For decades, physicians believed in the benefit of prompt transfusion of blood to keep the hemoglobin level at arbitrary, optimum levels, ie, close to normal values, especially in the critically ill, the elderly, and those with coronary syndromes, stroke, or renal failure.

However, the evidence supporting arbitrary hemoglobin values as an indication for transfusion was weak or nonexistent. Also, blood transfusion can have complications and adverse effects, and blood is costly and scarce. These considerations prompted research into when blood transfusion should be considered, and recommendations that it should be used more sparingly than in the past.

This review offers a perspective on the evidence supporting restrictive blood use. First, we focus on hemodilution studies that demonstrated that humans can tolerate anemia. Then, we look at studies that compared a restrictive transfusion strategy with a liberal one in patients with critical illness and active bleeding. We conclude with current recommendations for blood transfusion.

EVIDENCE FROM HEMODILUTION STUDIES

Hemoglobin is essential for tissue oxygenation, but the serum hemoglobin concentration is just one of several factors involved.^1–5 In anemia, the body can adapt not only by increasing production of red blood cells, but also by:

• Increasing cardiac output
• Increasing synthesis of 2,3-diphosphoglycerate (2,3-DPG), with a consequent shift in the oxyhemoglobin dissociation curve to the right, allowing enhanced release of oxygen at the tissue level
• Moving more carbon dioxide into the blood (the Bohr effect), which decreases pH and also shifts the dissociation curve to the right.

Just 20 years ago, physicians were using arbitrary cutoffs such as hemoglobin 10 g/dL or hematocrit 30% as indications for blood transfusion, without reasonable evidence to support these values. Not until acute normovolemic hemodilution studies were performed were we able to progressively appraise how well patients could tolerate lower levels of hemoglobin without significant adverse outcomes.

Acute normovolemic hemodilution involves withdrawing blood and replacing it with crystalloid or colloid solution to maintain the volume.⁶

Initial studies were done in animals and focused on the safety of acute anemia regarding splanchnic perfusion. Subsequently, studies proved that healthy, elderly, and stable cardiac patients can tolerate acute anemia with normal cardiovascular response. The targets in these studies were modest at first, but researchers aimed progressively for more aggressive hemodilution with lower hemoglobin targets and demonstrated that the body can tolerate and adapt to more severe anemia.^6–8

Studies in healthy patients

Weiskopf et al⁹ assessed the effect of severe anemia in 32 conscious healthy patients (11 presurgical patients and 21 volunteers not undergoing surgery) by performing acute normovolemic hemodilution with 5% human albumin, autologous plasma, or both, with a target hemoglobin level of 5 g/dL. The process was done gradually, obtaining aliquots of blood of 500 to 900 mL. Cardiac index increased, along with a mild increase in oxygen consumption with no increase in plasma lactate levels, suggesting that in conscious healthy patients, tissue oxygenation remains adequate even in severe anemia.

Leung et al¹⁰ addressed the electrocardiographic changes that occur with severe anemia (hemoglobin 5 g/dL) in 55 healthy volunteers. Three developed transient, reversible ST-segment depression, which was associated with a higher heart rate than in the volunteers with no electrocardiographic changes; however, the changes were reversible and asymptomatic, and thus were considered physiologic and benign.

Hemodilution in healthy elderly patients

Spahn et al¹¹ performed 6 and 12 mL/kg isovolemic exchange of blood for 6% hydroxyethyl starch in 20 patients older than 65 years (mean age 76, range 65–88) without underlying coronary disease.

The patients’ mean hemoglobin level decreased from 11.6 g/dL to 8.8 g/dL. Their cardiac index and oxygen extraction values increased adequately, with stable oxygen consumption during hemodilution. There were no electrocardiographic signs of ischemia.

Hemodilution in coronary artery disease

Spahn et al¹² performed hemodilution studies in 60 patients (ages 35–81) with coronary artery disease managed chronically with beta-blockers who were scheduled for coronary artery bypass graft surgery. Hemodilution was performed with 6- and 12-mL/kg isovolemic exchange of blood for 6% hydroxyethyl starch maintaining normovolemia and stable filling pressures. Hemoglobin levels decreased from 12.6 g/dL to 9.9 g/dL. The hemodilution process was done before the revascularization. The authors monitored hemodynamic variables, ST-segment deviation, and oxygen consumption before and after each hemodilution.

There was a compensatory increase in cardiac index and oxygen extraction with consequent stable oxygen consumption. These changes were independent of patient age or left ventricular function. In addition, there were no electrocardiographic signs of ischemia.

Licker et al¹³ studied the hemodynamic effect of preoperative hemodilution in 50 patients with coronary artery disease undergoing coronary artery bypass graft surgery, performing transesophageal echocardiography before and after hemodilution. The patients underwent isovolemic exchange with iso-oncotic starch to target a hematocrit of 28%.

Acute normovolemic hemodilution triggered an increase in cardiac stroke volume, which had a direct correlation with an increase in the central venous pressure and the left ventricular end-diastolic area. No signs of ischemia were seen in these patients on electrocardiography or echocardiography (eg, left ventricular wall-motion abnormalities).

Hemodilution in mitral regurgitation

Spahn et al¹⁴ performed acute isovolemic hemodilution with 6% hydroxyethyl starch in 20 patients with mitral regurgitation. The cardiac filling pressures were stable before and after hemodilution; the mean hemoglobin value decreased from 13 to 10.3 g/dL. The cardiac index and oxygen extraction increased proportionally, with stable oxygen consumption; these findings were the same regardless of whether the patient was in normal sinus rhythm or atrial fibrillation.

Effect of hemodilution on cognition

Weiskopf et al¹⁵ assessed the effect of anemia on executive and memory function by inducing progressive acute isovolemic anemia in 90 healthy volunteers (age 29 ± 5), reducing their hemoglobin values to 7, 6, and 5 g/dL and performing repetitive neuropsychological and memory testing before and after the hemodilution, as well as after autologous blood transfusion to return their hemoglobin level to 7 g/dL.

There were no changes in reaction time or error rate at a hemoglobin concentration of 7 g/dL compared with the performance at a baseline hemoglobin concentration of 14 g/dL. The volunteers got slower on a mathematics test at hemoglobin levels of 6 g/dL and 5 g/dL, but their error rate did not increase. Immediate and delayed memory were significantly impaired at hemoglobin of 5 g/dL but not at 6 g/dL. All tests normalized with blood transfusion once the hemoglobin level reached 7 g/dL.¹⁵

Weiskopf et al¹⁶ subsequently investigated whether giving supplemental oxygen to raise the arterial partial pressure of oxygen (Pao₂) to 350 mm Hg or greater would overcome the neurocognitive effects of severe acute anemia. They followed a protocol similar to the one in the earlier study¹⁵ and induced anemia in 31 healthy volunteers, age 28 ± 4 years, with a mean baseline hemoglobin concentration of 12.7 g/dL.

When the volunteers reached a hemoglobin concentration of 5.7 ± 0.3 g/dL, they were significantly slower on the mathematics test, and their delayed memory was significantly impaired. Then, in a double-blind fashion, they were given either room air or oxygen. Oxygen increased the Pao₂ to 406 mm Hg and normalized neurocognitive performance.

Hemodilution studies in surgical patients

Hemodilution studies paved the way for justifying a more conservative and restrictive transfusion strategy

A 2015 meta-analysis¹⁷ of 63 studies involving 3,819 surgical patients compared the risk of perioperative allogeneic blood transfusion as well as the overall volume of transfused blood in patients undergoing preoperative acute normovolemic hemodilution vs a control group. Though the overall data showed that the patients who underwent acute normovolemic hemodilution needed fewer transfusions and less blood (relative risk [RR] 0.74, 95% confidence interval [CI] 0.63–0.88, P = .0006), the authors noted significant heterogeneity and publication bias.

However, the hemodilution studies paved the way for justifying a more conservative and restrictive transfusion strategy, with a hemoglobin cutoff value of 7 g/dL, and in acute anemia, using oxygen to overcome acute neurocognitive effects while searching for and correcting the cause of the anemia.

STUDIES OF RESTRICTIVE VS LIBERAL TRANSFUSION STRATEGIES

Studies in critical care and high-risk patients

Hébert et al¹⁸ randomized 418 critical care patients to a restrictive transfusion approach (in which they were given red blood cells if their hemoglobin concentration dropped below 7.0 g/dL) and 420 patients to a liberal strategy (given red blood cells if their hemoglobin concentration dropped below 10.0 g/dL). Mortality rates (restrictive vs liberal strategy) were as follows:

• Overall at 30 days 18.7% vs 23.3%, P = .11
• In the subgroup with less-severe disease (Acute Physiology and Chronic Health Evaluation II [APACHE II] score < 20), 8.7% vs 16.1%, P = .03
• In the subgroup under age 55, 5.7% vs 13%, P = .02
• In the subgroup with clinically significant cardiac disease, 20.5% vs 22.9%, P = .69
• In the hospital, 22.2% vs 28.1%; P = .05.

This study demonstrated that parsimonious blood use did not worsen clinical outcomes in critical care patients.

Carson et al¹⁹ evaluated 2,016 patients age 50 and older who had a history of or risk factors for cardiovascular disease and a baseline hemoglobin level below 10 g/dL who underwent surgery for hip fracture. Patients were randomized to two transfusion strategies based on threshold hemoglobin level: restrictive (< 8 g/dL) or liberal (< 10 g/dL). The primary outcome was death or inability to walk without assistance at 60-day follow-up. The median number of units of blood used was 2 in the liberal group and 0 in the restrictive group.

There was no significant difference in the rates of the primary outcome (odds ratio [OR] 1.01, 95% CI 0.84–1.22), infection, venous thromboembolism, or reoperation. This study demonstrated that a liberal transfusion strategy offered no benefit over a restrictive one.

Rao et al²⁰ analyzed the impact of blood transfusion in 24,112 patients with acute coronary syndromes enrolled in three large trials. Ten percent of the patients received at least 1 blood transfusion during their hospitalization, and they were older and had more complex comorbidity.

At 30 days, the group that had received blood had higher rates of death (adjusted hazard ratio [HR] 3.94, 95% CI 3.26–4.75) and the combined outcome of death or myocardial infarction (HR 2.92, 95% CI 2.55–3.35). Transfusion in patients whose nadir hematocrit was higher than 25% was associated with worse outcomes.

This study suggests being cautious about routinely transfusing blood in stable patients with ischemic heart disease solely on the basis of arbitrary hematocrit levels.

Carson et al,²¹ however, in a later trial, found a trend toward worse outcomes with a restrictive strategy than with a liberal one. Here, 110 patients with acute coronary syndrome or stable angina undergoing cardiac catheterization were randomized to a target hemoglobin level of either at least 8 mg/dL or at least 10 g/dL. The primary outcome (a composite of death, myocardial infarction, or unscheduled revascularization 30 days after randomization) occurred in 14 patients (25.5%) in the restrictive group and 6 patients (10.9%) in the liberal group (P = .054), and 7 (13.0%) vs 1 (1.8%) of the patients died (P = .032).

These studies suggest the need for more definitive trials in patients with active coronary disease and in cardiac surgery patients

Murphy et al²² similarly found trends toward worse outcomes with a restrictive strategy in cardiac patients. The investigators randomized 2,007 elective cardiac surgery patients with a postoperative hemoglobin level lower than 9 g/dL to a hemoglobin transfusion threshold of either 7.5 or 9 g/dL. Outcomes (restrictive vs liberal strategies):

• Transfusion rates 53.4% vs 92.2%
• Rates of the primary outcome (a serious infection [sepsis or wound infection] or ischemic event [stroke, myocardial infarction, mesenteric ischemia, or acute kidney injury] within 3 months):
  35.1% vs 33.0%, OR 1.11, 95% CI 0.91–1.34, P = .30)
• Mortality rates 4.2% vs 2.6%, HR 1.64, 95% CI 1.00–2.67, P = .045
• Total costs did not differ significantly between the groups.

These studies^21,22 suggest the need for more definitive trials in patients with active coronary disease and in cardiac surgery patients.

Holst et al²³ randomized 998 intensive care patients in septic shock to hemoglobin thresholds for transfusion of 7 vs 9 g/dL. Mortality rates at 90 days (the primary outcome) were 43.0% vs 45.0%, RR 0.94, 95% CI 0.78–1.09, P = .44.

This study suggests that even in septic shock, a liberal transfusion strategy has no advantage over a parsimonious one.

Active bleeding, especially active gastrointestinal bleeding, poses a significant stress that may trigger empirical transfusion even without evidence of the real hemoglobin level.

Villanueva et al²⁴ randomized 921 patients with severe acute upper-gastrointestinal bleeding to two groups, with hemoglobin transfusion triggers of 7 vs 9 g/dL. The findings were impressive:

• Freedom from transfusion 51% vs 14% (P < .001)
• Survival rates at 6 weeks 95% vs 91% (HR 0.55, 95% CI 0.33–0.92, P = .02)
• Rebleeding 10% vs 16% (P = .01). 


Patients with peptic ulcer disease as well as those with cirrhosis stage Child-Pugh class A or B had higher survival rates with a restrictive transfusion strategy.

The RELIEVE trial²⁵ compared the effect of a restrictive transfusion strategy in elderly patients on mechanical ventilation in 6 intensive care units in the United Kingdom. Transfusion triggers were hemoglobin 7 vs 9 g/dL, and the mortality rate at 180 days was 55% vs 37%, RR 0.68, 95% CI 0.44–1.05, P = .073.

Meta-analyses and observational studies

Rohde et al²⁶ performed a systematic review and meta-analysis of 17 trials with 7,456 patients, which revealed that a restrictive strategy is associated with a lower risk of nosocomial infection, including pneumonia, wound infection, and sepsis.

The pooled risk of all serious infections was 10.6% in the restrictive group and 12.7% in the liberal group. Even after adjusting for the use of leukocyte reduction, the risk of infection was lower in the restrictive strategy group (RR 0.83, 95% CI 0.69–0.99). With a hemoglobin threshold of less than 7.0 g/dL, the risk of serious infection was 14% lower. Although this was not statistically significant overall (RR 0.86, 95% CI 0.72–1.02), the difference was statistically significant in the subgroup undergoing orthopedic surgery (RR 0.72, 95% CI 0.53–0.97) and the subgroup presenting with sepsis (RR 0.51, 95% CI 0.28–0.95).

Salpeter et al²⁷ performed a meta-analysis and systematic review of three randomized trials (N = 2,364) comparing a restrictive hemoglobin transfusion trigger (hemoglobin < 7 g/dL) vs a more liberal trigger. The groups with restrictive transfusion triggers had lower rates of:

• In-hospital mortality (RR 0.74, 95% CI 0.60–0.92)
• Total mortality (RR 0.80, 95% CI 0.65–0.98)
• Rebleeding (RR 0.64, 95% CI 0.45–0.90)
• Acute coronary syndrome (RR 0.44, 95% CI 0.22–0.89)
• Pulmonary edema (RR 0.48, 95% CI 0.33–0.72)
• Bacterial infections (RR 0.86, 95% CI 0.73–1.00).

Wang et al²⁸ performed a meta-analysis of 4 randomized controlled trials in patients with upper-gastrointestinal bleeding comparing restrictive (hemoglobin < 7 g/dL) vs liberal transfusion strategies. The primary outcomes were death and rebleeding. The restrictive strategy was associated with:

• A lower mortality rate (OR 0.52, 95% CI 0.31–0.87, P = .01)
• A lower rebleeding rate (OR 0.26, 95% CI 0.03–2.10, P = .21)
• Shorter hospitalizations (P = .009)
• Less blood transfused (P = .0005).

The more units of blood the patients received, the more likely they were to die

Vincent et al,²⁹ in a prospective observational study of 3,534 patients in intensive care units in 146 facilities in Western Europe, found a correlation between transfusion and mortality. Transfusion was done most often in elderly patients and those with a longer stay in the intensive care unit. The 28-day mortality rate was 22.7% in patients who received a transfusion and 17.1% in those who did not (P = .02). The more units of blood the patients received, the more likely they were to die, and receiving more than 4 units was associated with worse outcomes (P = .01).

Dunne et al³⁰ performed a study of 6,301 noncardiac surgical patients in the Veterans Affairs Maryland Healthcare System from the National Veterans Administration Surgical Quality Improvement Program from 1995 to 2000. Multiple logistic regression analysis revealed that the composite of low hematocrit before and after surgery and high transfusion rates (> 4 units per hospitalization) were associated with higher rates of death (P < .01) and postoperative pneumonia (P ≤ .05) and longer hospitalizations (P < .05). The risk of pneumonia increased proportionally with the decrease in hematocrit.

These findings support pharmacologic optimization of anemia with hematinic supplementation before surgery to decrease the risk of needing a transfusion, often with parenteral iron. The fact that the patient’s hemoglobin can be optimized preoperatively by nontransfusional means may decrease the likelihood of blood transfusion, as the hemoglobin will potentially remain above the transfusion threshold. For example, if a patient has a preoperative hemoglobin level of 10 g/dL, and it is optimized up to 12, then if postoperatively the hemoglobin level drops 3 g/dL instead of reaching the threshold of 7 g/dL, the nadir will be just 9 g/dL, far above that transfusion threshold.

Brunskill et al,³¹ in a Cochrane review of 6 trials with 2,722 patients undergoing surgery for hip fracture, found no difference in rates of mortality, functional recovery or postoperative morbidity with a restrictive transfusion strategy (hemoglobin target > 8 g/dL vs a liberal one (> 10 g/dL). However, the quality of evidence was rated as low. The authors concluded that there is no justification for liberal red blood cell transfusion thresholds (10 g/dL), and a more restrictive transfusion threshold is preferable.

Weinberg et al³² found that, in trauma patients, receiving more than 6 units of blood was associated with poor prognosis, and outcomes were worse when the blood was older than 2 weeks. However, the effect of blood age is not significant when using smaller transfusion volumes (1 to 2 units of red blood cells).

Studies in sickle cell disease

Sickle cell disease patients have high levels of hemoglobin S, which causes erythrocyte sickling and increases blood viscosity. Transfusion with normal erythrocytes increases the amount of hemoglobin A (the normal variant).^33,34

In trials in surgical patients,^35,36 conservative strategies for preoperative blood transfusion aiming at a hemoglobin level of 10 g/dL were as effective in preventing postoperative complications as decreasing the hemoglobin S levels to 30% by aggressive exchange transfusion.³⁵

In nonsurgical patients, blood transfusion should be based on formal risk-benefit assessments. Therefore, the expert panel report on sickle cell management advises against blood transfusion in sickle cell patients with uncomplicated vaso-occlusive crises, priapism, asymptomatic anemia, or acute kidney injury in the absence of multisystem organ failure.³⁴

Is hemoglobin the most relevant marker?

Most studies that compared restrictive and liberal transfusion strategies focused on using a lower hemoglobin threshold as the transfusion trigger, not on using fewer units of blood. Is the amount of blood transfused more important than the hemoglobin threshold? Perhaps a study focused both on a restrictive vs liberal strategy and also on the minimum amount of blood that each patient may benefit from would help to answer this question.

Beware of using the hemoglobin concentration as a threshold for transfusion and a marker of benefit

We should beware of routinely using the hemoglobin concentration as a threshold for transfusion and a surrogate marker of transfusion benefit because changes in hemoglobin concentration may not reflect changes in absolute red cell mass.³⁷ Changes in plasma volume (an increase or decrease) affect the hematocrit concentration without necessarily affecting the total red cell mass. Unfortunately, red cell mass is very difficult to measure; hence, the hemoglobin and hematocrit values are used instead. Studies addressing changes in red cell mass may be needed, perhaps even to validate using the hemoglobin concentration as the sole indicator for transfusion.

Is fresh blood better than old blood?

Using blood that is more than 14 days old may be associated with poor outcomes, for several possible reasons. Red blood cells age rapidly in refrigeration, and usually just 75% may remain viable 24 hours after phlebotomy. Adenosine triphosphate and 2,3-DPG levels steadily decrease, with a consequent decrease in capacity for appropriate tissue oxygen delivery. In addition, loss of membrane phospholipids causes progressive rigidity of the red cell membrane with consequent formation of echynocytes after 14 to 21 days.^38,39

The use of blood more than 14 days old in cardiac surgery patients has been associated with worse outcomes, including higher rates of death, prolonged intubation, acute renal failure, and sepsis.⁴⁰ Similar poor outcomes have been seen in trauma patients.³²

Lacroix et al,⁴¹ in a multicenter, randomized trial in critically ill adults, compared the outcomes of transfusion of fresh packed red cells (stored < 8 days) or old blood (stored for a mean of 22 days). The primary outcome was the mortality rate at 90 days: 37.0% in the fresh-blood group vs 35.3% in the old-blood group (HR 1.1, 95% CI 0.9–1.2, P = .38).

The authors concluded that using fresh blood compared with old blood was not associated with a lower 90-day mortality rate in critically ill adults.

RISKS ASSOCIATED WITH TRANSFUSION

Infections

The risk of infection from blood transfusion is small. Human immunodeficiency virus (HIV) is transmitted in 1 in 1.5 million transfused blood components, and hepatitis C virus in 1 in 1.1 million; these odds are similar to those of having a fatal airplane accident (1 in 1.7 million per flight). Hepatitis B virus infection is more common, the reported incidence being 1 in 357,000.⁴²

Noninfectious complications

Transfusion-associated circulatory overload occurs in 4% to 6% of patients who receive a transfusion. Therefore, circulatory overload is a greater danger from transfusion than infection is.⁴²

Febrile nonhemolytic transfusion reactions occur in 1.1% of patients with prestorage leukoreduction.

Transfusion-associated acute lung injury occurs in 0.8 per 10,000 blood components transfused.

Errors associated with blood transfusion include, in decreasing order of frequency, transfusion of the wrong blood component, handling and storage errors, inappropriate administration of anti-D immunoglobulin, and avoidable, delayed, or insufficient transfusions.⁴³

Surgery and condition-specific complications of red blood cell transfusion

Cardiovascular surgery. Transfusion is associated with a higher risk of postoperative stroke, respiratory failure, acute respiratory distress syndrome, prolonged intubation time, reintubation, in-hospital death, sepsis, and longer postoperative length of stay.⁴⁴

Malignancy. The use of blood in this setting has been found to be an independent predictor of recurrence, decreased survival, and increased risk of lymphoplasmacytic and marginal-zone lymphomas.^44–47

Vascular, orthopedic, and other surgeries. Transfusion is associated with a higher risk of death, thromboembolic events, acute kidney injury, death, composite morbidity, reoperation, sepsis, and pulmonary complications.⁴⁴

ST-segment elevation myocardial infarction, sepsis, and intensive care unit admissions. Transfusion is associated with an increased risk of rebleeding, death, and secondary infections.⁴⁴

COST OF RED BLOOD CELL TRANSFUSION

Up to 85 million units of red blood cells are transfused per year worldwide, 15 million of them in the United States.⁴² At our hospital in 2013, 1 unit of leukocyte-reduced red blood cells cost $957.27, which included the costs of acquisition, processing, banking, patient testing, administration, and monitoring.

