reported as obese.⁶ Complications of obesity such as cardiac disease, diabetes, and cancer lead to increased mortality risk.⁷ Obesity is difficult to reverse, as many people fail to lose weight with diet, exercise, and pharmacotherapy.

Given the difficulty of losing weight and the complications that arise from obesity, bariatric surgery has become increasingly popular. Not only do patients lose significantly more weight with bariatric surgery than with conventional measures, but surgery also reduces and often cures conditions associated with obesity.⁸

Nguyen et al⁹ reported that 671,959 patients underwent gastric bypass procedures in the United States from 2003 to 2008. In a registry maintained by the American Society for Metabolic and Bariatric Surgery¹⁰ from June 2007 to May 2009, the most common bariatric procedure in the United States was Roux-en-Y gastric bypass, followed by sleeve gastrectomy.

DIFFERENTIAL DIAGNOSIS AND DEFINITIONS

The differential diagnosis for hyperinsulinemic hypoglycemia after gastric bypass surgery includes exogenous and endogenous causes (Table 1). Exogenous causes include abuse of insulin secretagogues such as sulfonylureas or meglitinides and abuse of insulin, which may occur in patients with Munchausen syndrome, Munchausen syndrome by proxy, or malingering. Endogenous causes include insulinoma, early and late dumping syndromes, and PGBH.

When differentiating endogenous from exogenous hypoglycemia, insulin and C-peptide levels are useful (Table 2). The pancreas produces proinsulin, which is broken down into insulin and C-peptide. Since exogenous insulin does not have a C-peptide component, people abusing insulin have elevated insulin levels with a low C-peptide level.¹¹ Insulin secretagogues cause endogenous insulin secretion, resulting in elevated levels of both insulin and C-peptide. Thus, a screen for these medications is necessary to determine this as the cause.

Differentiating endogenous causes of hypoglycemia

Differentiating the endogenous causes (insulinoma, early or late dumping syndrome, and PGBH) can be challenging, as all 3 have similar biochemical profiles (Table 2).

Insulinoma is a tumor of pancreatic beta cells that produces excessive amounts of insulin. Unlike dumping syndrome, which only occurs postprandially, insulinoma primarily causes fasting hypoglycemia, although postprandial hypoglycemia can occur less commonly. Insulinoma after Roux-en-Y is rare. Only 7 cases have been reported.¹²

Dumping syndrome is classified as either early or late.

Early dumping syndrome usually occurs within 20 minutes of eating. The rapid transit of carbohydrates into the small intestine results in a fluid shift and a sympathetic response characterized by tachycardia, nausea, and diarrhea. Hypoglycemia is not present. Early dumping syndrome usually arises during the first few months after surgery.¹³

Late dumping syndrome usually occurs 1 to 4 hours after ingestion of a carbohydrate load, with symptoms of diaphoresis, dizziness, and fatigue caused by hypoglycemia from an excessive insulin release in response to the carbohydrates.¹³ It does not tend to cause neuroglycopenic symptoms.¹⁴ We define late dumping syndrome as postprandial hypoglycemic symptoms that occur after eating simple sugars and that resolve with dietary changes alone.

Differentiating late dumping syndrome from PGBH is difficult, as the line between the 2 processes is blurred.¹³

PGBH is defined as postprandial hypoglycemia (although it can be fasting in severe cases), often with neuroglycopenic symptoms, that occurs despite adherence to an acceptable bariatric diet (outlined in Table 3). We categorize PGBH as mild, moderate, or severe. Mild PGBH resolves with dietary changes with or without an alpha-glucosidase inhibitor. Moderate PGBH does not respond to an alpha-glucosidase inhibitor and dietary changes, and alternative or additional medication or medications are needed for resolution. Severe PGBH does not respond to dietary or medical interventions, and patients experience persistent episodes of neuroglycopenia.