The Premier Healthcare Alliance⁴⁸ analyzed data from 7.4 million discharges from 464 hospitals between April 2011 and March 2012. Blood use varied significantly among hospitals, and the hospitals in the lowest quartile of blood use had better patient outcomes. If all the hospitals used as little blood as those in the lowest quartile and had outcomes as good, blood product use would be reduced by 802,716 units, with savings of up to $165 million annually.

In addition to the economic cost of blood transfusion, the clinician must be aware of the cost in terms of comorbidities caused by unnecessary blood transfusion.^49,50

RECOMMENDATIONS FROM THE AABB

In view of all the current compelling evidence, a restrictive approach to transfusion is the single best strategy to minimize adverse outcomes.⁵¹ Below, we outline the current recommendations from the AABB (formerly the American Association of Blood Banks),⁴² which are similar to the national clinical guideline on blood transfusion in the United Kingdom,⁵² and have recently been updated, confirming the initial recommendations.⁵³

In critical care patients, transfusion should be considered if the hemoglobin concentration is 7 g/dL or less.

In postoperative patients and hospitalized patients with preexisting cardiovascular disease, transfusion should be considered if the hemoglobin concentration is 8 g/dL or less or if the patient has signs or symptoms of anemia such as chest pain, orthostatic hypotension, or tachycardia unresponsive to fluid resuscitation, or heart failure.

In hemodynamically stable patients with acute coronary syndrome, there is not enough evidence to allow a formal recommendation for or against a liberal or restrictive transfusion threshold.

Consider both the hemoglobin concentration and the symptoms when deciding whether to give a transfusion. This recommendation is shared by a National Institutes of Health consensus conference,⁵⁴ which indicates that multiple factors related to the patient’s clinical status and oxygen delivery should be considered before deciding to transfuse red blood cells.

The Society of Hospital Medicine⁵⁵ and the American Society of Hematology⁵⁶ concur with a parsimonious approach to blood use in their Choosing Wisely campaigns. The American Society of Hematology recommends that if transfusion of red blood cells is necessary, the minimum number of units should be given that relieve the symptoms of anemia or achieve a safe hemoglobin range (7–8 g/dL in stable noncardiac inpatients).⁵⁷

New electronic tools can monitor the ordering and use of blood products in real time and can identify the hemoglobin level used as the trigger for transfusion. They also provide data on blood use by physician, hospital, and department. These tools can reveal current practice at a glance and allow sharing of best practices among peers and institutions.⁵²

CONSIDER TRANSFUSION FOR HEMOGLOBIN BELOW 7 G/DL

The routine use of blood has come under scrutiny, given its association with increased healthcare costs and morbidity. The accepted practice in stable medical patients is a restrictive threshold approach for blood transfusion, which is to consider (not necessarily give) a single unit of packed red blood cells for a hemoglobin less than 7 g/dL.

However, studies in acute coronary syndrome patients and postoperative cardiac surgery patients have not shown the restrictive threshold to be superior to a liberal threshold in terms of outcomes and costs. This variability suggests the need for further studies to determine the best course of action in different patient subpopulations (eg, surgical, oncologic, trauma, critical illness).

Also, a limitation of most of the clinical studies was that only the hemoglobin concentration was used as a marker of anemia, with no strict assessment of changes in red cell mass with transfusion.

Despite the variability in certain populations, the overall weight of current evidence favors a restrictive approach to blood transfusion (hemoglobin < 7 g/dL), although perhaps in patients who have active coronary disease or are undergoing cardiac surgery, a more lenient threshold (< 8 g/dL) for transfusion should be considered.

For decades, physicians believed in the benefit of prompt transfusion of blood to keep the hemoglobin level at arbitrary, optimum levels, ie, close to normal values, especially in the critically ill, the elderly, and those with coronary syndromes, stroke, or renal failure.

However, the evidence supporting arbitrary hemoglobin values as an indication for transfusion was weak or nonexistent. Also, blood transfusion can have complications and adverse effects, and blood is costly and scarce. These considerations prompted research into when blood transfusion should be considered, and recommendations that it should be used more sparingly than in the past.

This review offers a perspective on the evidence supporting restrictive blood use. First, we focus on hemodilution studies that demonstrated that humans can tolerate anemia. Then, we look at studies that compared a restrictive transfusion strategy with a liberal one in patients with critical illness and active bleeding. We conclude with current recommendations for blood transfusion.

EVIDENCE FROM HEMODILUTION STUDIES

Hemoglobin is essential for tissue oxygenation, but the serum hemoglobin concentration is just one of several factors involved.^1–5 In anemia, the body can adapt not only by increasing production of red blood cells, but also by:

• Increasing cardiac output
• Increasing synthesis of 2,3-diphosphoglycerate (2,3-DPG), with a consequent shift in the oxyhemoglobin dissociation curve to the right, allowing enhanced release of oxygen at the tissue level
• Moving more carbon dioxide into the blood (the Bohr effect), which decreases pH and also shifts the dissociation curve to the right.

Just 20 years ago, physicians were using arbitrary cutoffs such as hemoglobin 10 g/dL or hematocrit 30% as indications for blood transfusion, without reasonable evidence to support these values. Not until acute normovolemic hemodilution studies were performed were we able to progressively appraise how well patients could tolerate lower levels of hemoglobin without significant adverse outcomes.

Acute normovolemic hemodilution involves withdrawing blood and replacing it with crystalloid or colloid solution to maintain the volume.⁶

Initial studies were done in animals and focused on the safety of acute anemia regarding splanchnic perfusion. Subsequently, studies proved that healthy, elderly, and stable cardiac patients can tolerate acute anemia with normal cardiovascular response. The targets in these studies were modest at first, but researchers aimed progressively for more aggressive hemodilution with lower hemoglobin targets and demonstrated that the body can tolerate and adapt to more severe anemia.^6–8

Studies in healthy patients

Weiskopf et al⁹ assessed the effect of severe anemia in 32 conscious healthy patients (11 presurgical patients and 21 volunteers not undergoing surgery) by performing acute normovolemic hemodilution with 5% human albumin, autologous plasma, or both, with a target hemoglobin level of 5 g/dL. The process was done gradually, obtaining aliquots of blood of 500 to 900 mL. Cardiac index increased, along with a mild increase in oxygen consumption with no increase in plasma lactate levels, suggesting that in conscious healthy patients, tissue oxygenation remains adequate even in severe anemia.

Leung et al¹⁰ addressed the electrocardiographic changes that occur with severe anemia (hemoglobin 5 g/dL) in 55 healthy volunteers. Three developed transient, reversible ST-segment depression, which was associated with a higher heart rate than in the volunteers with no electrocardiographic changes; however, the changes were reversible and asymptomatic, and thus were considered physiologic and benign.

Hemodilution in healthy elderly patients

Spahn et al¹¹ performed 6 and 12 mL/kg isovolemic exchange of blood for 6% hydroxyethyl starch in 20 patients older than 65 years (mean age 76, range 65–88) without underlying coronary disease.

The patients’ mean hemoglobin level decreased from 11.6 g/dL to 8.8 g/dL. Their cardiac index and oxygen extraction values increased adequately, with stable oxygen consumption during hemodilution. There were no electrocardiographic signs of ischemia.

Hemodilution in coronary artery disease

Spahn et al¹² performed hemodilution studies in 60 patients (ages 35–81) with coronary artery disease managed chronically with beta-blockers who were scheduled for coronary artery bypass graft surgery. Hemodilution was performed with 6- and 12-mL/kg isovolemic exchange of blood for 6% hydroxyethyl starch maintaining normovolemia and stable filling pressures. Hemoglobin levels decreased from 12.6 g/dL to 9.9 g/dL. The hemodilution process was done before the revascularization. The authors monitored hemodynamic variables, ST-segment deviation, and oxygen consumption before and after each hemodilution.

There was a compensatory increase in cardiac index and oxygen extraction with consequent stable oxygen consumption. These changes were independent of patient age or left ventricular function. In addition, there were no electrocardiographic signs of ischemia.

Licker et al¹³ studied the hemodynamic effect of preoperative hemodilution in 50 patients with coronary artery disease undergoing coronary artery bypass graft surgery, performing transesophageal echocardiography before and after hemodilution. The patients underwent isovolemic exchange with iso-oncotic starch to target a hematocrit of 28%.

Acute normovolemic hemodilution triggered an increase in cardiac stroke volume, which had a direct correlation with an increase in the central venous pressure and the left ventricular end-diastolic area. No signs of ischemia were seen in these patients on electrocardiography or echocardiography (eg, left ventricular wall-motion abnormalities).

Hemodilution in mitral regurgitation

Spahn et al¹⁴ performed acute isovolemic hemodilution with 6% hydroxyethyl starch in 20 patients with mitral regurgitation. The cardiac filling pressures were stable before and after hemodilution; the mean hemoglobin value decreased from 13 to 10.3 g/dL. The cardiac index and oxygen extraction increased proportionally, with stable oxygen consumption; these findings were the same regardless of whether the patient was in normal sinus rhythm or atrial fibrillation.

Effect of hemodilution on cognition

Weiskopf et al¹⁵ assessed the effect of anemia on executive and memory function by inducing progressive acute isovolemic anemia in 90 healthy volunteers (age 29 ± 5), reducing their hemoglobin values to 7, 6, and 5 g/dL and performing repetitive neuropsychological and memory testing before and after the hemodilution, as well as after autologous blood transfusion to return their hemoglobin level to 7 g/dL.

There were no changes in reaction time or error rate at a hemoglobin concentration of 7 g/dL compared with the performance at a baseline hemoglobin concentration of 14 g/dL. The volunteers got slower on a mathematics test at hemoglobin levels of 6 g/dL and 5 g/dL, but their error rate did not increase. Immediate and delayed memory were significantly impaired at hemoglobin of 5 g/dL but not at 6 g/dL. All tests normalized with blood transfusion once the hemoglobin level reached 7 g/dL.¹⁵

Weiskopf et al¹⁶ subsequently investigated whether giving supplemental oxygen to raise the arterial partial pressure of oxygen (Pao₂) to 350 mm Hg or greater would overcome the neurocognitive effects of severe acute anemia. They followed a protocol similar to the one in the earlier study¹⁵ and induced anemia in 31 healthy volunteers, age 28 ± 4 years, with a mean baseline hemoglobin concentration of 12.7 g/dL.

When the volunteers reached a hemoglobin concentration of 5.7 ± 0.3 g/dL, they were significantly slower on the mathematics test, and their delayed memory was significantly impaired. Then, in a double-blind fashion, they were given either room air or oxygen. Oxygen increased the Pao₂ to 406 mm Hg and normalized neurocognitive performance.

Hemodilution studies in surgical patients

Hemodilution studies paved the way for justifying a more conservative and restrictive transfusion strategy

A 2015 meta-analysis¹⁷ of 63 studies involving 3,819 surgical patients compared the risk of perioperative allogeneic blood transfusion as well as the overall volume of transfused blood in patients undergoing preoperative acute normovolemic hemodilution vs a control group. Though the overall data showed that the patients who underwent acute normovolemic hemodilution needed fewer transfusions and less blood (relative risk [RR] 0.74, 95% confidence interval [CI] 0.63–0.88, P = .0006), the authors noted significant heterogeneity and publication bias.

However, the hemodilution studies paved the way for justifying a more conservative and restrictive transfusion strategy, with a hemoglobin cutoff value of 7 g/dL, and in acute anemia, using oxygen to overcome acute neurocognitive effects while searching for and correcting the cause of the anemia.

STUDIES OF RESTRICTIVE VS LIBERAL TRANSFUSION STRATEGIES

Studies in critical care and high-risk patients

Hébert et al¹⁸ randomized 418 critical care patients to a restrictive transfusion approach (in which they were given red blood cells if their hemoglobin concentration dropped below 7.0 g/dL) and 420 patients to a liberal strategy (given red blood cells if their hemoglobin concentration dropped below 10.0 g/dL). Mortality rates (restrictive vs liberal strategy) were as follows:

• Overall at 30 days 18.7% vs 23.3%, P = .11
• In the subgroup with less-severe disease (Acute Physiology and Chronic Health Evaluation II [APACHE II] score < 20), 8.7% vs 16.1%, P = .03
• In the subgroup under age 55, 5.7% vs 13%, P = .02
• In the subgroup with clinically significant cardiac disease, 20.5% vs 22.9%, P = .69
• In the hospital, 22.2% vs 28.1%; P = .05.

This study demonstrated that parsimonious blood use did not worsen clinical outcomes in critical care patients.

Carson et al¹⁹ evaluated 2,016 patients age 50 and older who had a history of or risk factors for cardiovascular disease and a baseline hemoglobin level below 10 g/dL who underwent surgery for hip fracture. Patients were randomized to two transfusion strategies based on threshold hemoglobin level: restrictive (< 8 g/dL) or liberal (< 10 g/dL). The primary outcome was death or inability to walk without assistance at 60-day follow-up. The median number of units of blood used was 2 in the liberal group and 0 in the restrictive group.

There was no significant difference in the rates of the primary outcome (odds ratio [OR] 1.01, 95% CI 0.84–1.22), infection, venous thromboembolism, or reoperation. This study demonstrated that a liberal transfusion strategy offered no benefit over a restrictive one.

Rao et al²⁰ analyzed the impact of blood transfusion in 24,112 patients with acute coronary syndromes enrolled in three large trials. Ten percent of the patients received at least 1 blood transfusion during their hospitalization, and they were older and had more complex comorbidity.

At 30 days, the group that had received blood had higher rates of death (adjusted hazard ratio [HR] 3.94, 95% CI 3.26–4.75) and the combined outcome of death or myocardial infarction (HR 2.92, 95% CI 2.55–3.35). Transfusion in patients whose nadir hematocrit was higher than 25% was associated with worse outcomes.

This study suggests being cautious about routinely transfusing blood in stable patients with ischemic heart disease solely on the basis of arbitrary hematocrit levels.

Carson et al,²¹ however, in a later trial, found a trend toward worse outcomes with a restrictive strategy than with a liberal one. Here, 110 patients with acute coronary syndrome or stable angina undergoing cardiac catheterization were randomized to a target hemoglobin level of either at least 8 mg/dL or at least 10 g/dL. The primary outcome (a composite of death, myocardial infarction, or unscheduled revascularization 30 days after randomization) occurred in 14 patients (25.5%) in the restrictive group and 6 patients (10.9%) in the liberal group (P = .054), and 7 (13.0%) vs 1 (1.8%) of the patients died (P = .032).

These studies suggest the need for more definitive trials in patients with active coronary disease and in cardiac surgery patients

Murphy et al²² similarly found trends toward worse outcomes with a restrictive strategy in cardiac patients. The investigators randomized 2,007 elective cardiac surgery patients with a postoperative hemoglobin level lower than 9 g/dL to a hemoglobin transfusion threshold of either 7.5 or 9 g/dL. Outcomes (restrictive vs liberal strategies):

• Transfusion rates 53.4% vs 92.2%
• Rates of the primary outcome (a serious infection [sepsis or wound infection] or ischemic event [stroke, myocardial infarction, mesenteric ischemia, or acute kidney injury] within 3 months):
  35.1% vs 33.0%, OR 1.11, 95% CI 0.91–1.34, P = .30)
• Mortality rates 4.2% vs 2.6%, HR 1.64, 95% CI 1.00–2.67, P = .045
• Total costs did not differ significantly between the groups.

These studies^21,22 suggest the need for more definitive trials in patients with active coronary disease and in cardiac surgery patients.

Holst et al²³ randomized 998 intensive care patients in septic shock to hemoglobin thresholds for transfusion of 7 vs 9 g/dL. Mortality rates at 90 days (the primary outcome) were 43.0% vs 45.0%, RR 0.94, 95% CI 0.78–1.09, P = .44.

This study suggests that even in septic shock, a liberal transfusion strategy has no advantage over a parsimonious one.

Active bleeding, especially active gastrointestinal bleeding, poses a significant stress that may trigger empirical transfusion even without evidence of the real hemoglobin level.

Villanueva et al²⁴ randomized 921 patients with severe acute upper-gastrointestinal bleeding to two groups, with hemoglobin transfusion triggers of 7 vs 9 g/dL. The findings were impressive:

• Freedom from transfusion 51% vs 14% (P < .001)
• Survival rates at 6 weeks 95% vs 91% (HR 0.55, 95% CI 0.33–0.92, P = .02)
• Rebleeding 10% vs 16% (P = .01). 


Patients with peptic ulcer disease as well as those with cirrhosis stage Child-Pugh class A or B had higher survival rates with a restrictive transfusion strategy.

The RELIEVE trial²⁵ compared the effect of a restrictive transfusion strategy in elderly patients on mechanical ventilation in 6 intensive care units in the United Kingdom. Transfusion triggers were hemoglobin 7 vs 9 g/dL, and the mortality rate at 180 days was 55% vs 37%, RR 0.68, 95% CI 0.44–1.05, P = .073.

Meta-analyses and observational studies

Rohde et al²⁶ performed a systematic review and meta-analysis of 17 trials with 7,456 patients, which revealed that a restrictive strategy is associated with a lower risk of nosocomial infection, including pneumonia, wound infection, and sepsis.

The pooled risk of all serious infections was 10.6% in the restrictive group and 12.7% in the liberal group. Even after adjusting for the use of leukocyte reduction, the risk of infection was lower in the restrictive strategy group (RR 0.83, 95% CI 0.69–0.99). With a hemoglobin threshold of less than 7.0 g/dL, the risk of serious infection was 14% lower. Although this was not statistically significant overall (RR 0.86, 95% CI 0.72–1.02), the difference was statistically significant in the subgroup undergoing orthopedic surgery (RR 0.72, 95% CI 0.53–0.97) and the subgroup presenting with sepsis (RR 0.51, 95% CI 0.28–0.95).

Salpeter et al²⁷ performed a meta-analysis and systematic review of three randomized trials (N = 2,364) comparing a restrictive hemoglobin transfusion trigger (hemoglobin < 7 g/dL) vs a more liberal trigger. The groups with restrictive transfusion triggers had lower rates of:

• In-hospital mortality (RR 0.74, 95% CI 0.60–0.92)
• Total mortality (RR 0.80, 95% CI 0.65–0.98)
• Rebleeding (RR 0.64, 95% CI 0.45–0.90)
• Acute coronary syndrome (RR 0.44, 95% CI 0.22–0.89)
• Pulmonary edema (RR 0.48, 95% CI 0.33–0.72)
• Bacterial infections (RR 0.86, 95% CI 0.73–1.00).

Wang et al²⁸ performed a meta-analysis of 4 randomized controlled trials in patients with upper-gastrointestinal bleeding comparing restrictive (hemoglobin < 7 g/dL) vs liberal transfusion strategies. The primary outcomes were death and rebleeding. The restrictive strategy was associated with:

• A lower mortality rate (OR 0.52, 95% CI 0.31–0.87, P = .01)
• A lower rebleeding rate (OR 0.26, 95% CI 0.03–2.10, P = .21)
• Shorter hospitalizations (P = .009)
• Less blood transfused (P = .0005).

The more units of blood the patients received, the more likely they were to die

Vincent et al,²⁹ in a prospective observational study of 3,534 patients in intensive care units in 146 facilities in Western Europe, found a correlation between transfusion and mortality. Transfusion was done most often in elderly patients and those with a longer stay in the intensive care unit. The 28-day mortality rate was 22.7% in patients who received a transfusion and 17.1% in those who did not (P = .02). The more units of blood the patients received, the more likely they were to die, and receiving more than 4 units was associated with worse outcomes (P = .01).

Dunne et al³⁰ performed a study of 6,301 noncardiac surgical patients in the Veterans Affairs Maryland Healthcare System from the National Veterans Administration Surgical Quality Improvement Program from 1995 to 2000. Multiple logistic regression analysis revealed that the composite of low hematocrit before and after surgery and high transfusion rates (> 4 units per hospitalization) were associated with higher rates of death (P < .01) and postoperative pneumonia (P ≤ .05) and longer hospitalizations (P < .05). The risk of pneumonia increased proportionally with the decrease in hematocrit.

These findings support pharmacologic optimization of anemia with hematinic supplementation before surgery to decrease the risk of needing a transfusion, often with parenteral iron. The fact that the patient’s hemoglobin can be optimized preoperatively by nontransfusional means may decrease the likelihood of blood transfusion, as the hemoglobin will potentially remain above the transfusion threshold. For example, if a patient has a preoperative hemoglobin level of 10 g/dL, and it is optimized up to 12, then if postoperatively the hemoglobin level drops 3 g/dL instead of reaching the threshold of 7 g/dL, the nadir will be just 9 g/dL, far above that transfusion threshold.

Brunskill et al,³¹ in a Cochrane review of 6 trials with 2,722 patients undergoing surgery for hip fracture, found no difference in rates of mortality, functional recovery or postoperative morbidity with a restrictive transfusion strategy (hemoglobin target > 8 g/dL vs a liberal one (> 10 g/dL). However, the quality of evidence was rated as low. The authors concluded that there is no justification for liberal red blood cell transfusion thresholds (10 g/dL), and a more restrictive transfusion threshold is preferable.

Weinberg et al³² found that, in trauma patients, receiving more than 6 units of blood was associated with poor prognosis, and outcomes were worse when the blood was older than 2 weeks. However, the effect of blood age is not significant when using smaller transfusion volumes (1 to 2 units of red blood cells).

Studies in sickle cell disease

Sickle cell disease patients have high levels of hemoglobin S, which causes erythrocyte sickling and increases blood viscosity. Transfusion with normal erythrocytes increases the amount of hemoglobin A (the normal variant).^33,34

In trials in surgical patients,^35,36 conservative strategies for preoperative blood transfusion aiming at a hemoglobin level of 10 g/dL were as effective in preventing postoperative complications as decreasing the hemoglobin S levels to 30% by aggressive exchange transfusion.³⁵

In nonsurgical patients, blood transfusion should be based on formal risk-benefit assessments. Therefore, the expert panel report on sickle cell management advises against blood transfusion in sickle cell patients with uncomplicated vaso-occlusive crises, priapism, asymptomatic anemia, or acute kidney injury in the absence of multisystem organ failure.³⁴

Is hemoglobin the most relevant marker?

Most studies that compared restrictive and liberal transfusion strategies focused on using a lower hemoglobin threshold as the transfusion trigger, not on using fewer units of blood. Is the amount of blood transfused more important than the hemoglobin threshold? Perhaps a study focused both on a restrictive vs liberal strategy and also on the minimum amount of blood that each patient may benefit from would help to answer this question.

Beware of using the hemoglobin concentration as a threshold for transfusion and a marker of benefit

We should beware of routinely using the hemoglobin concentration as a threshold for transfusion and a surrogate marker of transfusion benefit because changes in hemoglobin concentration may not reflect changes in absolute red cell mass.³⁷ Changes in plasma volume (an increase or decrease) affect the hematocrit concentration without necessarily affecting the total red cell mass. Unfortunately, red cell mass is very difficult to measure; hence, the hemoglobin and hematocrit values are used instead. Studies addressing changes in red cell mass may be needed, perhaps even to validate using the hemoglobin concentration as the sole indicator for transfusion.

Is fresh blood better than old blood?

Using blood that is more than 14 days old may be associated with poor outcomes, for several possible reasons. Red blood cells age rapidly in refrigeration, and usually just 75% may remain viable 24 hours after phlebotomy. Adenosine triphosphate and 2,3-DPG levels steadily decrease, with a consequent decrease in capacity for appropriate tissue oxygen delivery. In addition, loss of membrane phospholipids causes progressive rigidity of the red cell membrane with consequent formation of echynocytes after 14 to 21 days.^38,39

The use of blood more than 14 days old in cardiac surgery patients has been associated with worse outcomes, including higher rates of death, prolonged intubation, acute renal failure, and sepsis.⁴⁰ Similar poor outcomes have been seen in trauma patients.³²

Lacroix et al,⁴¹ in a multicenter, randomized trial in critically ill adults, compared the outcomes of transfusion of fresh packed red cells (stored < 8 days) or old blood (stored for a mean of 22 days). The primary outcome was the mortality rate at 90 days: 37.0% in the fresh-blood group vs 35.3% in the old-blood group (HR 1.1, 95% CI 0.9–1.2, P = .38).

The authors concluded that using fresh blood compared with old blood was not associated with a lower 90-day mortality rate in critically ill adults.

RISKS ASSOCIATED WITH TRANSFUSION

Infections

The risk of infection from blood transfusion is small. Human immunodeficiency virus (HIV) is transmitted in 1 in 1.5 million transfused blood components, and hepatitis C virus in 1 in 1.1 million; these odds are similar to those of having a fatal airplane accident (1 in 1.7 million per flight). Hepatitis B virus infection is more common, the reported incidence being 1 in 357,000.⁴²

Noninfectious complications

Transfusion-associated circulatory overload occurs in 4% to 6% of patients who receive a transfusion. Therefore, circulatory overload is a greater danger from transfusion than infection is.⁴²

Febrile nonhemolytic transfusion reactions occur in 1.1% of patients with prestorage leukoreduction.

Transfusion-associated acute lung injury occurs in 0.8 per 10,000 blood components transfused.

Errors associated with blood transfusion include, in decreasing order of frequency, transfusion of the wrong blood component, handling and storage errors, inappropriate administration of anti-D immunoglobulin, and avoidable, delayed, or insufficient transfusions.⁴³

Surgery and condition-specific complications of red blood cell transfusion

Cardiovascular surgery. Transfusion is associated with a higher risk of postoperative stroke, respiratory failure, acute respiratory distress syndrome, prolonged intubation time, reintubation, in-hospital death, sepsis, and longer postoperative length of stay.⁴⁴

Malignancy. The use of blood in this setting has been found to be an independent predictor of recurrence, decreased survival, and increased risk of lymphoplasmacytic and marginal-zone lymphomas.^44–47

Vascular, orthopedic, and other surgeries. Transfusion is associated with a higher risk of death, thromboembolic events, acute kidney injury, death, composite morbidity, reoperation, sepsis, and pulmonary complications.⁴⁴

ST-segment elevation myocardial infarction, sepsis, and intensive care unit admissions. Transfusion is associated with an increased risk of rebleeding, death, and secondary infections.⁴⁴

COST OF RED BLOOD CELL TRANSFUSION

Up to 85 million units of red blood cells are transfused per year worldwide, 15 million of them in the United States.⁴² At our hospital in 2013, 1 unit of leukocyte-reduced red blood cells cost $957.27, which included the costs of acquisition, processing, banking, patient testing, administration, and monitoring.

The Premier Healthcare Alliance⁴⁸ analyzed data from 7.4 million discharges from 464 hospitals between April 2011 and March 2012. Blood use varied significantly among hospitals, and the hospitals in the lowest quartile of blood use had better patient outcomes. If all the hospitals used as little blood as those in the lowest quartile and had outcomes as good, blood product use would be reduced by 802,716 units, with savings of up to $165 million annually.

In addition to the economic cost of blood transfusion, the clinician must be aware of the cost in terms of comorbidities caused by unnecessary blood transfusion.^49,50

RECOMMENDATIONS FROM THE AABB

In view of all the current compelling evidence, a restrictive approach to transfusion is the single best strategy to minimize adverse outcomes.⁵¹ Below, we outline the current recommendations from the AABB (formerly the American Association of Blood Banks),⁴² which are similar to the national clinical guideline on blood transfusion in the United Kingdom,⁵² and have recently been updated, confirming the initial recommendations.⁵³

In critical care patients, transfusion should be considered if the hemoglobin concentration is 7 g/dL or less.

In postoperative patients and hospitalized patients with preexisting cardiovascular disease, transfusion should be considered if the hemoglobin concentration is 8 g/dL or less or if the patient has signs or symptoms of anemia such as chest pain, orthostatic hypotension, or tachycardia unresponsive to fluid resuscitation, or heart failure.

In hemodynamically stable patients with acute coronary syndrome, there is not enough evidence to allow a formal recommendation for or against a liberal or restrictive transfusion threshold.

Consider both the hemoglobin concentration and the symptoms when deciding whether to give a transfusion. This recommendation is shared by a National Institutes of Health consensus conference,⁵⁴ which indicates that multiple factors related to the patient’s clinical status and oxygen delivery should be considered before deciding to transfuse red blood cells.

The Society of Hospital Medicine⁵⁵ and the American Society of Hematology⁵⁶ concur with a parsimonious approach to blood use in their Choosing Wisely campaigns. The American Society of Hematology recommends that if transfusion of red blood cells is necessary, the minimum number of units should be given that relieve the symptoms of anemia or achieve a safe hemoglobin range (7–8 g/dL in stable noncardiac inpatients).⁵⁷

New electronic tools can monitor the ordering and use of blood products in real time and can identify the hemoglobin level used as the trigger for transfusion. They also provide data on blood use by physician, hospital, and department. These tools can reveal current practice at a glance and allow sharing of best practices among peers and institutions.⁵²

CONSIDER TRANSFUSION FOR HEMOGLOBIN BELOW 7 G/DL

The routine use of blood has come under scrutiny, given its association with increased healthcare costs and morbidity. The accepted practice in stable medical patients is a restrictive threshold approach for blood transfusion, which is to consider (not necessarily give) a single unit of packed red blood cells for a hemoglobin less than 7 g/dL.

However, studies in acute coronary syndrome patients and postoperative cardiac surgery patients have not shown the restrictive threshold to be superior to a liberal threshold in terms of outcomes and costs. This variability suggests the need for further studies to determine the best course of action in different patient subpopulations (eg, surgical, oncologic, trauma, critical illness).

Also, a limitation of most of the clinical studies was that only the hemoglobin concentration was used as a marker of anemia, with no strict assessment of changes in red cell mass with transfusion.

Despite the variability in certain populations, the overall weight of current evidence favors a restrictive approach to blood transfusion (hemoglobin < 7 g/dL), although perhaps in patients who have active coronary disease or are undergoing cardiac surgery, a more lenient threshold (< 8 g/dL) for transfusion should be considered.

For decades, physicians believed in the benefit of prompt transfusion of blood to keep the hemoglobin level at arbitrary, optimum levels, ie, close to normal values, especially in the critically ill, the elderly, and those with coronary syndromes, stroke, or renal failure.

However, the evidence supporting arbitrary hemoglobin values as an indication for transfusion was weak or nonexistent. Also, blood transfusion can have complications and adverse effects, and blood is costly and scarce. These considerations prompted research into when blood transfusion should be considered, and recommendations that it should be used more sparingly than in the past.

This review offers a perspective on the evidence supporting restrictive blood use. First, we focus on hemodilution studies that demonstrated that humans can tolerate anemia. Then, we look at studies that compared a restrictive transfusion strategy with a liberal one in patients with critical illness and active bleeding. We conclude with current recommendations for blood transfusion.

EVIDENCE FROM HEMODILUTION STUDIES

Hemoglobin is essential for tissue oxygenation, but the serum hemoglobin concentration is just one of several factors involved.^1–5 In anemia, the body can adapt not only by increasing production of red blood cells, but also by:

• Increasing cardiac output
• Increasing synthesis of 2,3-diphosphoglycerate (2,3-DPG), with a consequent shift in the oxyhemoglobin dissociation curve to the right, allowing enhanced release of oxygen at the tissue level
• Moving more carbon dioxide into the blood (the Bohr effect), which decreases pH and also shifts the dissociation curve to the right.

Just 20 years ago, physicians were using arbitrary cutoffs such as hemoglobin 10 g/dL or hematocrit 30% as indications for blood transfusion, without reasonable evidence to support these values. Not until acute normovolemic hemodilution studies were performed were we able to progressively appraise how well patients could tolerate lower levels of hemoglobin without significant adverse outcomes.

Acute normovolemic hemodilution involves withdrawing blood and replacing it with crystalloid or colloid solution to maintain the volume.⁶

Initial studies were done in animals and focused on the safety of acute anemia regarding splanchnic perfusion. Subsequently, studies proved that healthy, elderly, and stable cardiac patients can tolerate acute anemia with normal cardiovascular response. The targets in these studies were modest at first, but researchers aimed progressively for more aggressive hemodilution with lower hemoglobin targets and demonstrated that the body can tolerate and adapt to more severe anemia.^6–8

Studies in healthy patients

Weiskopf et al⁹ assessed the effect of severe anemia in 32 conscious healthy patients (11 presurgical patients and 21 volunteers not undergoing surgery) by performing acute normovolemic hemodilution with 5% human albumin, autologous plasma, or both, with a target hemoglobin level of 5 g/dL. The process was done gradually, obtaining aliquots of blood of 500 to 900 mL. Cardiac index increased, along with a mild increase in oxygen consumption with no increase in plasma lactate levels, suggesting that in conscious healthy patients, tissue oxygenation remains adequate even in severe anemia.

Leung et al¹⁰ addressed the electrocardiographic changes that occur with severe anemia (hemoglobin 5 g/dL) in 55 healthy volunteers. Three developed transient, reversible ST-segment depression, which was associated with a higher heart rate than in the volunteers with no electrocardiographic changes; however, the changes were reversible and asymptomatic, and thus were considered physiologic and benign.

Hemodilution in healthy elderly patients

Spahn et al¹¹ performed 6 and 12 mL/kg isovolemic exchange of blood for 6% hydroxyethyl starch in 20 patients older than 65 years (mean age 76, range 65–88) without underlying coronary disease.

The patients’ mean hemoglobin level decreased from 11.6 g/dL to 8.8 g/dL. Their cardiac index and oxygen extraction values increased adequately, with stable oxygen consumption during hemodilution. There were no electrocardiographic signs of ischemia.

Hemodilution in coronary artery disease

Spahn et al¹² performed hemodilution studies in 60 patients (ages 35–81) with coronary artery disease managed chronically with beta-blockers who were scheduled for coronary artery bypass graft surgery. Hemodilution was performed with 6- and 12-mL/kg isovolemic exchange of blood for 6% hydroxyethyl starch maintaining normovolemia and stable filling pressures. Hemoglobin levels decreased from 12.6 g/dL to 9.9 g/dL. The hemodilution process was done before the revascularization. The authors monitored hemodynamic variables, ST-segment deviation, and oxygen consumption before and after each hemodilution.

There was a compensatory increase in cardiac index and oxygen extraction with consequent stable oxygen consumption. These changes were independent of patient age or left ventricular function. In addition, there were no electrocardiographic signs of ischemia.

Licker et al¹³ studied the hemodynamic effect of preoperative hemodilution in 50 patients with coronary artery disease undergoing coronary artery bypass graft surgery, performing transesophageal echocardiography before and after hemodilution. The patients underwent isovolemic exchange with iso-oncotic starch to target a hematocrit of 28%.

Acute normovolemic hemodilution triggered an increase in cardiac stroke volume, which had a direct correlation with an increase in the central venous pressure and the left ventricular end-diastolic area. No signs of ischemia were seen in these patients on electrocardiography or echocardiography (eg, left ventricular wall-motion abnormalities).

Hemodilution in mitral regurgitation

Spahn et al¹⁴ performed acute isovolemic hemodilution with 6% hydroxyethyl starch in 20 patients with mitral regurgitation. The cardiac filling pressures were stable before and after hemodilution; the mean hemoglobin value decreased from 13 to 10.3 g/dL. The cardiac index and oxygen extraction increased proportionally, with stable oxygen consumption; these findings were the same regardless of whether the patient was in normal sinus rhythm or atrial fibrillation.

Effect of hemodilution on cognition

Weiskopf et al¹⁵ assessed the effect of anemia on executive and memory function by inducing progressive acute isovolemic anemia in 90 healthy volunteers (age 29 ± 5), reducing their hemoglobin values to 7, 6, and 5 g/dL and performing repetitive neuropsychological and memory testing before and after the hemodilution, as well as after autologous blood transfusion to return their hemoglobin level to 7 g/dL.

There were no changes in reaction time or error rate at a hemoglobin concentration of 7 g/dL compared with the performance at a baseline hemoglobin concentration of 14 g/dL. The volunteers got slower on a mathematics test at hemoglobin levels of 6 g/dL and 5 g/dL, but their error rate did not increase. Immediate and delayed memory were significantly impaired at hemoglobin of 5 g/dL but not at 6 g/dL. All tests normalized with blood transfusion once the hemoglobin level reached 7 g/dL.¹⁵

Weiskopf et al¹⁶ subsequently investigated whether giving supplemental oxygen to raise the arterial partial pressure of oxygen (Pao₂) to 350 mm Hg or greater would overcome the neurocognitive effects of severe acute anemia. They followed a protocol similar to the one in the earlier study¹⁵ and induced anemia in 31 healthy volunteers, age 28 ± 4 years, with a mean baseline hemoglobin concentration of 12.7 g/dL.

When the volunteers reached a hemoglobin concentration of 5.7 ± 0.3 g/dL, they were significantly slower on the mathematics test, and their delayed memory was significantly impaired. Then, in a double-blind fashion, they were given either room air or oxygen. Oxygen increased the Pao₂ to 406 mm Hg and normalized neurocognitive performance.

Hemodilution studies in surgical patients

Hemodilution studies paved the way for justifying a more conservative and restrictive transfusion strategy

A 2015 meta-analysis¹⁷ of 63 studies involving 3,819 surgical patients compared the risk of perioperative allogeneic blood transfusion as well as the overall volume of transfused blood in patients undergoing preoperative acute normovolemic hemodilution vs a control group. Though the overall data showed that the patients who underwent acute normovolemic hemodilution needed fewer transfusions and less blood (relative risk [RR] 0.74, 95% confidence interval [CI] 0.63–0.88, P = .0006), the authors noted significant heterogeneity and publication bias.

However, the hemodilution studies paved the way for justifying a more conservative and restrictive transfusion strategy, with a hemoglobin cutoff value of 7 g/dL, and in acute anemia, using oxygen to overcome acute neurocognitive effects while searching for and correcting the cause of the anemia.

STUDIES OF RESTRICTIVE VS LIBERAL TRANSFUSION STRATEGIES

Studies in critical care and high-risk patients

Hébert et al¹⁸ randomized 418 critical care patients to a restrictive transfusion approach (in which they were given red blood cells if their hemoglobin concentration dropped below 7.0 g/dL) and 420 patients to a liberal strategy (given red blood cells if their hemoglobin concentration dropped below 10.0 g/dL). Mortality rates (restrictive vs liberal strategy) were as follows:

• Overall at 30 days 18.7% vs 23.3%, P = .11
• In the subgroup with less-severe disease (Acute Physiology and Chronic Health Evaluation II [APACHE II] score < 20), 8.7% vs 16.1%, P = .03
• In the subgroup under age 55, 5.7% vs 13%, P = .02
• In the subgroup with clinically significant cardiac disease, 20.5% vs 22.9%, P = .69
• In the hospital, 22.2% vs 28.1%; P = .05.

This study demonstrated that parsimonious blood use did not worsen clinical outcomes in critical care patients.

Carson et al¹⁹ evaluated 2,016 patients age 50 and older who had a history of or risk factors for cardiovascular disease and a baseline hemoglobin level below 10 g/dL who underwent surgery for hip fracture. Patients were randomized to two transfusion strategies based on threshold hemoglobin level: restrictive (< 8 g/dL) or liberal (< 10 g/dL). The primary outcome was death or inability to walk without assistance at 60-day follow-up. The median number of units of blood used was 2 in the liberal group and 0 in the restrictive group.

There was no significant difference in the rates of the primary outcome (odds ratio [OR] 1.01, 95% CI 0.84–1.22), infection, venous thromboembolism, or reoperation. This study demonstrated that a liberal transfusion strategy offered no benefit over a restrictive one.

Rao et al²⁰ analyzed the impact of blood transfusion in 24,112 patients with acute coronary syndromes enrolled in three large trials. Ten percent of the patients received at least 1 blood transfusion during their hospitalization, and they were older and had more complex comorbidity.

At 30 days, the group that had received blood had higher rates of death (adjusted hazard ratio [HR] 3.94, 95% CI 3.26–4.75) and the combined outcome of death or myocardial infarction (HR 2.92, 95% CI 2.55–3.35). Transfusion in patients whose nadir hematocrit was higher than 25% was associated with worse outcomes.

This study suggests being cautious about routinely transfusing blood in stable patients with ischemic heart disease solely on the basis of arbitrary hematocrit levels.

Carson et al,²¹ however, in a later trial, found a trend toward worse outcomes with a restrictive strategy than with a liberal one. Here, 110 patients with acute coronary syndrome or stable angina undergoing cardiac catheterization were randomized to a target hemoglobin level of either at least 8 mg/dL or at least 10 g/dL. The primary outcome (a composite of death, myocardial infarction, or unscheduled revascularization 30 days after randomization) occurred in 14 patients (25.5%) in the restrictive group and 6 patients (10.9%) in the liberal group (P = .054), and 7 (13.0%) vs 1 (1.8%) of the patients died (P = .032).

These studies suggest the need for more definitive trials in patients with active coronary disease and in cardiac surgery patients

Murphy et al²² similarly found trends toward worse outcomes with a restrictive strategy in cardiac patients. The investigators randomized 2,007 elective cardiac surgery patients with a postoperative hemoglobin level lower than 9 g/dL to a hemoglobin transfusion threshold of either 7.5 or 9 g/dL. Outcomes (restrictive vs liberal strategies):

• Transfusion rates 53.4% vs 92.2%
• Rates of the primary outcome (a serious infection [sepsis or wound infection] or ischemic event [stroke, myocardial infarction, mesenteric ischemia, or acute kidney injury] within 3 months):
  35.1% vs 33.0%, OR 1.11, 95% CI 0.91–1.34, P = .30)
• Mortality rates 4.2% vs 2.6%, HR 1.64, 95% CI 1.00–2.67, P = .045
• Total costs did not differ significantly between the groups.

These studies^21,22 suggest the need for more definitive trials in patients with active coronary disease and in cardiac surgery patients.

Holst et al²³ randomized 998 intensive care patients in septic shock to hemoglobin thresholds for transfusion of 7 vs 9 g/dL. Mortality rates at 90 days (the primary outcome) were 43.0% vs 45.0%, RR 0.94, 95% CI 0.78–1.09, P = .44.

This study suggests that even in septic shock, a liberal transfusion strategy has no advantage over a parsimonious one.

Active bleeding, especially active gastrointestinal bleeding, poses a significant stress that may trigger empirical transfusion even without evidence of the real hemoglobin level.

Villanueva et al²⁴ randomized 921 patients with severe acute upper-gastrointestinal bleeding to two groups, with hemoglobin transfusion triggers of 7 vs 9 g/dL. The findings were impressive:

• Freedom from transfusion 51% vs 14% (P < .001)
• Survival rates at 6 weeks 95% vs 91% (HR 0.55, 95% CI 0.33–0.92, P = .02)
• Rebleeding 10% vs 16% (P = .01). 


Patients with peptic ulcer disease as well as those with cirrhosis stage Child-Pugh class A or B had higher survival rates with a restrictive transfusion strategy.

The RELIEVE trial²⁵ compared the effect of a restrictive transfusion strategy in elderly patients on mechanical ventilation in 6 intensive care units in the United Kingdom. Transfusion triggers were hemoglobin 7 vs 9 g/dL, and the mortality rate at 180 days was 55% vs 37%, RR 0.68, 95% CI 0.44–1.05, P = .073.

Meta-analyses and observational studies

Rohde et al²⁶ performed a systematic review and meta-analysis of 17 trials with 7,456 patients, which revealed that a restrictive strategy is associated with a lower risk of nosocomial infection, including pneumonia, wound infection, and sepsis.

The pooled risk of all serious infections was 10.6% in the restrictive group and 12.7% in the liberal group. Even after adjusting for the use of leukocyte reduction, the risk of infection was lower in the restrictive strategy group (RR 0.83, 95% CI 0.69–0.99). With a hemoglobin threshold of less than 7.0 g/dL, the risk of serious infection was 14% lower. Although this was not statistically significant overall (RR 0.86, 95% CI 0.72–1.02), the difference was statistically significant in the subgroup undergoing orthopedic surgery (RR 0.72, 95% CI 0.53–0.97) and the subgroup presenting with sepsis (RR 0.51, 95% CI 0.28–0.95).

Salpeter et al²⁷ performed a meta-analysis and systematic review of three randomized trials (N = 2,364) comparing a restrictive hemoglobin transfusion trigger (hemoglobin < 7 g/dL) vs a more liberal trigger. The groups with restrictive transfusion triggers had lower rates of:

• In-hospital mortality (RR 0.74, 95% CI 0.60–0.92)
• Total mortality (RR 0.80, 95% CI 0.65–0.98)
• Rebleeding (RR 0.64, 95% CI 0.45–0.90)
• Acute coronary syndrome (RR 0.44, 95% CI 0.22–0.89)
• Pulmonary edema (RR 0.48, 95% CI 0.33–0.72)
• Bacterial infections (RR 0.86, 95% CI 0.73–1.00).

Wang et al²⁸ performed a meta-analysis of 4 randomized controlled trials in patients with upper-gastrointestinal bleeding comparing restrictive (hemoglobin < 7 g/dL) vs liberal transfusion strategies. The primary outcomes were death and rebleeding. The restrictive strategy was associated with:

• A lower mortality rate (OR 0.52, 95% CI 0.31–0.87, P = .01)
• A lower rebleeding rate (OR 0.26, 95% CI 0.03–2.10, P = .21)
• Shorter hospitalizations (P = .009)
• Less blood transfused (P = .0005).