THE EXACT MECHANISM IS UNCERTAIN

Patients with PGBH have a significant postprandial rise in glucose (often with levels > 200 mg/dL), leading to a robust insulin response and a subsequent drop in blood glucose.¹⁵

The exact mechanisms causing hypoglycemia are unknown, but excessive release of the incretin hormones glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) are thought to contribute. GLP-1 is primarily secreted in the gut in response to nutrients, causing a glucose-dependent release of insulin and suppression of glucagon, as well as a delay in gastric emptying and motility. Salehi et al¹⁶ demonstrated excessive GLP-1 and insulin release after glucose administration in postbypass patients, with a more exaggerated response in those experiencing postprandial hypoglycemia.

Excessive incretin hormones may also contribute to pancreatic islet cell hyperplasia, leading to hyperinsulinism.¹⁷ Other proposed mechanisms of PGBH are the lack of a decrease in beta cell mass after gastric bypass, a postoperative increase in insulin sensitivity, a decrease in ghrelin (an insulin counterregulatory hormone), and an abnormal glucagon response.^13,17

Pathologic changes vary widely

PGBH is a challenging diagnosis to make pathologically. On review of pancreatic tissue from 36 patients undergoing partial pancreatectomy for PGBH, the pancreatic islet cells of the PGBH group were larger and more irregular compared with controls.^18,19 This histologic condition with islet-cell hypertrophy, hyperplasia, and other changes has been termed nesidioblastosis.^11,14,20 However, the pancreatic tissue appears grossly normal. The histopathologic findings can vary greatly in individual cases and in one-third of cases the pancreatic changes can be minimal, so that “normal” and PGBH cells can be nearly impossible to distinguish from each other.²¹

DIAGNOSIS AND TREATMENT

We recommend a stepwise approach to evaluating and treating PGBH (Figures 1 and 2).

Step 1: Evaluate blood glucose and Whipple triad

The first step is a thorough history, including food consumption and timing of hypoglycemic symptoms. Give the patient a glucometer to take home, with instructions to check blood glucose levels when hypoglycemic symptoms occur. The patient should keep a log documenting time tested, food consumed, symptoms, and blood glucose data.

Hypoglycemic symptoms are categorized as autonomic and neuroglycopenic. Autonomic symptoms include anxiety, palpitations, tremulousness, and diaphoresis. Neuroglycopenic symptoms include confusion, falls, seizures, and loss of consciousness.¹²

There are degrees of hypoglycemia and hypoglycemic symptoms. Clinical hypoglycemia—a blood glucose level low enough to cause signs or symptoms—can be confirmed by the Whipple triad:

• Measured low blood glucose
• Symptoms of low blood glucose
• Relief of symptoms when low blood glucose is corrected.

Hypoglycemic symptoms can occur when the blood glucose level falls to less than 55 mg/dL in healthy people, but this cutoff can shift lower in someone who has recurrent hypoglycemia.

When the Whipple triad is documented, rule out nonhyperinsulinemic causes of hypoglycemia such as hypothyroidism, adrenal insufficiency, underlying organ dysfunction (ie, liver disease), and medications that cause hypoglycemia.

Step 2: Modify the diet

If postprandial hypoglycemia is occurring, the next step is dietary modification. Two studies showed that a low-carbohydrate diet prevented hypoglycemia; however, these diets contained nearly no carbohydrates (with meals consisting of eggs, sausage, cheese, and black coffee or tea).^15,22

Instruct patients to never eat pure carbohydrates without fat or protein, as this can result in a more severe hypoglycemic response.²² In addition, foods with a high glycemic index (a measure of how a carbohydrate-containing food raises blood sugar) should be avoided, and a low glycemic index diet is recommended.²³ High glycemic index foods include white bread, bagels, pretzels, and pineapple. Low glycemic index foods include 100% stone-ground whole wheat or pumpernickel bread, lima beans, butter beans, peas, legumes, lentils, and nonstarchy vegetables.

Our bariatric surgeons provide all postbariatric surgery patients with the dietary guidelines shown in Table 3.²⁴ We also ask our patients with PGBH to limit carbohydrates to 15 to 30 g per meal and to limit added sugars to less than 4 g per meal, including regular and sugar alcohols (polyols). Snacks should contain only protein and fat. In severe cases, we further limit the diet to 15 g of carbohydrate per meal, with no added sugars.

The hypoglycemia occurring with PGBH is treated differently than the hypoglycemia that occurs in diabetic patients. Advise patients with PGBH to treat their hypoglycemic episodes with a simple sugar combined with a protein or fat (eg, a small handful of candy with a spoonful of peanut butter), as they will often have recurrent hypoglycemia if a simple sugar is used alone. If patients regain weight, ask them about frequent eating, which would be related to self-treatment of hypoglycemia.

Step 3: Start an alpha-glucosidase inhibitor

If postprandial hypoglycemia persists despite dietary modification, then start an alpha-glucosidase inhibitor such as acarbose. Acarbose inhibits carbohydrate absorption, resulting in a decreased insulin response; thus, it blunts the decline in postprandial blood glucose.

Unfortunately, gastrointestinal side effects such as flatulence, diarrhea, and abdominal pain occur in up to 20% of patients who take acarbose, often leading to its discontinuation.²⁵ To minimize gastrointestinal side effects, we usually start with 25 mg of acarbose with 1 meal daily for 1 week, then increase the dosage weekly to 25 mg with the other 2 meals. If tolerated, acarbose can be increased to 50 to 100 mg with 3 meals daily.

Step 4: Obtain a mixed meal tolerance test or a provocation meal test

If dietary changes and an alpha-glucosidase inhibitor do not prevent postprandial hypoglycemia from recurring, then confirmation of PGBH is needed, using a mixed meal tolerance test or a provocation meal test.

In a mixed meal tolerance test, the meal consists of 55% carbohydrate, 30% fat, and 15% protein. Patients with hyperinsulinemic hypoglycemia have a rapid rise in blood glucose (> 200 mg/dL) with a robust insulin response that is often followed by hypoglycemia after ingesting a meal containing carbohydrates in this test. Insulin levels that remain elevated after the plasma glucose level falls to less than 55 mg/dL indicate hyperinsulinism.¹¹

Nevertheless, a mixed meal tolerance test will not always induce hypoglycemia. In a study of 51 patients with PGBH, all wore a continuous glucose monitor, were instructed to follow their normal diet for 5 days, and then underwent a mixed meal tolerance test on day 6. The glucose monitor revealed hypoglycemia in 75% of patients, while the mixed meal tolerance test was positive in only 29%.⁵

Moreover, to date, there is no standardized mixed meal.^5,15 This might also explain the difference in prevalence of hypoglycemia detected by this test.

Based on these conflicting findings, we recommend a provocation meal test—ie, the patient is given foods that have induced hypoglycemia earlier.

Of note, the Endocrine Society guidelines on hypoglycemia state that an oral glucose tolerance test should never be used to document postprandial hypoglycemia.²⁶ Lev-Ran and Anderson²⁷ found that an oral glucose tolerance test could be positive in at least 10% of normal people.

Step 5: Consider other pharmacotherapy

For moderate to severe PGBH in which dietary modification and acarbose have failed, additional medical therapy is the next step. Medical therapies include calcium channel blockers, somatostatin analogues (eg, octreotide), and diazoxide.

Calcium channel blockers inhibit insulin release from beta cells²⁸ but at the risk of hypotension. Mordes and Alonso²⁹ treated 6 PGBH patients with nifedipine or verapamil with or without acarbose, and symptoms resolved in 5 of the 6 patients.

When we treat PGBH, we often add a calcium channel blocker as the next step in therapy if the patient has hypertension or if the blood pressure can tolerate this. If the patient’s blood pressure is low, then avoiding calcium channel blocker therapy may be necessary. The next step would be octreotide and then diazoxide.

Somatostatin analogues such as octreotide inhibit GLP-1 and insulin release.³⁰ The most common side effects of octreotide are diarrhea and abdominal pain. Bile stone formation can also occur, but this is not common.

Diazoxide opens adenosine triphosphate-sensitive potassium channels and reduces the opening of calcium channels, inhibiting insulin release and raising blood glucose. In a study of 6 Japanese patients with inoperable insulinoma, diazoxide was used to treat hypoglycemia.³¹ Unfortunately, the doses required to control the low blood sugars also led to adverse reactions, most of which involved edema secondary to volume overload and other heart failure symptoms. Diazoxide also commonly causes hypotension and hirsutism.