The more units of blood the patients received, the more likely they were to die

Vincent et al,²⁹ in a prospective observational study of 3,534 patients in intensive care units in 146 facilities in Western Europe, found a correlation between transfusion and mortality. Transfusion was done most often in elderly patients and those with a longer stay in the intensive care unit. The 28-day mortality rate was 22.7% in patients who received a transfusion and 17.1% in those who did not (P = .02). The more units of blood the patients received, the more likely they were to die, and receiving more than 4 units was associated with worse outcomes (P = .01).

Dunne et al³⁰ performed a study of 6,301 noncardiac surgical patients in the Veterans Affairs Maryland Healthcare System from the National Veterans Administration Surgical Quality Improvement Program from 1995 to 2000. Multiple logistic regression analysis revealed that the composite of low hematocrit before and after surgery and high transfusion rates (> 4 units per hospitalization) were associated with higher rates of death (P < .01) and postoperative pneumonia (P ≤ .05) and longer hospitalizations (P < .05). The risk of pneumonia increased proportionally with the decrease in hematocrit.

These findings support pharmacologic optimization of anemia with hematinic supplementation before surgery to decrease the risk of needing a transfusion, often with parenteral iron. The fact that the patient’s hemoglobin can be optimized preoperatively by nontransfusional means may decrease the likelihood of blood transfusion, as the hemoglobin will potentially remain above the transfusion threshold. For example, if a patient has a preoperative hemoglobin level of 10 g/dL, and it is optimized up to 12, then if postoperatively the hemoglobin level drops 3 g/dL instead of reaching the threshold of 7 g/dL, the nadir will be just 9 g/dL, far above that transfusion threshold.

Brunskill et al,³¹ in a Cochrane review of 6 trials with 2,722 patients undergoing surgery for hip fracture, found no difference in rates of mortality, functional recovery or postoperative morbidity with a restrictive transfusion strategy (hemoglobin target > 8 g/dL vs a liberal one (> 10 g/dL). However, the quality of evidence was rated as low. The authors concluded that there is no justification for liberal red blood cell transfusion thresholds (10 g/dL), and a more restrictive transfusion threshold is preferable.

Weinberg et al³² found that, in trauma patients, receiving more than 6 units of blood was associated with poor prognosis, and outcomes were worse when the blood was older than 2 weeks. However, the effect of blood age is not significant when using smaller transfusion volumes (1 to 2 units of red blood cells).

Studies in sickle cell disease

Sickle cell disease patients have high levels of hemoglobin S, which causes erythrocyte sickling and increases blood viscosity. Transfusion with normal erythrocytes increases the amount of hemoglobin A (the normal variant).^33,34

In trials in surgical patients,^35,36 conservative strategies for preoperative blood transfusion aiming at a hemoglobin level of 10 g/dL were as effective in preventing postoperative complications as decreasing the hemoglobin S levels to 30% by aggressive exchange transfusion.³⁵

In nonsurgical patients, blood transfusion should be based on formal risk-benefit assessments. Therefore, the expert panel report on sickle cell management advises against blood transfusion in sickle cell patients with uncomplicated vaso-occlusive crises, priapism, asymptomatic anemia, or acute kidney injury in the absence of multisystem organ failure.³⁴

Is hemoglobin the most relevant marker?

Most studies that compared restrictive and liberal transfusion strategies focused on using a lower hemoglobin threshold as the transfusion trigger, not on using fewer units of blood. Is the amount of blood transfused more important than the hemoglobin threshold? Perhaps a study focused both on a restrictive vs liberal strategy and also on the minimum amount of blood that each patient may benefit from would help to answer this question.

Beware of using the hemoglobin concentration as a threshold for transfusion and a marker of benefit

We should beware of routinely using the hemoglobin concentration as a threshold for transfusion and a surrogate marker of transfusion benefit because changes in hemoglobin concentration may not reflect changes in absolute red cell mass.³⁷ Changes in plasma volume (an increase or decrease) affect the hematocrit concentration without necessarily affecting the total red cell mass. Unfortunately, red cell mass is very difficult to measure; hence, the hemoglobin and hematocrit values are used instead. Studies addressing changes in red cell mass may be needed, perhaps even to validate using the hemoglobin concentration as the sole indicator for transfusion.

Is fresh blood better than old blood?

Using blood that is more than 14 days old may be associated with poor outcomes, for several possible reasons. Red blood cells age rapidly in refrigeration, and usually just 75% may remain viable 24 hours after phlebotomy. Adenosine triphosphate and 2,3-DPG levels steadily decrease, with a consequent decrease in capacity for appropriate tissue oxygen delivery. In addition, loss of membrane phospholipids causes progressive rigidity of the red cell membrane with consequent formation of echynocytes after 14 to 21 days.^38,39

The use of blood more than 14 days old in cardiac surgery patients has been associated with worse outcomes, including higher rates of death, prolonged intubation, acute renal failure, and sepsis.⁴⁰ Similar poor outcomes have been seen in trauma patients.³²

Lacroix et al,⁴¹ in a multicenter, randomized trial in critically ill adults, compared the outcomes of transfusion of fresh packed red cells (stored < 8 days) or old blood (stored for a mean of 22 days). The primary outcome was the mortality rate at 90 days: 37.0% in the fresh-blood group vs 35.3% in the old-blood group (HR 1.1, 95% CI 0.9–1.2, P = .38).

The authors concluded that using fresh blood compared with old blood was not associated with a lower 90-day mortality rate in critically ill adults.

RISKS ASSOCIATED WITH TRANSFUSION

Infections

The risk of infection from blood transfusion is small. Human immunodeficiency virus (HIV) is transmitted in 1 in 1.5 million transfused blood components, and hepatitis C virus in 1 in 1.1 million; these odds are similar to those of having a fatal airplane accident (1 in 1.7 million per flight). Hepatitis B virus infection is more common, the reported incidence being 1 in 357,000.⁴²

Noninfectious complications

Transfusion-associated circulatory overload occurs in 4% to 6% of patients who receive a transfusion. Therefore, circulatory overload is a greater danger from transfusion than infection is.⁴²

Febrile nonhemolytic transfusion reactions occur in 1.1% of patients with prestorage leukoreduction.

Transfusion-associated acute lung injury occurs in 0.8 per 10,000 blood components transfused.

Errors associated with blood transfusion include, in decreasing order of frequency, transfusion of the wrong blood component, handling and storage errors, inappropriate administration of anti-D immunoglobulin, and avoidable, delayed, or insufficient transfusions.⁴³

Surgery and condition-specific complications of red blood cell transfusion

Cardiovascular surgery. Transfusion is associated with a higher risk of postoperative stroke, respiratory failure, acute respiratory distress syndrome, prolonged intubation time, reintubation, in-hospital death, sepsis, and longer postoperative length of stay.⁴⁴

Malignancy. The use of blood in this setting has been found to be an independent predictor of recurrence, decreased survival, and increased risk of lymphoplasmacytic and marginal-zone lymphomas.^44–47

Vascular, orthopedic, and other surgeries. Transfusion is associated with a higher risk of death, thromboembolic events, acute kidney injury, death, composite morbidity, reoperation, sepsis, and pulmonary complications.⁴⁴

ST-segment elevation myocardial infarction, sepsis, and intensive care unit admissions. Transfusion is associated with an increased risk of rebleeding, death, and secondary infections.⁴⁴

COST OF RED BLOOD CELL TRANSFUSION

Up to 85 million units of red blood cells are transfused per year worldwide, 15 million of them in the United States.⁴² At our hospital in 2013, 1 unit of leukocyte-reduced red blood cells cost $957.27, which included the costs of acquisition, processing, banking, patient testing, administration, and monitoring.

The Premier Healthcare Alliance⁴⁸ analyzed data from 7.4 million discharges from 464 hospitals between April 2011 and March 2012. Blood use varied significantly among hospitals, and the hospitals in the lowest quartile of blood use had better patient outcomes. If all the hospitals used as little blood as those in the lowest quartile and had outcomes as good, blood product use would be reduced by 802,716 units, with savings of up to $165 million annually.

In addition to the economic cost of blood transfusion, the clinician must be aware of the cost in terms of comorbidities caused by unnecessary blood transfusion.^49,50

RECOMMENDATIONS FROM THE AABB

In view of all the current compelling evidence, a restrictive approach to transfusion is the single best strategy to minimize adverse outcomes.⁵¹ Below, we outline the current recommendations from the AABB (formerly the American Association of Blood Banks),⁴² which are similar to the national clinical guideline on blood transfusion in the United Kingdom,⁵² and have recently been updated, confirming the initial recommendations.⁵³

In critical care patients, transfusion should be considered if the hemoglobin concentration is 7 g/dL or less.

In postoperative patients and hospitalized patients with preexisting cardiovascular disease, transfusion should be considered if the hemoglobin concentration is 8 g/dL or less or if the patient has signs or symptoms of anemia such as chest pain, orthostatic hypotension, or tachycardia unresponsive to fluid resuscitation, or heart failure.

In hemodynamically stable patients with acute coronary syndrome, there is not enough evidence to allow a formal recommendation for or against a liberal or restrictive transfusion threshold.

Consider both the hemoglobin concentration and the symptoms when deciding whether to give a transfusion. This recommendation is shared by a National Institutes of Health consensus conference,⁵⁴ which indicates that multiple factors related to the patient’s clinical status and oxygen delivery should be considered before deciding to transfuse red blood cells.

The Society of Hospital Medicine⁵⁵ and the American Society of Hematology⁵⁶ concur with a parsimonious approach to blood use in their Choosing Wisely campaigns. The American Society of Hematology recommends that if transfusion of red blood cells is necessary, the minimum number of units should be given that relieve the symptoms of anemia or achieve a safe hemoglobin range (7–8 g/dL in stable noncardiac inpatients).⁵⁷

New electronic tools can monitor the ordering and use of blood products in real time and can identify the hemoglobin level used as the trigger for transfusion. They also provide data on blood use by physician, hospital, and department. These tools can reveal current practice at a glance and allow sharing of best practices among peers and institutions.⁵²

CONSIDER TRANSFUSION FOR HEMOGLOBIN BELOW 7 G/DL

The routine use of blood has come under scrutiny, given its association with increased healthcare costs and morbidity. The accepted practice in stable medical patients is a restrictive threshold approach for blood transfusion, which is to consider (not necessarily give) a single unit of packed red blood cells for a hemoglobin less than 7 g/dL.

However, studies in acute coronary syndrome patients and postoperative cardiac surgery patients have not shown the restrictive threshold to be superior to a liberal threshold in terms of outcomes and costs. This variability suggests the need for further studies to determine the best course of action in different patient subpopulations (eg, surgical, oncologic, trauma, critical illness).

Also, a limitation of most of the clinical studies was that only the hemoglobin concentration was used as a marker of anemia, with no strict assessment of changes in red cell mass with transfusion.

Despite the variability in certain populations, the overall weight of current evidence favors a restrictive approach to blood transfusion (hemoglobin < 7 g/dL), although perhaps in patients who have active coronary disease or are undergoing cardiac surgery, a more lenient threshold (< 8 g/dL) for transfusion should be considered.

A 78-year-old black woman with a history of osteoarthrosis and chronic diffuse joint pain presents with altered mental status and tachypnea, which began 3 hours earlier. She lives alone, and her family suspects she abuses both alcohol and her pain medications. She has not been eating well and has lost approximately 10 pounds over the past 3 months. Her analgesic regimen includes acetaminophen and acetaminophen-oxycodone.

In the emergency department her temperature is 98.6°F (37.0°C), pulse 100 beats per minute and regular, respiratory rate 22 per minute, and blood pressure 136/98 mm Hg. She is obtunded but has no focal neurologic defects or meningismus. She has no signs of heart failure (jugular venous distention, cardiomegaly, or gallops), and examination of the lungs and abdomen is unremarkable.

Suspecting that the patient may have taken too much oxycodone, the physician gives her naloxone, but her mental status does not improve. Results of chest radiography and cranial computed tomography are unremarkable. The physician’s initial impression is that the patient has “metabolic encephalopathy of unknown etiology.”

The patient’s laboratory values are shown in Table 1.

WHICH ACID-BASE DISORDER DOES SHE HAVE?

1. Which acid-base disorder does this patient have?

• Metabolic acidosis and respiratory alkalosis
• Metabolic acidosis and respiratory acidosis
• Metabolic acidosis with an elevated anion gap
• A triple disturbance: metabolic acidosis, respiratory acidosis, and metabolic alkalosis

A 5-step approach

Acid-base disorders can be diagnosed and characterized using a systematic approach known as the “Rules of 5” (Table 2)¹:

1. Determine the arterial pH status.

2. Determine whether the primary process is respiratory, metabolic, or both.

3. Calculate the anion gap.

4. Check the degree of compensation (respiratory or metabolic).

5. If the patient has metabolic acidosis with an elevated anion gap, check whether the bicarbonate level has decreased as much as the anion gap has increased (ie, whether there is a delta gap).

Let us apply this approach to the patient described above.

1. What is her pH status?

An arterial pH less than 7.40 is acidemic, whereas a pH higher than 7.44 is alkalemic. (Acidemia and alkalemia refer to the abnormal laboratory value, while acidosis and alkalosis refer to the process causing the abnormal value—a subtle distinction, but worth keeping in mind.)

Caveat. A patient may have a significant acid-base disorder even if the pH is normal. Therefore, even if the pH is normal, one should verify that the partial pressure of carbon dioxide (Pco₂), bicarbonate level, and anion gap are normal. If they are not, the patient may have a mixed acid-base disorder such as respiratory acidosis superimposed on metabolic alkalosis.

Our patient’s pH is 7.25, which is in the acidemic range.

2. Is her acidosis respiratory, metabolic, or both?

Respiratory acidosis and alkalosis affect the Pco₂. The Pco₂ is high in respiratory acidosis (due to failure to get rid of excess carbon dioxide), whereas it is low in respiratory alkalosis (due to loss of too much carbon dioxide through hyperventilation).

Metabolic acidosis and alkalosis, on the other hand, affect the serum bicarbonate level. In metabolic acidosis the bicarbonate level is low, whereas in metabolic alkalosis the bicarbonate level is high.

Moreover, in mixed respiratory and metabolic acidosis, the bicarbonate level can be low and the Pco₂ can be high. In mixed metabolic and respiratory alkalosis, the bicarbonate level can be high and the Pco₂ can be low (Table 2).

Our patient’s serum bicarbonate level is low at 16.0 mmol/L, indicating that the process is metabolic. Her Pco₂ is also low (28 mm Hg), which reflects an appropriate response to compensate for the acidosis.

3. What is her anion gap?

Always calculate the anion gap, ie, the serum sodium concentration minus the serum chloride and serum bicarbonate concentrations. If the patient’s serum albumin level is low, for every 1 gram it is below normal, an additional 2.5 mmol/L should be added to the calculated anion gap. We consider an anion gap of 10 mmol/L or less as normal.

Caveats. The blood sample used to calculate the anion gap should be drawn close in time to the arterial blood gas sample.

Although the anion gap is an effective tool in assessing acid-base disorders, further investigation is warranted if clinical judgment suggests that an anion gap calculation is inconsistent with the patient’s circumstances.²

Our patient’s anion gap is elevated (21 mmol/L). Her serum albumin level is in the normal range, so her anion gap does not need to be adjusted.

4. Is the degree of compensation appropriate for the primary acid-base disturbance?

The kidneys compensate for the lungs, and vice versa. That is, in respiratory acidosis or alkalosis, the kidneys adjust the bicarbonate levels, and in metabolic acidosis, the lungs adjust the Pco₂ (although in metabolic alkalosis, it is hard for patients to breathe less, especially if they are already hypoxic).

In metabolic acidosis, people compensate by breathing harder to get rid of more carbon dioxide. For every 1-mmol/L decrease in the bicarbonate level, the Pco₂ should decrease by 1.3 mm Hg.

Compensation does not return pH to normal; rather, it mitigates the impact of an acid or alkali excess or deficit. If the pH is normalized with an underlying acid-base disturbance, there may be mixed acid-base processes rather than compensation.

Our patient’s bicarbonate level is 16 mmol/L, which is 9 mmol/L lower than normal (for acid-base calculations, we use 25 mmol/L as the nominal normal level). If she is compensating appropriately, her Pco₂ should decline from 40 mm Hg (the nominal normal level) by about 11.7 mm Hg (9 × 1.3), to approximately 28.3 mm Hg. Her Pco₂ is, indeed, 28 mm Hg, indicating that she is compensating adequately for her metabolic acidosis.

If we use Winter’s formula instead (Pco₂ = [1.5 × the bicarbonate level] + 8 ± 2),³ the lowest calculated Pco₂ would be 30 mm Hg, which is within 2 mm Hg of the Rules of 5 calculation. Other formulas for calculating compensation are available.³

This information rules out the first two answers to question 1, ie, metabolic acidosis with respiratory alkalosis or acidosis.

5. Is there a delta gap?

Although we know the patient has metabolic acidosis with an elevated anion gap, we have not ruled out the possibility that she may have a triple disturbance. For this reason we need to check her delta gap. 

In metabolic acidosis with an elevated anion gap, as the bicarbonate level decreases, the anion gap should increase by the same amount. If the bicarbonate level decreases more than the anion gap increases, the additional decline is the result of a second process—an additional normal-anion-gap acidosis. If the bicarbonate level does not decrease as much as the anion gap increases, there is an additional metabolic alkalosis.

Our patient’s bicarbonate level decreased 9 mmol/L (from the nominal normal level of 25 to 16), and therefore her anion gap should have increased approximately the same amount—and it did. (A normal anion gap for problem-solving is 10, and this patient’s anion gap has increased to 21. A difference of ± 2 is insignificant.) This conclusion verifies that a triple acid-base disturbance is not present, so the last answer is incorrect.

So, the correct answer to the question posed above is metabolic acidosis with an elevated anion gap (that is, metabolic acidosis with appropriate respiratory compensation).

‘MUD PILES’: FINDING THE CAUSE OF ANION GAP METABOLIC ACIDOSIS

The possible causes of metabolic acidosis with an elevated anion gap (as in our patient) can be summarized in the mnemonic MUD PILES (methanol, uremia, diabetes, paraldehyde, isoniazid, lactate, ethylene glycol, and salicylates), which has been used for many years. Parts of it are no longer useful, but rather than discard it, we propose to update it (Table 3).

Methanol and ethylene glycol

We will address toxic ingestion of methanol and ethylene glycol (the “M” and “E” of MUD PILES) at the same time. 

In cases of suspected ingestion of toxic substances such as these, it is useful to examine the osmol gap, ie, the difference between the calculated and the measured serum osmolality. Serum osmolality (in mOsm/kg) is calculated as the sodium concentration in mmol/L times 2, plus the glucose concentration in mg/dL divided by 18, plus the blood urea nitrogen concentration in mg/dL divided by 2.8 (Table 4). If the measured osmolality is higher than this calculated value, the difference may be due to solutes in the blood that should not be there such as ethylene glycol, diethylene glycol, methanol, and their many metabolic products.

In our patient, ingestion of both methanol and ethylene glycol should be considered, since she lives alone and has been suspected of alcohol and opioid abuse. Her calculated osmol gap is 278 mOsm/kg. Her measured osmolality is 318 mOsm/kg (Table 1). The osmol gap is 40 mOsm/kg (normal is ≤ 10).^4,5 Therefore, her osmol gap is elevated.

Identifying the specific substance the patient ingested that caused metabolic acidosis with anion gap may be difficult. Poisonings with these agents do not always increase the osmol gap.⁶ A high index of suspicion is essential. It is helpful to have the family search for any sources of ethylene glycol and methanol at home and initiate treatment early if an ingestion is suspected, using fomepizole (an alcohol dehydrogenase inhibitor) or parenteral ethanol and hemodialysis.⁷ Liquid chromatography identifies these two toxins, but results are not available emergently.

Diethylene glycol ingestion should also be considered.⁸ Since it is diagnosed and treated like ethylene glycol intoxication, it can be placed with the “E” of (di)ethylene glycol in the mnemonic.

Uremia

Renal failure can lead to metabolic acidosis.⁹ Our patient has no history of kidney disease, but her blood urea nitrogen and creatinine concentrations are above normal, and her estimated glomerular filtration rate by the Modification of Diet in Renal Disease formula is 48 mL/min/1.73 m²—low, but not uremic.  

Rhabdomyolysis (suspected by elevated creatine kinase values) should be considered in any patient with mental status changes, suspected toxic ingestion, and metabolic acidosis (see the “I” in MUD PILES below). Compartment syndromes with muscle necrosis may present in a subtle fashion. Therefore, renal failure from rhabdomyolysis may complicate this patient’s course later, and should be kept in mind.

Diabetes

The patient has no history of diabetes and has a normal blood glucose level. Blood testing did not reveal ketones. She is not taking metformin (alleged to cause lactic acidosis) or a sodium-glucose cotransporter 2 inhibitor (which have been associated with ketoacidosis).¹⁰

There is another, less common cause of ketoacidosis: alcohol.¹¹ Although alcoholism is common, alcoholic ketoacidosis is uncommon, even in heavy drinkers. Ethyl alcohol causing metabolic acidosis is similar to metabolic acidosis with (di)ethylene glycol and methanol, and if suspected it should be treated empirically (first with thiamine, then dextrose and saline, and correcting other electrolyte disturbances such as hypokalemia and hypomagnesemia) before specific identification is made. Ketones (predominantly beta-hydroxybutyrate) may persist up to 2 weeks after alcohol ingestion has stopped.¹¹ Ketosis in the setting of alcoholic ketoacidosis is frequently accompanied by other markers of alcohol target organ injury: elevated bilirubin, aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase levels. The term “ketohepatitis” has been suggested as an alternative to alcoholic ketosis.¹¹

This patient did not have an elevated blood ethanol level, and her liver markers were otherwise normal.

THE NEW MUD PILES

2. Which of the following is (are) true? Regarding the remaining letters of the MUD PILES mnemonic:

• The “P” (paraldehyde) has been replaced by pyroglutamic acid (5-oxoproline) and propylene glycol.
• There are two isomers of lactate (dextro and levo), and consequently two clinical varieties of lactic acidosis.
• Isoniazid is no longer associated with metabolic acidosis with elevated anion gap.
• Salicylates can paradoxically be associated both with elevated and low anion gaps.

Isoniazid is still associated with metabolic acidosis with elevated anion gap, and so the third answer choice is false; the rest are true.

Paraldehyde, isoniazid, lactate

The “P,” “I,” and “L” (d-lactate) of the revamped MUD PILES acronym are less common than the others. They should be considered when the more typical causes of metabolic acidosis are not present, as in this patient.

UPDATING THE ‘P’ IN MUD PILES

Paraldehyde is rarely prescribed anymore. A PubMed search on December 21, 2015 applying the terms paraldehyde and metabolic acidosis yielded 17 results. Those specific to anion gap metabolic acidosis were from 1957 to 1986 (n = 9).^12–20

Therefore, we can eliminate paraldehyde from the MUD PILES mnemonic and replace it with pyroglutamic acid and propylene glycol.

5-Oxoproline or pyroglutamic acid, a metabolite of acetaminophen

Acetaminophen depletes glutathione stores in acute overdoses, in patients with inborn errors of metabolism, and after chronic ingestion of excessive, frequent doses. Depletion of glutathione increases metabolic products, including pyroglutamic acid, which dissociates into hydrogen ions (leading to metabolic acidosis and an anion gap), and 5-oxoproline, (which can be detected in the urine).^21,22

Risk factors for metabolic acidosis with acetaminophen ingestion include malnutrition, chronic alcoholism, liver disease, and female sex. In fact, most cases have been reported in females, and altered mental status has been common.

Metabolic acidosis with pyroglutamic acid can occur without elevated acetaminophen levels. Serum and urine levels of pyroglutamic acid may assist with diagnosis. Since identification of urine pyroglutamic acid usually requires outside laboratory assistance, a clinical diagnosis is often made initially and corroborated later by laboratory results. When the anion gap metabolic acidosis is multifactorial, as it was suspected to be in a case reported by Tan et al,²³ the osmol gap may be elevated as a consequence of additional toxic ingestions, as it was in the reported patient.

No controlled studies of treatment have been done. n-Acetylcysteine may be of benefit. Occasional patients have been dialyzed for removal of excess pyroglutamic acid.

Propylene glycol, a component of parenteral lorazepam

Lorazepam is a hydrophobic drug, so when it is given parenterally, it must be mixed with a suitable solvent. A typical formulation adds propylene glycol. In patients receiving high doses of lorazepam as relaxation therapy for acute respiratory distress syndrome in the intensive care unit, or as treatment of alcohol withdrawal, the propylene glycol component can precipitate anion gap metabolic acidosis.^24,25

Although nearly one-half of the administered propylene glycol is excreted by the kidneys, the remaining substrate is metabolized by alcohol dehydrogenase into d,l-lactaldehyde, then converted into d- or l-lactate. l-Lactate can be metabolized, but d-lactate cannot and leads to anion gap metabolic acidosis. This is another toxic metabolic acidosis associated with an elevated osmol gap. An increasing osmol gap in the intensive care unit can serve as a surrogate marker of excessive propylene glycol administration.²³

Isoniazid

Although it is uncommon, there are reports of isoniazid-induced anion gap metabolic acidosis,²⁶ either due to overdoses, or less commonly, with normal dosing. Isoniazid should therefore remain in the mnemonic MUD PILES and may be suspected when metabolic acidosis is accompanied by seizures unresponsive to usual therapy. The seizures respond to pyridoxine.

The “I” should also be augmented by newer causes of metabolic acidosis associated with “ingestions.” Ecstasy, or 3,4-methylenedioxymethamphetamine, can cause metabolic acidosis and seizures. Ecstasy has been associated with rhabdomyolysis and uremia, also leading to anion gap metabolic acidosis.²⁷ A newer class of abused substances, synthetic cathinones (“bath salts”), are associated with metabolic acidosis, compartment syndrome, and renal failure.²⁸

Lactic acidosis

Lactic acidosis and metabolic acidosis can result from hypoperfusion (type A) or other causes (type B). Not all lactic acidosis is contingent on l-lactate, which humans can metabolize. Metabolic acidosis may be a consequence of d-lactate (mammals have no d-lactate dehydrogenase). d-Lactic acidosis as a result of short bowel syndrome has been known for more than a generation.²⁹ However, d-lactic acidosis occurs in another new setting. The new “P” in MUD PILES, propylene glycol, can generate substantial amounts of d-lactate.²⁹

d-lactic metabolic acidosis is always accompanied by neurologic manifestations (slurred speech, confusion, somnolence, ataxia, abusive behavior, and others).³⁰ With short bowel syndrome, the neurologic manifestations occur after eating and clear later.³⁰

Although our patient’s anion gap is more than 20 mmol/L, her blood level of lactate is not elevated, and she had no history to suggest short-bowel syndrome.

Salicylates

Salicylate overdose can cause a mixed acid-base disorder: metabolic acidosis with elevated anion gap and respiratory alkalosis.

Although our patient does not have respiratory alkalosis, an aspirin overdose must be considered. A salicylate level was ordered; it was negative.

Despite the typical association of salicylates with an elevated anion gap, they may also cause a negative anion gap.³¹ Chloride-sensing ion-specific electrodes contain a membrane permeable to chloride. Salicylates can increase the chloride permeability of these membranes, generating pseudohyperchloremia, and consequently, a negative anion gap.

WHAT ELSE MUST BE CONSIDERED?

3. In view of her anion gap metabolic acidosis, elevated osmol gap, and absence of diabetes, renal failure, or lactate excess, what are the remaining diagnoses to consider in this patient? (Choose all that are potential sources of metabolic acidosis and an increased anion gap.)

• Methanol, ethylene, or diethylene glycol
• Excessive, chronic acetaminophen ingestion
• Salicylate toxicity
• Alcoholic ketoacidosis

All of the above can potentially contribute to metabolic acidosis.

A search of the patient’s home did not reveal a source of methanol or either ethylene or diethylene glycol. Similarly, no aspirin was found, and the patient’s salicylate levels were not elevated. The patient’s laboratory work did not reveal increased ketones.

Since none of the common causes of metabolic acidosis were discovered, and since the patient had been taking acetaminophen, the diagnosis of excessive chronic acetaminophen ingestion was suspected pending laboratory verification. Identification of 5-oxoproline in the urine may take a week or more since the sample is usually sent to special laboratories. Acetaminophen levels in this patient were significantly elevated, as were urinary oxyproline levels, which returned later.

The patient was diagnosed with pyroglutamic acid metabolic acidosis. She was treated supportively and with n-acetylcysteine intravenously, although there have been no controlled studies of the efficacy of this drug. Seventy-two hours after admission, she had improved. Her acid-base status returned to normal.

GOLD MARK: ANOTHER WAY TO REMEMBER

Another mnemonic device for remembering the causes of metabolic acidosis with elevated anion gap is “GOLD MARK”: glycols (ethylene and propylene), oxoproline (instead of pyroglutamic acid from acetaminophen), l-lactate, d-lactate, methanol, aspirin, renal failure, and ketoacidosis).³²

ACID-BASE DISORDERS IN DIFFERENT DISEASES

Diverse diseases cause distinctive acid-base abnormalities. Matching the appropriate acid-base abnormality with its associated disease may lead to more timely diagnosis and treatment:

Type 2 diabetes mellitus, for example, can lead to lactic acidosis, ketoacidosis, or type 4 renal tubular acidosis.³³

Heart failure, although not typically framed in the context of acid-base physiology, can lead to elevated lactate, which is associated with a worse prognosis.³⁴

Acquired immunodeficiency syndrome. Abacavir can cause normal anion gap metabolic acidosis.^35,36

Cancer^37,38 can be associated with proximal tubular renal tubular acidosis and lactic acidosis.

An expanding array of toxic ingestions

Metabolic acidosis may be the most prominent and potentially lethal clinical acid-base disturbance. When metabolic acidosis occurs in certain disease states—lactic acidosis with hypoperfusion or methanol ingestion with metabolic acidosis, for example—there is increased morbidity and mortality.

As reflected in the revisions to MUD PILES and in the newer GOLD MARK acronym, the osmol gap has become more valuable in differential diagnosis of metabolic acidosis with an elevated anion gap consequent to an expanding array of toxic ingestions (methanol, propylene glycol, pyroglutamic acid-oxoproline, ethylene glycol, and diethylene glycol), which may accompany pyroglutamic acid-oxoproline.

A 78-year-old black woman with a history of osteoarthrosis and chronic diffuse joint pain presents with altered mental status and tachypnea, which began 3 hours earlier. She lives alone, and her family suspects she abuses both alcohol and her pain medications. She has not been eating well and has lost approximately 10 pounds over the past 3 months. Her analgesic regimen includes acetaminophen and acetaminophen-oxycodone.

In the emergency department her temperature is 98.6°F (37.0°C), pulse 100 beats per minute and regular, respiratory rate 22 per minute, and blood pressure 136/98 mm Hg. She is obtunded but has no focal neurologic defects or meningismus. She has no signs of heart failure (jugular venous distention, cardiomegaly, or gallops), and examination of the lungs and abdomen is unremarkable.

Suspecting that the patient may have taken too much oxycodone, the physician gives her naloxone, but her mental status does not improve. Results of chest radiography and cranial computed tomography are unremarkable. The physician’s initial impression is that the patient has “metabolic encephalopathy of unknown etiology.”

The patient’s laboratory values are shown in Table 1.

WHICH ACID-BASE DISORDER DOES SHE HAVE?

1. Which acid-base disorder does this patient have?

• Metabolic acidosis and respiratory alkalosis
• Metabolic acidosis and respiratory acidosis
• Metabolic acidosis with an elevated anion gap
• A triple disturbance: metabolic acidosis, respiratory acidosis, and metabolic alkalosis

A 5-step approach

Acid-base disorders can be diagnosed and characterized using a systematic approach known as the “Rules of 5” (Table 2)¹:

1. Determine the arterial pH status.

2. Determine whether the primary process is respiratory, metabolic, or both.

3. Calculate the anion gap.

4. Check the degree of compensation (respiratory or metabolic).

5. If the patient has metabolic acidosis with an elevated anion gap, check whether the bicarbonate level has decreased as much as the anion gap has increased (ie, whether there is a delta gap).

Let us apply this approach to the patient described above.

1. What is her pH status?

An arterial pH less than 7.40 is acidemic, whereas a pH higher than 7.44 is alkalemic. (Acidemia and alkalemia refer to the abnormal laboratory value, while acidosis and alkalosis refer to the process causing the abnormal value—a subtle distinction, but worth keeping in mind.)

Caveat. A patient may have a significant acid-base disorder even if the pH is normal. Therefore, even if the pH is normal, one should verify that the partial pressure of carbon dioxide (Pco₂), bicarbonate level, and anion gap are normal. If they are not, the patient may have a mixed acid-base disorder such as respiratory acidosis superimposed on metabolic alkalosis.

Our patient’s pH is 7.25, which is in the acidemic range.

2. Is her acidosis respiratory, metabolic, or both?

Respiratory acidosis and alkalosis affect the Pco₂. The Pco₂ is high in respiratory acidosis (due to failure to get rid of excess carbon dioxide), whereas it is low in respiratory alkalosis (due to loss of too much carbon dioxide through hyperventilation).

Metabolic acidosis and alkalosis, on the other hand, affect the serum bicarbonate level. In metabolic acidosis the bicarbonate level is low, whereas in metabolic alkalosis the bicarbonate level is high.

Moreover, in mixed respiratory and metabolic acidosis, the bicarbonate level can be low and the Pco₂ can be high. In mixed metabolic and respiratory alkalosis, the bicarbonate level can be high and the Pco₂ can be low (Table 2).

Our patient’s serum bicarbonate level is low at 16.0 mmol/L, indicating that the process is metabolic. Her Pco₂ is also low (28 mm Hg), which reflects an appropriate response to compensate for the acidosis.

3. What is her anion gap?

Always calculate the anion gap, ie, the serum sodium concentration minus the serum chloride and serum bicarbonate concentrations. If the patient’s serum albumin level is low, for every 1 gram it is below normal, an additional 2.5 mmol/L should be added to the calculated anion gap. We consider an anion gap of 10 mmol/L or less as normal.

Caveats. The blood sample used to calculate the anion gap should be drawn close in time to the arterial blood gas sample.

Although the anion gap is an effective tool in assessing acid-base disorders, further investigation is warranted if clinical judgment suggests that an anion gap calculation is inconsistent with the patient’s circumstances.²

Our patient’s anion gap is elevated (21 mmol/L). Her serum albumin level is in the normal range, so her anion gap does not need to be adjusted.

4. Is the degree of compensation appropriate for the primary acid-base disturbance?

The kidneys compensate for the lungs, and vice versa. That is, in respiratory acidosis or alkalosis, the kidneys adjust the bicarbonate levels, and in metabolic acidosis, the lungs adjust the Pco₂ (although in metabolic alkalosis, it is hard for patients to breathe less, especially if they are already hypoxic).

In metabolic acidosis, people compensate by breathing harder to get rid of more carbon dioxide. For every 1-mmol/L decrease in the bicarbonate level, the Pco₂ should decrease by 1.3 mm Hg.

Compensation does not return pH to normal; rather, it mitigates the impact of an acid or alkali excess or deficit. If the pH is normalized with an underlying acid-base disturbance, there may be mixed acid-base processes rather than compensation.

Our patient’s bicarbonate level is 16 mmol/L, which is 9 mmol/L lower than normal (for acid-base calculations, we use 25 mmol/L as the nominal normal level). If she is compensating appropriately, her Pco₂ should decline from 40 mm Hg (the nominal normal level) by about 11.7 mm Hg (9 × 1.3), to approximately 28.3 mm Hg. Her Pco₂ is, indeed, 28 mm Hg, indicating that she is compensating adequately for her metabolic acidosis.

If we use Winter’s formula instead (Pco₂ = [1.5 × the bicarbonate level] + 8 ± 2),³ the lowest calculated Pco₂ would be 30 mm Hg, which is within 2 mm Hg of the Rules of 5 calculation. Other formulas for calculating compensation are available.³

This information rules out the first two answers to question 1, ie, metabolic acidosis with respiratory alkalosis or acidosis.

5. Is there a delta gap?

Although we know the patient has metabolic acidosis with an elevated anion gap, we have not ruled out the possibility that she may have a triple disturbance. For this reason we need to check her delta gap. 

In metabolic acidosis with an elevated anion gap, as the bicarbonate level decreases, the anion gap should increase by the same amount. If the bicarbonate level decreases more than the anion gap increases, the additional decline is the result of a second process—an additional normal-anion-gap acidosis. If the bicarbonate level does not decrease as much as the anion gap increases, there is an additional metabolic alkalosis.

Our patient’s bicarbonate level decreased 9 mmol/L (from the nominal normal level of 25 to 16), and therefore her anion gap should have increased approximately the same amount—and it did. (A normal anion gap for problem-solving is 10, and this patient’s anion gap has increased to 21. A difference of ± 2 is insignificant.) This conclusion verifies that a triple acid-base disturbance is not present, so the last answer is incorrect.

So, the correct answer to the question posed above is metabolic acidosis with an elevated anion gap (that is, metabolic acidosis with appropriate respiratory compensation).

‘MUD PILES’: FINDING THE CAUSE OF ANION GAP METABOLIC ACIDOSIS

The possible causes of metabolic acidosis with an elevated anion gap (as in our patient) can be summarized in the mnemonic MUD PILES (methanol, uremia, diabetes, paraldehyde, isoniazid, lactate, ethylene glycol, and salicylates), which has been used for many years. Parts of it are no longer useful, but rather than discard it, we propose to update it (Table 3).

Methanol and ethylene glycol

We will address toxic ingestion of methanol and ethylene glycol (the “M” and “E” of MUD PILES) at the same time. 

In cases of suspected ingestion of toxic substances such as these, it is useful to examine the osmol gap, ie, the difference between the calculated and the measured serum osmolality. Serum osmolality (in mOsm/kg) is calculated as the sodium concentration in mmol/L times 2, plus the glucose concentration in mg/dL divided by 18, plus the blood urea nitrogen concentration in mg/dL divided by 2.8 (Table 4). If the measured osmolality is higher than this calculated value, the difference may be due to solutes in the blood that should not be there such as ethylene glycol, diethylene glycol, methanol, and their many metabolic products.

In our patient, ingestion of both methanol and ethylene glycol should be considered, since she lives alone and has been suspected of alcohol and opioid abuse. Her calculated osmol gap is 278 mOsm/kg. Her measured osmolality is 318 mOsm/kg (Table 1). The osmol gap is 40 mOsm/kg (normal is ≤ 10).^4,5 Therefore, her osmol gap is elevated.

Identifying the specific substance the patient ingested that caused metabolic acidosis with anion gap may be difficult. Poisonings with these agents do not always increase the osmol gap.⁶ A high index of suspicion is essential. It is helpful to have the family search for any sources of ethylene glycol and methanol at home and initiate treatment early if an ingestion is suspected, using fomepizole (an alcohol dehydrogenase inhibitor) or parenteral ethanol and hemodialysis.⁷ Liquid chromatography identifies these two toxins, but results are not available emergently.

Diethylene glycol ingestion should also be considered.⁸ Since it is diagnosed and treated like ethylene glycol intoxication, it can be placed with the “E” of (di)ethylene glycol in the mnemonic.

Uremia

Renal failure can lead to metabolic acidosis.⁹ Our patient has no history of kidney disease, but her blood urea nitrogen and creatinine concentrations are above normal, and her estimated glomerular filtration rate by the Modification of Diet in Renal Disease formula is 48 mL/min/1.73 m²—low, but not uremic.  

Rhabdomyolysis (suspected by elevated creatine kinase values) should be considered in any patient with mental status changes, suspected toxic ingestion, and metabolic acidosis (see the “I” in MUD PILES below). Compartment syndromes with muscle necrosis may present in a subtle fashion. Therefore, renal failure from rhabdomyolysis may complicate this patient’s course later, and should be kept in mind.

Diabetes

The patient has no history of diabetes and has a normal blood glucose level. Blood testing did not reveal ketones. She is not taking metformin (alleged to cause lactic acidosis) or a sodium-glucose cotransporter 2 inhibitor (which have been associated with ketoacidosis).¹⁰

There is another, less common cause of ketoacidosis: alcohol.¹¹ Although alcoholism is common, alcoholic ketoacidosis is uncommon, even in heavy drinkers. Ethyl alcohol causing metabolic acidosis is similar to metabolic acidosis with (di)ethylene glycol and methanol, and if suspected it should be treated empirically (first with thiamine, then dextrose and saline, and correcting other electrolyte disturbances such as hypokalemia and hypomagnesemia) before specific identification is made. Ketones (predominantly beta-hydroxybutyrate) may persist up to 2 weeks after alcohol ingestion has stopped.¹¹ Ketosis in the setting of alcoholic ketoacidosis is frequently accompanied by other markers of alcohol target organ injury: elevated bilirubin, aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase levels. The term “ketohepatitis” has been suggested as an alternative to alcoholic ketosis.¹¹

This patient did not have an elevated blood ethanol level, and her liver markers were otherwise normal.

THE NEW MUD PILES

2. Which of the following is (are) true? Regarding the remaining letters of the MUD PILES mnemonic:

• The “P” (paraldehyde) has been replaced by pyroglutamic acid (5-oxoproline) and propylene glycol.
• There are two isomers of lactate (dextro and levo), and consequently two clinical varieties of lactic acidosis.
• Isoniazid is no longer associated with metabolic acidosis with elevated anion gap.
• Salicylates can paradoxically be associated both with elevated and low anion gaps.

Isoniazid is still associated with metabolic acidosis with elevated anion gap, and so the third answer choice is false; the rest are true.

Paraldehyde, isoniazid, lactate

The “P,” “I,” and “L” (d-lactate) of the revamped MUD PILES acronym are less common than the others. They should be considered when the more typical causes of metabolic acidosis are not present, as in this patient.

UPDATING THE ‘P’ IN MUD PILES

Paraldehyde is rarely prescribed anymore. A PubMed search on December 21, 2015 applying the terms paraldehyde and metabolic acidosis yielded 17 results. Those specific to anion gap metabolic acidosis were from 1957 to 1986 (n = 9).^12–20

Therefore, we can eliminate paraldehyde from the MUD PILES mnemonic and replace it with pyroglutamic acid and propylene glycol.

5-Oxoproline or pyroglutamic acid, a metabolite of acetaminophen

Acetaminophen depletes glutathione stores in acute overdoses, in patients with inborn errors of metabolism, and after chronic ingestion of excessive, frequent doses. Depletion of glutathione increases metabolic products, including pyroglutamic acid, which dissociates into hydrogen ions (leading to metabolic acidosis and an anion gap), and 5-oxoproline, (which can be detected in the urine).^21,22

Risk factors for metabolic acidosis with acetaminophen ingestion include malnutrition, chronic alcoholism, liver disease, and female sex. In fact, most cases have been reported in females, and altered mental status has been common.

Metabolic acidosis with pyroglutamic acid can occur without elevated acetaminophen levels. Serum and urine levels of pyroglutamic acid may assist with diagnosis. Since identification of urine pyroglutamic acid usually requires outside laboratory assistance, a clinical diagnosis is often made initially and corroborated later by laboratory results. When the anion gap metabolic acidosis is multifactorial, as it was suspected to be in a case reported by Tan et al,²³ the osmol gap may be elevated as a consequence of additional toxic ingestions, as it was in the reported patient.

No controlled studies of treatment have been done. n-Acetylcysteine may be of benefit. Occasional patients have been dialyzed for removal of excess pyroglutamic acid.

Propylene glycol, a component of parenteral lorazepam

Lorazepam is a hydrophobic drug, so when it is given parenterally, it must be mixed with a suitable solvent. A typical formulation adds propylene glycol. In patients receiving high doses of lorazepam as relaxation therapy for acute respiratory distress syndrome in the intensive care unit, or as treatment of alcohol withdrawal, the propylene glycol component can precipitate anion gap metabolic acidosis.^24,25

Although nearly one-half of the administered propylene glycol is excreted by the kidneys, the remaining substrate is metabolized by alcohol dehydrogenase into d,l-lactaldehyde, then converted into d- or l-lactate. l-Lactate can be metabolized, but d-lactate cannot and leads to anion gap metabolic acidosis. This is another toxic metabolic acidosis associated with an elevated osmol gap. An increasing osmol gap in the intensive care unit can serve as a surrogate marker of excessive propylene glycol administration.²³

Isoniazid

Although it is uncommon, there are reports of isoniazid-induced anion gap metabolic acidosis,²⁶ either due to overdoses, or less commonly, with normal dosing. Isoniazid should therefore remain in the mnemonic MUD PILES and may be suspected when metabolic acidosis is accompanied by seizures unresponsive to usual therapy. The seizures respond to pyridoxine.