Step 6: 72-hour fast

A 72-hour fast is recommended in severe cases of PGBH in patients for whom dietary modification and the additional pharmacotherapy outlined in step 5 have failed. A 72-hour fast is always indicated in evaluating confirmed fasting hypoglycemia. People with insulinoma usually have fasting hypoglycemia, while patients with dumping syndrome do not. Patients with PGBH usually do not have fasting hypoglycemia, but they can in severe cases.¹¹

For safety, this test should be done in the hospital. Baseline plasma levels of insulin, C-peptide, proinsulin, beta-hydroxybutyrate, and glucose should be obtained. The patient then fasts, consuming only noncaloric and noncaffeinated beverages for 72 hours. During this time, capillary glucose checks are performed every 6 hours. If the capillary glucose level falls below 55 mg/dL,^11,26 then the baseline tests are redrawn along with a sulfonylurea screen. To reduce costs and unnecessary testing, the tests are not sent for laboratory processing unless the plasma glucose is less than 55 mg/dL.

When the plasma glucose is less than 55 mg/dL, insulin production should cease. Elevated insulin levels and insulin byproducts raise concern for hyperinsulinism. These values confirm hyperinsulinemic hypoglycemia²⁶:

• Glucose < 55 mg/dL
• Insulin ≥ 3 µU/mL
• C-peptide ≥ 0.2 nmol/L
• Proinsulin ≥ 5.0 pmol/L.

After hypoglycemia is confirmed, 1 mg of glucagon is given intravenously, and plasma glucose levels are obtained at 10, 20, and 30 minutes.^11,26 A rise in plasma glucose of at least 25 mg/dL after intravenous glucagon injection indicates hypoglycemia due to hyperinsulinemia. Two-thirds of patients with insulinoma experience hypoglycemia within the first 24 hours, and nearly all experience hypoglycemia within 48 hours.²⁶

Step 7: Obtain pancreatic imaging

If fasting hypoglycemia is present and hyperinsulinemic hypoglycemia is confirmed during a 72-hour fast, then pancreatic imaging should be obtained to evaluate for an insulinoma. We also recommend pancreatic imaging to rule out insulinoma when severe PGBH has not responded to dietary modification or pharmacotherapy.

Imaging is not recommended in PGBH that has been successfully treated with dietary modification with or without pharmacotherapy.

Endoscopic ultrasonography alone has 80% to 92% sensitivity for localizing a pancreatic mass as small as 5 mm. However, when coupled with computed tomography or magnetic resonance imaging, the sensitivity increases to nearly 100%.¹²

Step 8: Selective arterial calcium stimulation test

If a patient is found to have hyperinsulinemic hypoglycemia during a 72-hour fast but pancreatic imaging is negative, then selective arterial calcium stimulation testing (SACST) and hepatic vein sampling should be performed. Also, for severe PGBH, in which hypoglycemia has persisted despite dietary modification and pharmacotherapy, SACST can be performed to evaluate for possible localization of hyperinsulinism in patients considering surgery. For mild and moderate cases of PGBH, in which the hypoglycemia has been successfully treated with dietary changes with or without pharmacotherapy, SACST is not necessary.

This test can localize the area of excess insulin production in the pancreas in patients with an insulinoma. Patients with severe PGBH usually have diffuse hyperinsulinism without localization on SACST.^32,33

When SACST is performed, a sampling catheter is placed in the femoral vein. Calcium gluconate is injected into the major arteries of the pancreas (superior mesenteric, gastroduodenal, and splenic arteries). Calcium stimulates release of insulin from an insulinoma or hyperplastic beta cells. Resultant insulin levels are measured in the hepatic vein. If there is a greater than twofold increase in insulin release from 2 segments, then the test is considered positive.