The “I” should also be augmented by newer causes of metabolic acidosis associated with “ingestions.” Ecstasy, or 3,4-methylenedioxymethamphetamine, can cause metabolic acidosis and seizures. Ecstasy has been associated with rhabdomyolysis and uremia, also leading to anion gap metabolic acidosis.²⁷ A newer class of abused substances, synthetic cathinones (“bath salts”), are associated with metabolic acidosis, compartment syndrome, and renal failure.²⁸

Lactic acidosis

Lactic acidosis and metabolic acidosis can result from hypoperfusion (type A) or other causes (type B). Not all lactic acidosis is contingent on l-lactate, which humans can metabolize. Metabolic acidosis may be a consequence of d-lactate (mammals have no d-lactate dehydrogenase). d-Lactic acidosis as a result of short bowel syndrome has been known for more than a generation.²⁹ However, d-lactic acidosis occurs in another new setting. The new “P” in MUD PILES, propylene glycol, can generate substantial amounts of d-lactate.²⁹

d-lactic metabolic acidosis is always accompanied by neurologic manifestations (slurred speech, confusion, somnolence, ataxia, abusive behavior, and others).³⁰ With short bowel syndrome, the neurologic manifestations occur after eating and clear later.³⁰

Although our patient’s anion gap is more than 20 mmol/L, her blood level of lactate is not elevated, and she had no history to suggest short-bowel syndrome.

Salicylates

Salicylate overdose can cause a mixed acid-base disorder: metabolic acidosis with elevated anion gap and respiratory alkalosis.

Although our patient does not have respiratory alkalosis, an aspirin overdose must be considered. A salicylate level was ordered; it was negative.

Despite the typical association of salicylates with an elevated anion gap, they may also cause a negative anion gap.³¹ Chloride-sensing ion-specific electrodes contain a membrane permeable to chloride. Salicylates can increase the chloride permeability of these membranes, generating pseudohyperchloremia, and consequently, a negative anion gap.

WHAT ELSE MUST BE CONSIDERED?

3. In view of her anion gap metabolic acidosis, elevated osmol gap, and absence of diabetes, renal failure, or lactate excess, what are the remaining diagnoses to consider in this patient? (Choose all that are potential sources of metabolic acidosis and an increased anion gap.)

• Methanol, ethylene, or diethylene glycol
• Excessive, chronic acetaminophen ingestion
• Salicylate toxicity
• Alcoholic ketoacidosis

All of the above can potentially contribute to metabolic acidosis.

A search of the patient’s home did not reveal a source of methanol or either ethylene or diethylene glycol. Similarly, no aspirin was found, and the patient’s salicylate levels were not elevated. The patient’s laboratory work did not reveal increased ketones.

Since none of the common causes of metabolic acidosis were discovered, and since the patient had been taking acetaminophen, the diagnosis of excessive chronic acetaminophen ingestion was suspected pending laboratory verification. Identification of 5-oxoproline in the urine may take a week or more since the sample is usually sent to special laboratories. Acetaminophen levels in this patient were significantly elevated, as were urinary oxyproline levels, which returned later.

The patient was diagnosed with pyroglutamic acid metabolic acidosis. She was treated supportively and with n-acetylcysteine intravenously, although there have been no controlled studies of the efficacy of this drug. Seventy-two hours after admission, she had improved. Her acid-base status returned to normal.

GOLD MARK: ANOTHER WAY TO REMEMBER

Another mnemonic device for remembering the causes of metabolic acidosis with elevated anion gap is “GOLD MARK”: glycols (ethylene and propylene), oxoproline (instead of pyroglutamic acid from acetaminophen), l-lactate, d-lactate, methanol, aspirin, renal failure, and ketoacidosis).³²

ACID-BASE DISORDERS IN DIFFERENT DISEASES

Diverse diseases cause distinctive acid-base abnormalities. Matching the appropriate acid-base abnormality with its associated disease may lead to more timely diagnosis and treatment:

Type 2 diabetes mellitus, for example, can lead to lactic acidosis, ketoacidosis, or type 4 renal tubular acidosis.³³

Heart failure, although not typically framed in the context of acid-base physiology, can lead to elevated lactate, which is associated with a worse prognosis.³⁴

Acquired immunodeficiency syndrome. Abacavir can cause normal anion gap metabolic acidosis.^35,36

Cancer^37,38 can be associated with proximal tubular renal tubular acidosis and lactic acidosis.

An expanding array of toxic ingestions

Metabolic acidosis may be the most prominent and potentially lethal clinical acid-base disturbance. When metabolic acidosis occurs in certain disease states—lactic acidosis with hypoperfusion or methanol ingestion with metabolic acidosis, for example—there is increased morbidity and mortality.

As reflected in the revisions to MUD PILES and in the newer GOLD MARK acronym, the osmol gap has become more valuable in differential diagnosis of metabolic acidosis with an elevated anion gap consequent to an expanding array of toxic ingestions (methanol, propylene glycol, pyroglutamic acid-oxoproline, ethylene glycol, and diethylene glycol), which may accompany pyroglutamic acid-oxoproline.

A 78-year-old black woman with a history of osteoarthrosis and chronic diffuse joint pain presents with altered mental status and tachypnea, which began 3 hours earlier. She lives alone, and her family suspects she abuses both alcohol and her pain medications. She has not been eating well and has lost approximately 10 pounds over the past 3 months. Her analgesic regimen includes acetaminophen and acetaminophen-oxycodone.

In the emergency department her temperature is 98.6°F (37.0°C), pulse 100 beats per minute and regular, respiratory rate 22 per minute, and blood pressure 136/98 mm Hg. She is obtunded but has no focal neurologic defects or meningismus. She has no signs of heart failure (jugular venous distention, cardiomegaly, or gallops), and examination of the lungs and abdomen is unremarkable.

Suspecting that the patient may have taken too much oxycodone, the physician gives her naloxone, but her mental status does not improve. Results of chest radiography and cranial computed tomography are unremarkable. The physician’s initial impression is that the patient has “metabolic encephalopathy of unknown etiology.”

The patient’s laboratory values are shown in Table 1.

WHICH ACID-BASE DISORDER DOES SHE HAVE?

1. Which acid-base disorder does this patient have?

• Metabolic acidosis and respiratory alkalosis
• Metabolic acidosis and respiratory acidosis
• Metabolic acidosis with an elevated anion gap
• A triple disturbance: metabolic acidosis, respiratory acidosis, and metabolic alkalosis

A 5-step approach

Acid-base disorders can be diagnosed and characterized using a systematic approach known as the “Rules of 5” (Table 2)¹:

1. Determine the arterial pH status.

2. Determine whether the primary process is respiratory, metabolic, or both.

3. Calculate the anion gap.

4. Check the degree of compensation (respiratory or metabolic).

5. If the patient has metabolic acidosis with an elevated anion gap, check whether the bicarbonate level has decreased as much as the anion gap has increased (ie, whether there is a delta gap).

Let us apply this approach to the patient described above.

1. What is her pH status?

An arterial pH less than 7.40 is acidemic, whereas a pH higher than 7.44 is alkalemic. (Acidemia and alkalemia refer to the abnormal laboratory value, while acidosis and alkalosis refer to the process causing the abnormal value—a subtle distinction, but worth keeping in mind.)

Caveat. A patient may have a significant acid-base disorder even if the pH is normal. Therefore, even if the pH is normal, one should verify that the partial pressure of carbon dioxide (Pco₂), bicarbonate level, and anion gap are normal. If they are not, the patient may have a mixed acid-base disorder such as respiratory acidosis superimposed on metabolic alkalosis.

Our patient’s pH is 7.25, which is in the acidemic range.

2. Is her acidosis respiratory, metabolic, or both?

Respiratory acidosis and alkalosis affect the Pco₂. The Pco₂ is high in respiratory acidosis (due to failure to get rid of excess carbon dioxide), whereas it is low in respiratory alkalosis (due to loss of too much carbon dioxide through hyperventilation).

Metabolic acidosis and alkalosis, on the other hand, affect the serum bicarbonate level. In metabolic acidosis the bicarbonate level is low, whereas in metabolic alkalosis the bicarbonate level is high.

Moreover, in mixed respiratory and metabolic acidosis, the bicarbonate level can be low and the Pco₂ can be high. In mixed metabolic and respiratory alkalosis, the bicarbonate level can be high and the Pco₂ can be low (Table 2).

Our patient’s serum bicarbonate level is low at 16.0 mmol/L, indicating that the process is metabolic. Her Pco₂ is also low (28 mm Hg), which reflects an appropriate response to compensate for the acidosis.

3. What is her anion gap?

Always calculate the anion gap, ie, the serum sodium concentration minus the serum chloride and serum bicarbonate concentrations. If the patient’s serum albumin level is low, for every 1 gram it is below normal, an additional 2.5 mmol/L should be added to the calculated anion gap. We consider an anion gap of 10 mmol/L or less as normal.

Caveats. The blood sample used to calculate the anion gap should be drawn close in time to the arterial blood gas sample.

Although the anion gap is an effective tool in assessing acid-base disorders, further investigation is warranted if clinical judgment suggests that an anion gap calculation is inconsistent with the patient’s circumstances.²

Our patient’s anion gap is elevated (21 mmol/L). Her serum albumin level is in the normal range, so her anion gap does not need to be adjusted.

4. Is the degree of compensation appropriate for the primary acid-base disturbance?

The kidneys compensate for the lungs, and vice versa. That is, in respiratory acidosis or alkalosis, the kidneys adjust the bicarbonate levels, and in metabolic acidosis, the lungs adjust the Pco₂ (although in metabolic alkalosis, it is hard for patients to breathe less, especially if they are already hypoxic).

In metabolic acidosis, people compensate by breathing harder to get rid of more carbon dioxide. For every 1-mmol/L decrease in the bicarbonate level, the Pco₂ should decrease by 1.3 mm Hg.

Compensation does not return pH to normal; rather, it mitigates the impact of an acid or alkali excess or deficit. If the pH is normalized with an underlying acid-base disturbance, there may be mixed acid-base processes rather than compensation.

Our patient’s bicarbonate level is 16 mmol/L, which is 9 mmol/L lower than normal (for acid-base calculations, we use 25 mmol/L as the nominal normal level). If she is compensating appropriately, her Pco₂ should decline from 40 mm Hg (the nominal normal level) by about 11.7 mm Hg (9 × 1.3), to approximately 28.3 mm Hg. Her Pco₂ is, indeed, 28 mm Hg, indicating that she is compensating adequately for her metabolic acidosis.

If we use Winter’s formula instead (Pco₂ = [1.5 × the bicarbonate level] + 8 ± 2),³ the lowest calculated Pco₂ would be 30 mm Hg, which is within 2 mm Hg of the Rules of 5 calculation. Other formulas for calculating compensation are available.³

This information rules out the first two answers to question 1, ie, metabolic acidosis with respiratory alkalosis or acidosis.

5. Is there a delta gap?

Although we know the patient has metabolic acidosis with an elevated anion gap, we have not ruled out the possibility that she may have a triple disturbance. For this reason we need to check her delta gap. 

In metabolic acidosis with an elevated anion gap, as the bicarbonate level decreases, the anion gap should increase by the same amount. If the bicarbonate level decreases more than the anion gap increases, the additional decline is the result of a second process—an additional normal-anion-gap acidosis. If the bicarbonate level does not decrease as much as the anion gap increases, there is an additional metabolic alkalosis.

Our patient’s bicarbonate level decreased 9 mmol/L (from the nominal normal level of 25 to 16), and therefore her anion gap should have increased approximately the same amount—and it did. (A normal anion gap for problem-solving is 10, and this patient’s anion gap has increased to 21. A difference of ± 2 is insignificant.) This conclusion verifies that a triple acid-base disturbance is not present, so the last answer is incorrect.

So, the correct answer to the question posed above is metabolic acidosis with an elevated anion gap (that is, metabolic acidosis with appropriate respiratory compensation).

‘MUD PILES’: FINDING THE CAUSE OF ANION GAP METABOLIC ACIDOSIS

The possible causes of metabolic acidosis with an elevated anion gap (as in our patient) can be summarized in the mnemonic MUD PILES (methanol, uremia, diabetes, paraldehyde, isoniazid, lactate, ethylene glycol, and salicylates), which has been used for many years. Parts of it are no longer useful, but rather than discard it, we propose to update it (Table 3).

Methanol and ethylene glycol

We will address toxic ingestion of methanol and ethylene glycol (the “M” and “E” of MUD PILES) at the same time. 

In cases of suspected ingestion of toxic substances such as these, it is useful to examine the osmol gap, ie, the difference between the calculated and the measured serum osmolality. Serum osmolality (in mOsm/kg) is calculated as the sodium concentration in mmol/L times 2, plus the glucose concentration in mg/dL divided by 18, plus the blood urea nitrogen concentration in mg/dL divided by 2.8 (Table 4). If the measured osmolality is higher than this calculated value, the difference may be due to solutes in the blood that should not be there such as ethylene glycol, diethylene glycol, methanol, and their many metabolic products.

In our patient, ingestion of both methanol and ethylene glycol should be considered, since she lives alone and has been suspected of alcohol and opioid abuse. Her calculated osmol gap is 278 mOsm/kg. Her measured osmolality is 318 mOsm/kg (Table 1). The osmol gap is 40 mOsm/kg (normal is ≤ 10).^4,5 Therefore, her osmol gap is elevated.

Identifying the specific substance the patient ingested that caused metabolic acidosis with anion gap may be difficult. Poisonings with these agents do not always increase the osmol gap.⁶ A high index of suspicion is essential. It is helpful to have the family search for any sources of ethylene glycol and methanol at home and initiate treatment early if an ingestion is suspected, using fomepizole (an alcohol dehydrogenase inhibitor) or parenteral ethanol and hemodialysis.⁷ Liquid chromatography identifies these two toxins, but results are not available emergently.

Diethylene glycol ingestion should also be considered.⁸ Since it is diagnosed and treated like ethylene glycol intoxication, it can be placed with the “E” of (di)ethylene glycol in the mnemonic.

Uremia

Renal failure can lead to metabolic acidosis.⁹ Our patient has no history of kidney disease, but her blood urea nitrogen and creatinine concentrations are above normal, and her estimated glomerular filtration rate by the Modification of Diet in Renal Disease formula is 48 mL/min/1.73 m²—low, but not uremic.  

Rhabdomyolysis (suspected by elevated creatine kinase values) should be considered in any patient with mental status changes, suspected toxic ingestion, and metabolic acidosis (see the “I” in MUD PILES below). Compartment syndromes with muscle necrosis may present in a subtle fashion. Therefore, renal failure from rhabdomyolysis may complicate this patient’s course later, and should be kept in mind.

Diabetes

The patient has no history of diabetes and has a normal blood glucose level. Blood testing did not reveal ketones. She is not taking metformin (alleged to cause lactic acidosis) or a sodium-glucose cotransporter 2 inhibitor (which have been associated with ketoacidosis).¹⁰

There is another, less common cause of ketoacidosis: alcohol.¹¹ Although alcoholism is common, alcoholic ketoacidosis is uncommon, even in heavy drinkers. Ethyl alcohol causing metabolic acidosis is similar to metabolic acidosis with (di)ethylene glycol and methanol, and if suspected it should be treated empirically (first with thiamine, then dextrose and saline, and correcting other electrolyte disturbances such as hypokalemia and hypomagnesemia) before specific identification is made. Ketones (predominantly beta-hydroxybutyrate) may persist up to 2 weeks after alcohol ingestion has stopped.¹¹ Ketosis in the setting of alcoholic ketoacidosis is frequently accompanied by other markers of alcohol target organ injury: elevated bilirubin, aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase levels. The term “ketohepatitis” has been suggested as an alternative to alcoholic ketosis.¹¹

This patient did not have an elevated blood ethanol level, and her liver markers were otherwise normal.

THE NEW MUD PILES

2. Which of the following is (are) true? Regarding the remaining letters of the MUD PILES mnemonic:

• The “P” (paraldehyde) has been replaced by pyroglutamic acid (5-oxoproline) and propylene glycol.
• There are two isomers of lactate (dextro and levo), and consequently two clinical varieties of lactic acidosis.
• Isoniazid is no longer associated with metabolic acidosis with elevated anion gap.
• Salicylates can paradoxically be associated both with elevated and low anion gaps.

Isoniazid is still associated with metabolic acidosis with elevated anion gap, and so the third answer choice is false; the rest are true.

Paraldehyde, isoniazid, lactate

The “P,” “I,” and “L” (d-lactate) of the revamped MUD PILES acronym are less common than the others. They should be considered when the more typical causes of metabolic acidosis are not present, as in this patient.

UPDATING THE ‘P’ IN MUD PILES

Paraldehyde is rarely prescribed anymore. A PubMed search on December 21, 2015 applying the terms paraldehyde and metabolic acidosis yielded 17 results. Those specific to anion gap metabolic acidosis were from 1957 to 1986 (n = 9).^12–20

Therefore, we can eliminate paraldehyde from the MUD PILES mnemonic and replace it with pyroglutamic acid and propylene glycol.

5-Oxoproline or pyroglutamic acid, a metabolite of acetaminophen

Acetaminophen depletes glutathione stores in acute overdoses, in patients with inborn errors of metabolism, and after chronic ingestion of excessive, frequent doses. Depletion of glutathione increases metabolic products, including pyroglutamic acid, which dissociates into hydrogen ions (leading to metabolic acidosis and an anion gap), and 5-oxoproline, (which can be detected in the urine).^21,22

Risk factors for metabolic acidosis with acetaminophen ingestion include malnutrition, chronic alcoholism, liver disease, and female sex. In fact, most cases have been reported in females, and altered mental status has been common.

Metabolic acidosis with pyroglutamic acid can occur without elevated acetaminophen levels. Serum and urine levels of pyroglutamic acid may assist with diagnosis. Since identification of urine pyroglutamic acid usually requires outside laboratory assistance, a clinical diagnosis is often made initially and corroborated later by laboratory results. When the anion gap metabolic acidosis is multifactorial, as it was suspected to be in a case reported by Tan et al,²³ the osmol gap may be elevated as a consequence of additional toxic ingestions, as it was in the reported patient.

No controlled studies of treatment have been done. n-Acetylcysteine may be of benefit. Occasional patients have been dialyzed for removal of excess pyroglutamic acid.

Propylene glycol, a component of parenteral lorazepam

Lorazepam is a hydrophobic drug, so when it is given parenterally, it must be mixed with a suitable solvent. A typical formulation adds propylene glycol. In patients receiving high doses of lorazepam as relaxation therapy for acute respiratory distress syndrome in the intensive care unit, or as treatment of alcohol withdrawal, the propylene glycol component can precipitate anion gap metabolic acidosis.^24,25

Although nearly one-half of the administered propylene glycol is excreted by the kidneys, the remaining substrate is metabolized by alcohol dehydrogenase into d,l-lactaldehyde, then converted into d- or l-lactate. l-Lactate can be metabolized, but d-lactate cannot and leads to anion gap metabolic acidosis. This is another toxic metabolic acidosis associated with an elevated osmol gap. An increasing osmol gap in the intensive care unit can serve as a surrogate marker of excessive propylene glycol administration.²³

Isoniazid

Although it is uncommon, there are reports of isoniazid-induced anion gap metabolic acidosis,²⁶ either due to overdoses, or less commonly, with normal dosing. Isoniazid should therefore remain in the mnemonic MUD PILES and may be suspected when metabolic acidosis is accompanied by seizures unresponsive to usual therapy. The seizures respond to pyridoxine.

The “I” should also be augmented by newer causes of metabolic acidosis associated with “ingestions.” Ecstasy, or 3,4-methylenedioxymethamphetamine, can cause metabolic acidosis and seizures. Ecstasy has been associated with rhabdomyolysis and uremia, also leading to anion gap metabolic acidosis.²⁷ A newer class of abused substances, synthetic cathinones (“bath salts”), are associated with metabolic acidosis, compartment syndrome, and renal failure.²⁸

Lactic acidosis

Lactic acidosis and metabolic acidosis can result from hypoperfusion (type A) or other causes (type B). Not all lactic acidosis is contingent on l-lactate, which humans can metabolize. Metabolic acidosis may be a consequence of d-lactate (mammals have no d-lactate dehydrogenase). d-Lactic acidosis as a result of short bowel syndrome has been known for more than a generation.²⁹ However, d-lactic acidosis occurs in another new setting. The new “P” in MUD PILES, propylene glycol, can generate substantial amounts of d-lactate.²⁹

d-lactic metabolic acidosis is always accompanied by neurologic manifestations (slurred speech, confusion, somnolence, ataxia, abusive behavior, and others).³⁰ With short bowel syndrome, the neurologic manifestations occur after eating and clear later.³⁰

Although our patient’s anion gap is more than 20 mmol/L, her blood level of lactate is not elevated, and she had no history to suggest short-bowel syndrome.

Salicylates

Salicylate overdose can cause a mixed acid-base disorder: metabolic acidosis with elevated anion gap and respiratory alkalosis.

Although our patient does not have respiratory alkalosis, an aspirin overdose must be considered. A salicylate level was ordered; it was negative.

Despite the typical association of salicylates with an elevated anion gap, they may also cause a negative anion gap.³¹ Chloride-sensing ion-specific electrodes contain a membrane permeable to chloride. Salicylates can increase the chloride permeability of these membranes, generating pseudohyperchloremia, and consequently, a negative anion gap.

WHAT ELSE MUST BE CONSIDERED?

3. In view of her anion gap metabolic acidosis, elevated osmol gap, and absence of diabetes, renal failure, or lactate excess, what are the remaining diagnoses to consider in this patient? (Choose all that are potential sources of metabolic acidosis and an increased anion gap.)

• Methanol, ethylene, or diethylene glycol
• Excessive, chronic acetaminophen ingestion
• Salicylate toxicity
• Alcoholic ketoacidosis

All of the above can potentially contribute to metabolic acidosis.

A search of the patient’s home did not reveal a source of methanol or either ethylene or diethylene glycol. Similarly, no aspirin was found, and the patient’s salicylate levels were not elevated. The patient’s laboratory work did not reveal increased ketones.

Since none of the common causes of metabolic acidosis were discovered, and since the patient had been taking acetaminophen, the diagnosis of excessive chronic acetaminophen ingestion was suspected pending laboratory verification. Identification of 5-oxoproline in the urine may take a week or more since the sample is usually sent to special laboratories. Acetaminophen levels in this patient were significantly elevated, as were urinary oxyproline levels, which returned later.

The patient was diagnosed with pyroglutamic acid metabolic acidosis. She was treated supportively and with n-acetylcysteine intravenously, although there have been no controlled studies of the efficacy of this drug. Seventy-two hours after admission, she had improved. Her acid-base status returned to normal.

GOLD MARK: ANOTHER WAY TO REMEMBER

Another mnemonic device for remembering the causes of metabolic acidosis with elevated anion gap is “GOLD MARK”: glycols (ethylene and propylene), oxoproline (instead of pyroglutamic acid from acetaminophen), l-lactate, d-lactate, methanol, aspirin, renal failure, and ketoacidosis).³²

ACID-BASE DISORDERS IN DIFFERENT DISEASES

Diverse diseases cause distinctive acid-base abnormalities. Matching the appropriate acid-base abnormality with its associated disease may lead to more timely diagnosis and treatment:

Type 2 diabetes mellitus, for example, can lead to lactic acidosis, ketoacidosis, or type 4 renal tubular acidosis.³³

Heart failure, although not typically framed in the context of acid-base physiology, can lead to elevated lactate, which is associated with a worse prognosis.³⁴

Acquired immunodeficiency syndrome. Abacavir can cause normal anion gap metabolic acidosis.^35,36

Cancer^37,38 can be associated with proximal tubular renal tubular acidosis and lactic acidosis.

An expanding array of toxic ingestions

Metabolic acidosis may be the most prominent and potentially lethal clinical acid-base disturbance. When metabolic acidosis occurs in certain disease states—lactic acidosis with hypoperfusion or methanol ingestion with metabolic acidosis, for example—there is increased morbidity and mortality.

As reflected in the revisions to MUD PILES and in the newer GOLD MARK acronym, the osmol gap has become more valuable in differential diagnosis of metabolic acidosis with an elevated anion gap consequent to an expanding array of toxic ingestions (methanol, propylene glycol, pyroglutamic acid-oxoproline, ethylene glycol, and diethylene glycol), which may accompany pyroglutamic acid-oxoproline.

Roflumilast has been shown to reduce rates of acute exacerbation in patients with severe chronic obstructive pulmonary disease (COPD), ie, forced expiratory volume in 1 second (FEV₁) less than 50% with symptoms of chronic bronchitis and a history of exacerbations.

Roflumilast is a selective phosphodiesterase 4 (PDE4) inhibitor that acts on airway smooth muscle cells and various inflammatory cells. By blocking PDE4, roflumilast raises cyclic adenosine monophosphate levels within these cells, curtailing the inflammatory response.^1,2

Roflumilast is not a bronchodilator, although modest improvements in FEV₁ have been documented in clinical trials when it was used as maintenance therapy.

TRIALS OF ROFLUMILAST

Several trials have investigated the efficacy of roflumilast in COPD (Table 1).

The RECORD trial

The RECORD trial¹ in 2005 was the first large randomized controlled trial of roflumilast in moderate to severe COPD. At a dose of 500 µg orally daily, there was a modest but statistically significant improvement in the postbronchodilator FEV₁. There was also improvement in the St. George Respiratory Questionnaire score in the treatment arm, but this was not statistically significant. The study also found a reduction in acute exacerbations of COPD with roflumilast, which was a secondary end point.¹

The results of this study spurred interest in roflumilast as well as criticism of the design of the study. First, COPD patients on inhaled maintenance therapy such as an inhaled corticosteroid and long-acting beta-agonist combination or a long-acting muscarinic antagonist had their medications held during the study. Second, the average FEV₁ was 54% of predicted, indicative of a study population with less severe disease.¹

The RATIO trial

Taking into account the results of the RECORD trial, the RATIO trial³ in 2007 recruited patients with more severe COPD—ie, Global Initiative for Chronic Obstructive Lung Disease (GOLD) class III and IV—and included the rate of acute exacerbations as a primary end point. Maintenance therapy with inhaled corticosteroids was continued in patients already taking them. However, long-acting beta-agonists and long-acting muscarinic antagonist therapies were held.³

Again, roflumilast improved postbronchodilator FEV₁ compared with placebo. A reduction in acute exacerbations was seen but was not statistically significant except in subgroup analysis, where a statistically significant reduction in acute exacerbations was noted for patients with very severe (GOLD class IV) COPD.³

Post hoc analysis from the RATIO trial suggested that patients with chronic bronchitis and patients with a history of frequent exacerbations were more likely to respond to roflumilast.²

The EOS and HELIOS trials

In 2009, the results of the EOS and HELIOS trials of roflumilast in patients with severe COPD were published.⁴ These trials allowed continuation of long-acting beta-agonists and muscarinic antagonists. The prebronchodilator FEV₁ improved modestly when roflumilast was added to a long-acting bronchodilator. These studies ran for only 24 weeks, and the rate of acute exacerbations was not a primary end point, although the results did show a trend toward reduction of exacerbations.⁴

The AURA and HERMES trials

Also in 2009 was the publication of the results of two 52-week placebo-controlled trials (AURA and HERMES) of roflumilast in patients with severe COPD with chronic bronchitis and a history of frequent exacerbations.⁵ Maintenance therapy with long-acting beta-agonists was continued, whereas inhaled corticosteroids and long-acting muscarinic antagonists were held. Statistically significant improvements in prebronchodilator FEV₁ and reduction in the rate of exacerbations were observed in the roflumilast group (17% reduction, 95% confidence interval 8–25, P < .0003).⁵

The REACT trial

The REACT trial⁶ randomized 1,945 patients with severe COPD already on maximal recommended combination inhaled corticosteroid and long-acting beta-agonist therapy to receive either roflumilast or placebo. The patients’ ratio of FEV₁ to forced vital capacity was less than 70%, their postbronchodilator FEV₁ was less than 50%, and they had chronic bronchitis and a history of at least two acute exacerbations during the past year. They had also been on combination therapy for the previous year. Patients who were on long-acting muscarinic-antagonist therapy (70% of the cohort) were included, and continued with their medication.

Patients were followed for 52 weeks. There was a significant reduction in the rate of exacerbations in the roflumilast group vs placebo (0.823 vs 0.959; risk ratio 0.858; 95% confidence interval 0.740–0.995; P = .0424).⁶ As in previous trials, the roflumilast group showed an improvement in postbronchodilator FEV₁. The study also showed a reduction in hospital admissions in the treatment group.⁶

ADVERSE EFFECTS OF ROFLUMILAST

Roflumilast is known to have adverse effects significant enough to reduce compliance, the most common being diarrhea, weight loss, and nausea.^2,6,7 In the REACT trial,⁶ 11% of patients in the roflumilast group vs 5% in the placebo group dropped out of the study because of adverse drug effects. Diarrhea was reported in 10% and weight loss in 9% of patients taking roflumilast. Weight loss has been shown to be reversible upon stopping roflumilast.² There has been no evidence of increased risk of death or serious adverse events in studies of roflumilast in patients with COPD.² However, the benefit-to-harm ratio suggests that roflumilast provides a net benefit only in patients at high risk of severe exacerbations.⁷

Roflumilast has been shown to reduce rates of acute exacerbation in patients with severe chronic obstructive pulmonary disease (COPD), ie, forced expiratory volume in 1 second (FEV₁) less than 50% with symptoms of chronic bronchitis and a history of exacerbations.

Roflumilast is a selective phosphodiesterase 4 (PDE4) inhibitor that acts on airway smooth muscle cells and various inflammatory cells. By blocking PDE4, roflumilast raises cyclic adenosine monophosphate levels within these cells, curtailing the inflammatory response.^1,2

Roflumilast is not a bronchodilator, although modest improvements in FEV₁ have been documented in clinical trials when it was used as maintenance therapy.

TRIALS OF ROFLUMILAST

Several trials have investigated the efficacy of roflumilast in COPD (Table 1).

The RECORD trial

The RECORD trial¹ in 2005 was the first large randomized controlled trial of roflumilast in moderate to severe COPD. At a dose of 500 µg orally daily, there was a modest but statistically significant improvement in the postbronchodilator FEV₁. There was also improvement in the St. George Respiratory Questionnaire score in the treatment arm, but this was not statistically significant. The study also found a reduction in acute exacerbations of COPD with roflumilast, which was a secondary end point.¹

The results of this study spurred interest in roflumilast as well as criticism of the design of the study. First, COPD patients on inhaled maintenance therapy such as an inhaled corticosteroid and long-acting beta-agonist combination or a long-acting muscarinic antagonist had their medications held during the study. Second, the average FEV₁ was 54% of predicted, indicative of a study population with less severe disease.¹

The RATIO trial

Taking into account the results of the RECORD trial, the RATIO trial³ in 2007 recruited patients with more severe COPD—ie, Global Initiative for Chronic Obstructive Lung Disease (GOLD) class III and IV—and included the rate of acute exacerbations as a primary end point. Maintenance therapy with inhaled corticosteroids was continued in patients already taking them. However, long-acting beta-agonists and long-acting muscarinic antagonist therapies were held.³

Again, roflumilast improved postbronchodilator FEV₁ compared with placebo. A reduction in acute exacerbations was seen but was not statistically significant except in subgroup analysis, where a statistically significant reduction in acute exacerbations was noted for patients with very severe (GOLD class IV) COPD.³

Post hoc analysis from the RATIO trial suggested that patients with chronic bronchitis and patients with a history of frequent exacerbations were more likely to respond to roflumilast.²

The EOS and HELIOS trials

In 2009, the results of the EOS and HELIOS trials of roflumilast in patients with severe COPD were published.⁴ These trials allowed continuation of long-acting beta-agonists and muscarinic antagonists. The prebronchodilator FEV₁ improved modestly when roflumilast was added to a long-acting bronchodilator. These studies ran for only 24 weeks, and the rate of acute exacerbations was not a primary end point, although the results did show a trend toward reduction of exacerbations.⁴

The AURA and HERMES trials

Also in 2009 was the publication of the results of two 52-week placebo-controlled trials (AURA and HERMES) of roflumilast in patients with severe COPD with chronic bronchitis and a history of frequent exacerbations.⁵ Maintenance therapy with long-acting beta-agonists was continued, whereas inhaled corticosteroids and long-acting muscarinic antagonists were held. Statistically significant improvements in prebronchodilator FEV₁ and reduction in the rate of exacerbations were observed in the roflumilast group (17% reduction, 95% confidence interval 8–25, P < .0003).⁵

The REACT trial

The REACT trial⁶ randomized 1,945 patients with severe COPD already on maximal recommended combination inhaled corticosteroid and long-acting beta-agonist therapy to receive either roflumilast or placebo. The patients’ ratio of FEV₁ to forced vital capacity was less than 70%, their postbronchodilator FEV₁ was less than 50%, and they had chronic bronchitis and a history of at least two acute exacerbations during the past year. They had also been on combination therapy for the previous year. Patients who were on long-acting muscarinic-antagonist therapy (70% of the cohort) were included, and continued with their medication.

Patients were followed for 52 weeks. There was a significant reduction in the rate of exacerbations in the roflumilast group vs placebo (0.823 vs 0.959; risk ratio 0.858; 95% confidence interval 0.740–0.995; P = .0424).⁶ As in previous trials, the roflumilast group showed an improvement in postbronchodilator FEV₁. The study also showed a reduction in hospital admissions in the treatment group.⁶

ADVERSE EFFECTS OF ROFLUMILAST

Roflumilast is known to have adverse effects significant enough to reduce compliance, the most common being diarrhea, weight loss, and nausea.^2,6,7 In the REACT trial,⁶ 11% of patients in the roflumilast group vs 5% in the placebo group dropped out of the study because of adverse drug effects. Diarrhea was reported in 10% and weight loss in 9% of patients taking roflumilast. Weight loss has been shown to be reversible upon stopping roflumilast.² There has been no evidence of increased risk of death or serious adverse events in studies of roflumilast in patients with COPD.² However, the benefit-to-harm ratio suggests that roflumilast provides a net benefit only in patients at high risk of severe exacerbations.⁷

Roflumilast has been shown to reduce rates of acute exacerbation in patients with severe chronic obstructive pulmonary disease (COPD), ie, forced expiratory volume in 1 second (FEV₁) less than 50% with symptoms of chronic bronchitis and a history of exacerbations.

Roflumilast is a selective phosphodiesterase 4 (PDE4) inhibitor that acts on airway smooth muscle cells and various inflammatory cells. By blocking PDE4, roflumilast raises cyclic adenosine monophosphate levels within these cells, curtailing the inflammatory response.^1,2

Roflumilast is not a bronchodilator, although modest improvements in FEV₁ have been documented in clinical trials when it was used as maintenance therapy.

TRIALS OF ROFLUMILAST

Several trials have investigated the efficacy of roflumilast in COPD (Table 1).

The RECORD trial

The RECORD trial¹ in 2005 was the first large randomized controlled trial of roflumilast in moderate to severe COPD. At a dose of 500 µg orally daily, there was a modest but statistically significant improvement in the postbronchodilator FEV₁. There was also improvement in the St. George Respiratory Questionnaire score in the treatment arm, but this was not statistically significant. The study also found a reduction in acute exacerbations of COPD with roflumilast, which was a secondary end point.¹

The results of this study spurred interest in roflumilast as well as criticism of the design of the study. First, COPD patients on inhaled maintenance therapy such as an inhaled corticosteroid and long-acting beta-agonist combination or a long-acting muscarinic antagonist had their medications held during the study. Second, the average FEV₁ was 54% of predicted, indicative of a study population with less severe disease.¹

The RATIO trial

Taking into account the results of the RECORD trial, the RATIO trial³ in 2007 recruited patients with more severe COPD—ie, Global Initiative for Chronic Obstructive Lung Disease (GOLD) class III and IV—and included the rate of acute exacerbations as a primary end point. Maintenance therapy with inhaled corticosteroids was continued in patients already taking them. However, long-acting beta-agonists and long-acting muscarinic antagonist therapies were held.³

Again, roflumilast improved postbronchodilator FEV₁ compared with placebo. A reduction in acute exacerbations was seen but was not statistically significant except in subgroup analysis, where a statistically significant reduction in acute exacerbations was noted for patients with very severe (GOLD class IV) COPD.³

Post hoc analysis from the RATIO trial suggested that patients with chronic bronchitis and patients with a history of frequent exacerbations were more likely to respond to roflumilast.²

The EOS and HELIOS trials

In 2009, the results of the EOS and HELIOS trials of roflumilast in patients with severe COPD were published.⁴ These trials allowed continuation of long-acting beta-agonists and muscarinic antagonists. The prebronchodilator FEV₁ improved modestly when roflumilast was added to a long-acting bronchodilator. These studies ran for only 24 weeks, and the rate of acute exacerbations was not a primary end point, although the results did show a trend toward reduction of exacerbations.⁴

The AURA and HERMES trials

Also in 2009 was the publication of the results of two 52-week placebo-controlled trials (AURA and HERMES) of roflumilast in patients with severe COPD with chronic bronchitis and a history of frequent exacerbations.⁵ Maintenance therapy with long-acting beta-agonists was continued, whereas inhaled corticosteroids and long-acting muscarinic antagonists were held. Statistically significant improvements in prebronchodilator FEV₁ and reduction in the rate of exacerbations were observed in the roflumilast group (17% reduction, 95% confidence interval 8–25, P < .0003).⁵

The REACT trial

The REACT trial⁶ randomized 1,945 patients with severe COPD already on maximal recommended combination inhaled corticosteroid and long-acting beta-agonist therapy to receive either roflumilast or placebo. The patients’ ratio of FEV₁ to forced vital capacity was less than 70%, their postbronchodilator FEV₁ was less than 50%, and they had chronic bronchitis and a history of at least two acute exacerbations during the past year. They had also been on combination therapy for the previous year. Patients who were on long-acting muscarinic-antagonist therapy (70% of the cohort) were included, and continued with their medication.

Patients were followed for 52 weeks. There was a significant reduction in the rate of exacerbations in the roflumilast group vs placebo (0.823 vs 0.959; risk ratio 0.858; 95% confidence interval 0.740–0.995; P = .0424).⁶ As in previous trials, the roflumilast group showed an improvement in postbronchodilator FEV₁. The study also showed a reduction in hospital admissions in the treatment group.⁶

ADVERSE EFFECTS OF ROFLUMILAST

Roflumilast is known to have adverse effects significant enough to reduce compliance, the most common being diarrhea, weight loss, and nausea.^2,6,7 In the REACT trial,⁶ 11% of patients in the roflumilast group vs 5% in the placebo group dropped out of the study because of adverse drug effects. Diarrhea was reported in 10% and weight loss in 9% of patients taking roflumilast. Weight loss has been shown to be reversible upon stopping roflumilast.² There has been no evidence of increased risk of death or serious adverse events in studies of roflumilast in patients with COPD.² However, the benefit-to-harm ratio suggests that roflumilast provides a net benefit only in patients at high risk of severe exacerbations.⁷

A 31-year-old man presented to the emergency department with meatal inflammation, dysuria, and mucopurulent penile discharge, diagnosed as urethritis and treated empirically with levofloxacin. He was referred to the genitourinary medicine clinic for a full screening for sexually transmitted disease. The results were negative.

Two months later, he returned with pain and redness in his left eye and inflammatory lumbar pain. The glans penis had small pustules that ruptured, leaving painless superficial erosions that coalesced to form a serpiginous pattern (Figure 1). Radiography and magnetic resonance imaging revealed features of grade 3 bilateral sacroiliitis (Figure 2): subchondral sclerosis of both sacral and iliac articular margins (predominantly on the iliac side), erosions, reduced articular space, widening of the joint space, and incipient ankylosis. A diagnosis of reactive arthritis was made based on the presence of urethritis, ocular symptoms, circinate balanitis, and radiologic evidence of sacroiliitis. In addition, the chronic inflammatory back pain and bilateral sacroiliitis indicated developing ankylosing spondylitis according to the modified New York criteria.

Our patient’s circinate balanitis resolved with hydrocortisone cream, and treatment with a nonsteroidal anti-inflammatory drug brought improvement of the joint symptoms.

THE MANY FEATURES OF REACTIVE ARTHRITIS

The American Rheumatology Association diagnostic criteria for reactive arthritis include asymmetric arthritis that lasts at least 1 month and at least one of the following symptoms: urethritis, inflammatory eye disease, mouth ulcers, circinate balanitis, and radiographic evidence of sarcoiliitis, periostitis, or heel spurs.^1,2

Keratoderma blennorrhagicum is another extra-articular manifestation. These symptoms typically start within 1 to 6 weeks after urogenital infection with Chlamydia trachomatis or gastrointestinal infection with Salmonella, Shigella, Yersinia, or Campylobacter species.^1–3

There is great variation in the severity, number, and timing of clinical features in reactive arthritis. The diagnosis can be difficult because only about one-third of patients show the complete classic triad (conjunctivitis, urethritis, arthritis). HLA-B27 positivity is associated with more frequent skin lesions and axial involvement.^4,5

A 31-year-old man presented to the emergency department with meatal inflammation, dysuria, and mucopurulent penile discharge, diagnosed as urethritis and treated empirically with levofloxacin. He was referred to the genitourinary medicine clinic for a full screening for sexually transmitted disease. The results were negative.

Two months later, he returned with pain and redness in his left eye and inflammatory lumbar pain. The glans penis had small pustules that ruptured, leaving painless superficial erosions that coalesced to form a serpiginous pattern (Figure 1). Radiography and magnetic resonance imaging revealed features of grade 3 bilateral sacroiliitis (Figure 2): subchondral sclerosis of both sacral and iliac articular margins (predominantly on the iliac side), erosions, reduced articular space, widening of the joint space, and incipient ankylosis. A diagnosis of reactive arthritis was made based on the presence of urethritis, ocular symptoms, circinate balanitis, and radiologic evidence of sacroiliitis. In addition, the chronic inflammatory back pain and bilateral sacroiliitis indicated developing ankylosing spondylitis according to the modified New York criteria.

Our patient’s circinate balanitis resolved with hydrocortisone cream, and treatment with a nonsteroidal anti-inflammatory drug brought improvement of the joint symptoms.

THE MANY FEATURES OF REACTIVE ARTHRITIS

The American Rheumatology Association diagnostic criteria for reactive arthritis include asymmetric arthritis that lasts at least 1 month and at least one of the following symptoms: urethritis, inflammatory eye disease, mouth ulcers, circinate balanitis, and radiographic evidence of sarcoiliitis, periostitis, or heel spurs.^1,2

Keratoderma blennorrhagicum is another extra-articular manifestation. These symptoms typically start within 1 to 6 weeks after urogenital infection with Chlamydia trachomatis or gastrointestinal infection with Salmonella, Shigella, Yersinia, or Campylobacter species.^1–3

There is great variation in the severity, number, and timing of clinical features in reactive arthritis. The diagnosis can be difficult because only about one-third of patients show the complete classic triad (conjunctivitis, urethritis, arthritis). HLA-B27 positivity is associated with more frequent skin lesions and axial involvement.^4,5

A 31-year-old man presented to the emergency department with meatal inflammation, dysuria, and mucopurulent penile discharge, diagnosed as urethritis and treated empirically with levofloxacin. He was referred to the genitourinary medicine clinic for a full screening for sexually transmitted disease. The results were negative.

Two months later, he returned with pain and redness in his left eye and inflammatory lumbar pain. The glans penis had small pustules that ruptured, leaving painless superficial erosions that coalesced to form a serpiginous pattern (Figure 1). Radiography and magnetic resonance imaging revealed features of grade 3 bilateral sacroiliitis (Figure 2): subchondral sclerosis of both sacral and iliac articular margins (predominantly on the iliac side), erosions, reduced articular space, widening of the joint space, and incipient ankylosis. A diagnosis of reactive arthritis was made based on the presence of urethritis, ocular symptoms, circinate balanitis, and radiologic evidence of sacroiliitis. In addition, the chronic inflammatory back pain and bilateral sacroiliitis indicated developing ankylosing spondylitis according to the modified New York criteria.

Our patient’s circinate balanitis resolved with hydrocortisone cream, and treatment with a nonsteroidal anti-inflammatory drug brought improvement of the joint symptoms.

THE MANY FEATURES OF REACTIVE ARTHRITIS

The American Rheumatology Association diagnostic criteria for reactive arthritis include asymmetric arthritis that lasts at least 1 month and at least one of the following symptoms: urethritis, inflammatory eye disease, mouth ulcers, circinate balanitis, and radiographic evidence of sarcoiliitis, periostitis, or heel spurs.^1,2

Keratoderma blennorrhagicum is another extra-articular manifestation. These symptoms typically start within 1 to 6 weeks after urogenital infection with Chlamydia trachomatis or gastrointestinal infection with Salmonella, Shigella, Yersinia, or Campylobacter species.^1–3

There is great variation in the severity, number, and timing of clinical features in reactive arthritis. The diagnosis can be difficult because only about one-third of patients show the complete classic triad (conjunctivitis, urethritis, arthritis). HLA-B27 positivity is associated with more frequent skin lesions and axial involvement.^4,5

A 51-year-old woman with no significant medical history presented to her primary care physician because of blurred vision, increased fatigue, palpitations, and intermittent episodes of epistaxis. Vital signs were within normal limits except for a heart rate of 110 beats per minute. Physical examination revealed pale conjunctivae and bilateral white-centered retinal hemorrhages and microaneurysms
(Figures 1–4).