Thompson et al³⁴ documented that insulin release from insulinoma is almost 4 times higher than in diffuse nesidioblastosis. SACST has a sensitivity of 96% for detecting insulinomas.³⁵

Step 9: Other alternatives and surgery

In patients with severe PGBH for whom dietary modification and all pharmacotherapy have failed and who continue to have debilitating neuroglycopenia, there are options before proceeding with surgery, the last resort in this condition.

Continuous glucose monitoring is helpful in many patients with severe PGBH. Many of them have hypoglycemia unawareness, and the monitor alerts them when their blood sugar is low. In addition, the monitor indicates when the blood sugar is dropping, so that intervention can occur before hypoglycemia occurs.

Unfortunately, insurance coverage for continuous monitors in this patient population is limited. We argue that insurance should cover the cost for these severe cases.

Pasireotide, a somatostatin analogue that is longer-acting than octreotide, is approved for use in Cushing disease and acromegaly and actually causes hyperglycemia. In a case report of a 50-year-old woman, pasireotide resulted in less hypoglycemia and higher glucagon levels then octreotide.³⁶ Pasireotide is available from Novartis for compassionate use in patients with severe PGBH.

Glucocorticoids are another off-label option. However, in excess, they can lead to iatrogenic Cushing syndrome, which has its own complications. Prednisone and diazoxide have been used together to help prevent hypoglycemia in a patients with inoperable insulinoma.³¹

Tube feeding. Some researchers have studied altering nutrition access through surgical means. McLaughlin et al³⁷ discussed a case of gastric tube insertion into the remnant stomach of a patient with PGBH, with resolution of hypoglycemic symptoms and hypoglycemia; however, this does not always provide complete resolution of symptoms.^37,38 If gastric bypass reversal is being considered, a trial of solely remnant stomach tube feeds (with no oral intake) should be pursued first. If this ameliorates the hypoglycemia, then gastric bypass reversal may be of benefit.

Surgery is the last resort if all of the above treatments have failed and severe debilitating neuroglycopenia persists. However, surgery poses risks, and the success rate in correcting hypoglycemia is not ideal. Surgical options include Roux-en-Y reversal, gastric pouch resection, and pancreatic resection.

In a review by Mala,² 75 patients with documented PGBH underwent surgical therapy. Hypoglycemic symptoms resolved in 34 of 51 pancreatic resections, 13 of 17 Roux-en-Y reversals, and 9 of 11 gastric pouch resections. However, the follow-up period was short.

As noted above, we recommend calcium stimulation testing only for severe cases of PGBH when surgery is being considered to evaluate for possible localization of hyperinsulinism for which partial pancreatectomy would be of benefit. Since there is no localization in many PGBH cases and the success rates are slightly higher in gastric bypass reversal, bypass reversal is usually preferred over partial or complete pancreatectomy.^2,32,33

POTENTIAL FUTURE THERAPIES

Given the elevated GLP-1 levels and robust insulin response to glucose observed in PGBH, blocking GLP-1 may provide clinical benefit. Salehi et al¹⁶ found that a GLP-1 antagonist prevented surges in GLP-1 and reduced hypoglycemic episodes in patients with PGBH. Unfortunately, the medication they used was given as a continuous infusion and is not currently available.

Conversely, a GLP-1 agonist showed benefit in a series of 5 cases of PGBH.³⁹ In addition, an insulin receptor antibody is undergoing phase 2 trials and has been shown to reverse insulin-induced hypoglycemia in rodents and humans; it may be a novel therapy in the future for hyperinsulinemic hypoglycemia.⁴⁰

MORE STUDY NEEDED

As the prevalence of obesity continues to rise and more people opt for bariatric surgery for weight loss, we will likely continue to see an increase in PGBH, since the onset of PGBH can be delayed for many years after surgery.²⁸

Unfortunately, the disease process involved in PGBH is not well understood. For example, we do not know why GLP-1 elevations or a robust insulin response causing hypoglycemia occurs in some but not all gastric bypass patients. Study is needed to elucidate the pathophysiology to further understand why most patients have no hypoglycemia after gastric bypass, some have mild to moderate PGBH, and a small percentage have severe PGBH with debilitating neuroglycopenia unresponsive to dietary changes and medications.