The results of laboratory studies:

• Hemoglobin 2.4 g/dL (reference range 12–16)
• Platelet count 78 × 10⁹/L (150–400)
• White blood cell count 4.0 × 10⁹/L (3.7–11.0)
• Atypical lymphocytes 18% (0.0–3.0%)
• Reticulocyte index 0.3 (0.5–2.5%)
• Gamma gap 7.0 g/dL (< 4)
• Immunoglobulin A (IgA) 5,560 mg/dL (61–356).

Bone marrow biopsy study showed complete effacement of the hematopoietic elements of normal marrow, and the diagnosis of B cell lymphoplasmacytic lymphoma was made. Serum electrophoresis showed an elevated kappa-to-lambda ratio of 4.6500 (reference range 0.2600–1.6500). B cells expressed monotypic kappa surface immunoglobulin light chains CD19, CD20, and CD22. They did not express CD5. No testing was done for the MYD88 point mutation.

ROTH SPOTS

White-centered retinal hemorrhages, or Roth spots, are the result of rupture of retinal vessels with subsequent accumulation of platelets and fibrin surrounded by blood.¹ Although Roth spots are mistakenly believed to be caused only by infective endocarditis, they are seen in a variety of conditions, including leukemia, anemia, thrombocytopenia, and hypoxia. Each of these conditions has a different mechanism for vessel rupture, which can include fragility of the smooth muscle vessel wall from hypoxemia and increased hydrostatic pressure in hyperviscosity syndrome.

Hypergammaglobulinemia is the most common cause of hyperviscosity syndrome and is usually associated with Waldenström macroglobulinemia, a type of lymphoplasmacytic lymphoma associated with the largest immunoglobulin, IgM. However, our patient presented with a variant of Waldenström macroglobulinemia with high levels of IgA, a small molecule that in high quantities can also cause hyperviscosity.

Immediate treatment is aimed at decreasing blood viscosity with plasmapheresis and controlling the underlying disease with chemotherapy.² There have been cases of cancer-related Roth spots, in which the lesions disappeared after chemotherapy.³

DIFFERENTIAL DIAGNOSIS OF ROTH SPOTS

Roth spots share morphologic features with other retinal abnormalities such as “cotton wool” spots, Purtscher retinopathy, and cytomegalovirus retinitis. A thorough history and careful ophthalmologic examination can help differentiate these from Roth spots.

Cotton wool spots are a nonspecific sign of vascular insufficiency and represent an ischemic, inflammatory, or infectious condition or an embolic or neoplastic process. Most often, they represent retinopathy from poorly controlled diabetes mellitus or hypertension. On funduscopic examination, cotton wool spots are small, irregularly shaped, yellow-white plaques that may appear raised. They are often found over the posterior pole of the fundus. In contrast, Roth spots appear white or pale on a background of hemorrhage.

Purtscher retinopathy. Polygonal retinal whitening with sharp demarcation against the normal retina is pathognomonic of Purtscher retinopathy.⁴ Purtscher lesions may represent a traumatic or nontraumatic condition, including closed head injury, barotrauma, pancreatic disorder, connective tissue disease, fat embolism after long bone fracture, and even microangiopathic hemolytic anemia. Patients usually describe diminished visual acuity in the context of injury or other systemic illness.

Cytomegalovirus retinitis is an important consideration in the immunocompromised patient presenting with retinal hemorrhage and is the most common cause of blindness in acquired immunodeficiency syndrome (AIDS).⁵ It is a slowly progressive disease, initially asymptomatic and involving one eye, but in some untreated patients with AIDS it may progress to the contralateral eye. When it progresses, patients usually present with floaters or vision loss. The retina can have cotton wool spots with a more diffuse pattern of hemorrhage on the periphery and white sheathing along blood vessels, eloquently described as “frosted branch angiitis.”

Our patient’s lesions appeared more punctate, in contrast to the often fulminant hemorrhagic necrosis or perivascular white lesions surrounding retinal vessels characteristic of cytomegalovirus retinitis.

THE NEED FOR ACTION

New-onset blurred vision should prompt a comprehensive history and physical examination, as it may be secondary to a life-threatening systemic disease. A thorough funduscopic examination may provide vital information and guide management and expeditious referrals for patients with time-sensitive conditions such as cancer.

Our patient decided to undergo treatment outside our hospital and so was lost to follow-up.

A 51-year-old woman with no significant medical history presented to her primary care physician because of blurred vision, increased fatigue, palpitations, and intermittent episodes of epistaxis. Vital signs were within normal limits except for a heart rate of 110 beats per minute. Physical examination revealed pale conjunctivae and bilateral white-centered retinal hemorrhages and microaneurysms
(Figures 1–4).

The results of laboratory studies:

• Hemoglobin 2.4 g/dL (reference range 12–16)
• Platelet count 78 × 10⁹/L (150–400)
• White blood cell count 4.0 × 10⁹/L (3.7–11.0)
• Atypical lymphocytes 18% (0.0–3.0%)
• Reticulocyte index 0.3 (0.5–2.5%)
• Gamma gap 7.0 g/dL (< 4)
• Immunoglobulin A (IgA) 5,560 mg/dL (61–356).

Bone marrow biopsy study showed complete effacement of the hematopoietic elements of normal marrow, and the diagnosis of B cell lymphoplasmacytic lymphoma was made. Serum electrophoresis showed an elevated kappa-to-lambda ratio of 4.6500 (reference range 0.2600–1.6500). B cells expressed monotypic kappa surface immunoglobulin light chains CD19, CD20, and CD22. They did not express CD5. No testing was done for the MYD88 point mutation.

ROTH SPOTS

White-centered retinal hemorrhages, or Roth spots, are the result of rupture of retinal vessels with subsequent accumulation of platelets and fibrin surrounded by blood.¹ Although Roth spots are mistakenly believed to be caused only by infective endocarditis, they are seen in a variety of conditions, including leukemia, anemia, thrombocytopenia, and hypoxia. Each of these conditions has a different mechanism for vessel rupture, which can include fragility of the smooth muscle vessel wall from hypoxemia and increased hydrostatic pressure in hyperviscosity syndrome.

Hypergammaglobulinemia is the most common cause of hyperviscosity syndrome and is usually associated with Waldenström macroglobulinemia, a type of lymphoplasmacytic lymphoma associated with the largest immunoglobulin, IgM. However, our patient presented with a variant of Waldenström macroglobulinemia with high levels of IgA, a small molecule that in high quantities can also cause hyperviscosity.

Immediate treatment is aimed at decreasing blood viscosity with plasmapheresis and controlling the underlying disease with chemotherapy.² There have been cases of cancer-related Roth spots, in which the lesions disappeared after chemotherapy.³

DIFFERENTIAL DIAGNOSIS OF ROTH SPOTS

Roth spots share morphologic features with other retinal abnormalities such as “cotton wool” spots, Purtscher retinopathy, and cytomegalovirus retinitis. A thorough history and careful ophthalmologic examination can help differentiate these from Roth spots.

Cotton wool spots are a nonspecific sign of vascular insufficiency and represent an ischemic, inflammatory, or infectious condition or an embolic or neoplastic process. Most often, they represent retinopathy from poorly controlled diabetes mellitus or hypertension. On funduscopic examination, cotton wool spots are small, irregularly shaped, yellow-white plaques that may appear raised. They are often found over the posterior pole of the fundus. In contrast, Roth spots appear white or pale on a background of hemorrhage.

Purtscher retinopathy. Polygonal retinal whitening with sharp demarcation against the normal retina is pathognomonic of Purtscher retinopathy.⁴ Purtscher lesions may represent a traumatic or nontraumatic condition, including closed head injury, barotrauma, pancreatic disorder, connective tissue disease, fat embolism after long bone fracture, and even microangiopathic hemolytic anemia. Patients usually describe diminished visual acuity in the context of injury or other systemic illness.

Cytomegalovirus retinitis is an important consideration in the immunocompromised patient presenting with retinal hemorrhage and is the most common cause of blindness in acquired immunodeficiency syndrome (AIDS).⁵ It is a slowly progressive disease, initially asymptomatic and involving one eye, but in some untreated patients with AIDS it may progress to the contralateral eye. When it progresses, patients usually present with floaters or vision loss. The retina can have cotton wool spots with a more diffuse pattern of hemorrhage on the periphery and white sheathing along blood vessels, eloquently described as “frosted branch angiitis.”

Our patient’s lesions appeared more punctate, in contrast to the often fulminant hemorrhagic necrosis or perivascular white lesions surrounding retinal vessels characteristic of cytomegalovirus retinitis.

THE NEED FOR ACTION

New-onset blurred vision should prompt a comprehensive history and physical examination, as it may be secondary to a life-threatening systemic disease. A thorough funduscopic examination may provide vital information and guide management and expeditious referrals for patients with time-sensitive conditions such as cancer.

Our patient decided to undergo treatment outside our hospital and so was lost to follow-up.

A 51-year-old woman with no significant medical history presented to her primary care physician because of blurred vision, increased fatigue, palpitations, and intermittent episodes of epistaxis. Vital signs were within normal limits except for a heart rate of 110 beats per minute. Physical examination revealed pale conjunctivae and bilateral white-centered retinal hemorrhages and microaneurysms
(Figures 1–4).

The results of laboratory studies:

• Hemoglobin 2.4 g/dL (reference range 12–16)
• Platelet count 78 × 10⁹/L (150–400)
• White blood cell count 4.0 × 10⁹/L (3.7–11.0)
• Atypical lymphocytes 18% (0.0–3.0%)
• Reticulocyte index 0.3 (0.5–2.5%)
• Gamma gap 7.0 g/dL (< 4)
• Immunoglobulin A (IgA) 5,560 mg/dL (61–356).

Bone marrow biopsy study showed complete effacement of the hematopoietic elements of normal marrow, and the diagnosis of B cell lymphoplasmacytic lymphoma was made. Serum electrophoresis showed an elevated kappa-to-lambda ratio of 4.6500 (reference range 0.2600–1.6500). B cells expressed monotypic kappa surface immunoglobulin light chains CD19, CD20, and CD22. They did not express CD5. No testing was done for the MYD88 point mutation.

ROTH SPOTS

White-centered retinal hemorrhages, or Roth spots, are the result of rupture of retinal vessels with subsequent accumulation of platelets and fibrin surrounded by blood.¹ Although Roth spots are mistakenly believed to be caused only by infective endocarditis, they are seen in a variety of conditions, including leukemia, anemia, thrombocytopenia, and hypoxia. Each of these conditions has a different mechanism for vessel rupture, which can include fragility of the smooth muscle vessel wall from hypoxemia and increased hydrostatic pressure in hyperviscosity syndrome.

Hypergammaglobulinemia is the most common cause of hyperviscosity syndrome and is usually associated with Waldenström macroglobulinemia, a type of lymphoplasmacytic lymphoma associated with the largest immunoglobulin, IgM. However, our patient presented with a variant of Waldenström macroglobulinemia with high levels of IgA, a small molecule that in high quantities can also cause hyperviscosity.

Immediate treatment is aimed at decreasing blood viscosity with plasmapheresis and controlling the underlying disease with chemotherapy.² There have been cases of cancer-related Roth spots, in which the lesions disappeared after chemotherapy.³

DIFFERENTIAL DIAGNOSIS OF ROTH SPOTS

Roth spots share morphologic features with other retinal abnormalities such as “cotton wool” spots, Purtscher retinopathy, and cytomegalovirus retinitis. A thorough history and careful ophthalmologic examination can help differentiate these from Roth spots.

Cotton wool spots are a nonspecific sign of vascular insufficiency and represent an ischemic, inflammatory, or infectious condition or an embolic or neoplastic process. Most often, they represent retinopathy from poorly controlled diabetes mellitus or hypertension. On funduscopic examination, cotton wool spots are small, irregularly shaped, yellow-white plaques that may appear raised. They are often found over the posterior pole of the fundus. In contrast, Roth spots appear white or pale on a background of hemorrhage.

Purtscher retinopathy. Polygonal retinal whitening with sharp demarcation against the normal retina is pathognomonic of Purtscher retinopathy.⁴ Purtscher lesions may represent a traumatic or nontraumatic condition, including closed head injury, barotrauma, pancreatic disorder, connective tissue disease, fat embolism after long bone fracture, and even microangiopathic hemolytic anemia. Patients usually describe diminished visual acuity in the context of injury or other systemic illness.

Cytomegalovirus retinitis is an important consideration in the immunocompromised patient presenting with retinal hemorrhage and is the most common cause of blindness in acquired immunodeficiency syndrome (AIDS).⁵ It is a slowly progressive disease, initially asymptomatic and involving one eye, but in some untreated patients with AIDS it may progress to the contralateral eye. When it progresses, patients usually present with floaters or vision loss. The retina can have cotton wool spots with a more diffuse pattern of hemorrhage on the periphery and white sheathing along blood vessels, eloquently described as “frosted branch angiitis.”

Our patient’s lesions appeared more punctate, in contrast to the often fulminant hemorrhagic necrosis or perivascular white lesions surrounding retinal vessels characteristic of cytomegalovirus retinitis.

THE NEED FOR ACTION

New-onset blurred vision should prompt a comprehensive history and physical examination, as it may be secondary to a life-threatening systemic disease. A thorough funduscopic examination may provide vital information and guide management and expeditious referrals for patients with time-sensitive conditions such as cancer.

Our patient decided to undergo treatment outside our hospital and so was lost to follow-up.

A 66-year-old man with chronic obstructive pulmonary disease (COPD) was brought to the emergency department with a 2-week history of progressive dyspnea followed by altered mental status. He had no history of diabetes mellitus, hypertension, or drug abuse.

On physical examination, he was stuporous. He had no fever or hypotension, but his pulse and breathing were rapid, and he had central cyanosis, bilateral conjunctival congestion, a puffy face, generalized wheezing, basilar crackles in both lungs, and leg edema.

Laboratory testing showed hypoxia and severe hypercarbia. His hematocrit was 65% (reference range 39–51) and his hemoglobin level was 21.5 g/dL (13–17).

The patient was diagnosed with an exacerbation of COPD. He was intubated, placed on mechanical ventilation, and admitted to the intensive care unit.

Computed tomography (CT) performed because of his decreased level of consciousness (Figure 1) showed increased attenuation in the ambient cistern and the lateral aspect of the lateral cerebral fissure, suggesting subarachnoid hemorrhage. The attenuation value in these areas was 89 Hounsfield units (typical values for brain tissue are in the 20s to 30s, and for blood in the 30s to 40s). To further evaluate for subarachnoid hemorrhage, lumbar puncture was performed, but analysis of the fluid sample showed normal protein and glucose levels and no cells.

Based on the results of cerebrospinal fluid evaluation and on the CT attenuation value, a diagnosis of pseudosubarachnoid hemorrhage due to polycythemia was made.

SUBARACHNOID VS PSEUDOSUBARACHNOID HEMORRHAGE

Subarachnoid hemorrhage typically begins with a “thunder-clap” headache (beginning suddenly and described by patients as “the worst headache ever.”) While not all patients have this presentation, if imaging suggests subarachnoid hemorrhage but the patient has atypical signs and symptoms (eg, other than headache), then pseudosubarachnoid hemorrhage should be considered.

Brain CT is one of the most reliable tools for diagnosing subarachnoid hemorrhage in the emergency department. Done within 6 hours of symptom onset, it has a sensitivity of 98.7% and a specificity of 99.9%.¹ Magnetic resonance imaging can also visualize subarachnoid hemorrhage within the first 12 hours, typically as a hyperintensity in the subarachnoid space on fluid-attenuated inversion-recovery sequences² and on susceptibility-weighted sequences.

Lumbar puncture is also an important diagnostic tool but carries a risk of brain herniation in patients with brain edema.

Pseudosubarachnoid hemorrhage is an artifact of CT imaging. It is rare, and its prevalence is unknown.³ However, it may be seen in up to 20% of patients after resuscitation, as a result of diffuse cerebral edema that lowers the attenuation of brain tissue on CT, making the vessels relatively conspicuous. It can also be seen in purulent meningitis (due to proteinaceous influx after blood-brain barrier disruption),⁴ in meningeal leukemia (due to increased cellularity in the leptomeninges), and in severe polycythemia (from a higher concentration of blood and hemoglobin in the vessels).^3,5–7

Although the level of attenuation on CT may help distinguish subarachnoid from pseudosubarachnoid hemorrhage, its accuracy has not been defined. Inspecting the CT images may clarify whether areas with high attenuation look like blood vessels vs subarachnoid hemorrhage.

Our patient recovered and had an uneventful follow-up. The cause of his elevated hematocrit was likely chronic hypoxia from COPD.

Acknowledgment: We thank Dr. Saeide Khanbagi and Dr. Azade Nasr-lari for their cooperation.

A 66-year-old man with chronic obstructive pulmonary disease (COPD) was brought to the emergency department with a 2-week history of progressive dyspnea followed by altered mental status. He had no history of diabetes mellitus, hypertension, or drug abuse.

On physical examination, he was stuporous. He had no fever or hypotension, but his pulse and breathing were rapid, and he had central cyanosis, bilateral conjunctival congestion, a puffy face, generalized wheezing, basilar crackles in both lungs, and leg edema.

Laboratory testing showed hypoxia and severe hypercarbia. His hematocrit was 65% (reference range 39–51) and his hemoglobin level was 21.5 g/dL (13–17).

The patient was diagnosed with an exacerbation of COPD. He was intubated, placed on mechanical ventilation, and admitted to the intensive care unit.

Computed tomography (CT) performed because of his decreased level of consciousness (Figure 1) showed increased attenuation in the ambient cistern and the lateral aspect of the lateral cerebral fissure, suggesting subarachnoid hemorrhage. The attenuation value in these areas was 89 Hounsfield units (typical values for brain tissue are in the 20s to 30s, and for blood in the 30s to 40s). To further evaluate for subarachnoid hemorrhage, lumbar puncture was performed, but analysis of the fluid sample showed normal protein and glucose levels and no cells.

Based on the results of cerebrospinal fluid evaluation and on the CT attenuation value, a diagnosis of pseudosubarachnoid hemorrhage due to polycythemia was made.

SUBARACHNOID VS PSEUDOSUBARACHNOID HEMORRHAGE

Subarachnoid hemorrhage typically begins with a “thunder-clap” headache (beginning suddenly and described by patients as “the worst headache ever.”) While not all patients have this presentation, if imaging suggests subarachnoid hemorrhage but the patient has atypical signs and symptoms (eg, other than headache), then pseudosubarachnoid hemorrhage should be considered.

Brain CT is one of the most reliable tools for diagnosing subarachnoid hemorrhage in the emergency department. Done within 6 hours of symptom onset, it has a sensitivity of 98.7% and a specificity of 99.9%.¹ Magnetic resonance imaging can also visualize subarachnoid hemorrhage within the first 12 hours, typically as a hyperintensity in the subarachnoid space on fluid-attenuated inversion-recovery sequences² and on susceptibility-weighted sequences.

Lumbar puncture is also an important diagnostic tool but carries a risk of brain herniation in patients with brain edema.

Pseudosubarachnoid hemorrhage is an artifact of CT imaging. It is rare, and its prevalence is unknown.³ However, it may be seen in up to 20% of patients after resuscitation, as a result of diffuse cerebral edema that lowers the attenuation of brain tissue on CT, making the vessels relatively conspicuous. It can also be seen in purulent meningitis (due to proteinaceous influx after blood-brain barrier disruption),⁴ in meningeal leukemia (due to increased cellularity in the leptomeninges), and in severe polycythemia (from a higher concentration of blood and hemoglobin in the vessels).^3,5–7

Although the level of attenuation on CT may help distinguish subarachnoid from pseudosubarachnoid hemorrhage, its accuracy has not been defined. Inspecting the CT images may clarify whether areas with high attenuation look like blood vessels vs subarachnoid hemorrhage.

Our patient recovered and had an uneventful follow-up. The cause of his elevated hematocrit was likely chronic hypoxia from COPD.

Acknowledgment: We thank Dr. Saeide Khanbagi and Dr. Azade Nasr-lari for their cooperation.

A 66-year-old man with chronic obstructive pulmonary disease (COPD) was brought to the emergency department with a 2-week history of progressive dyspnea followed by altered mental status. He had no history of diabetes mellitus, hypertension, or drug abuse.

On physical examination, he was stuporous. He had no fever or hypotension, but his pulse and breathing were rapid, and he had central cyanosis, bilateral conjunctival congestion, a puffy face, generalized wheezing, basilar crackles in both lungs, and leg edema.

Laboratory testing showed hypoxia and severe hypercarbia. His hematocrit was 65% (reference range 39–51) and his hemoglobin level was 21.5 g/dL (13–17).

The patient was diagnosed with an exacerbation of COPD. He was intubated, placed on mechanical ventilation, and admitted to the intensive care unit.

Computed tomography (CT) performed because of his decreased level of consciousness (Figure 1) showed increased attenuation in the ambient cistern and the lateral aspect of the lateral cerebral fissure, suggesting subarachnoid hemorrhage. The attenuation value in these areas was 89 Hounsfield units (typical values for brain tissue are in the 20s to 30s, and for blood in the 30s to 40s). To further evaluate for subarachnoid hemorrhage, lumbar puncture was performed, but analysis of the fluid sample showed normal protein and glucose levels and no cells.

Based on the results of cerebrospinal fluid evaluation and on the CT attenuation value, a diagnosis of pseudosubarachnoid hemorrhage due to polycythemia was made.

SUBARACHNOID VS PSEUDOSUBARACHNOID HEMORRHAGE

Subarachnoid hemorrhage typically begins with a “thunder-clap” headache (beginning suddenly and described by patients as “the worst headache ever.”) While not all patients have this presentation, if imaging suggests subarachnoid hemorrhage but the patient has atypical signs and symptoms (eg, other than headache), then pseudosubarachnoid hemorrhage should be considered.

Brain CT is one of the most reliable tools for diagnosing subarachnoid hemorrhage in the emergency department. Done within 6 hours of symptom onset, it has a sensitivity of 98.7% and a specificity of 99.9%.¹ Magnetic resonance imaging can also visualize subarachnoid hemorrhage within the first 12 hours, typically as a hyperintensity in the subarachnoid space on fluid-attenuated inversion-recovery sequences² and on susceptibility-weighted sequences.

Lumbar puncture is also an important diagnostic tool but carries a risk of brain herniation in patients with brain edema.

Pseudosubarachnoid hemorrhage is an artifact of CT imaging. It is rare, and its prevalence is unknown.³ However, it may be seen in up to 20% of patients after resuscitation, as a result of diffuse cerebral edema that lowers the attenuation of brain tissue on CT, making the vessels relatively conspicuous. It can also be seen in purulent meningitis (due to proteinaceous influx after blood-brain barrier disruption),⁴ in meningeal leukemia (due to increased cellularity in the leptomeninges), and in severe polycythemia (from a higher concentration of blood and hemoglobin in the vessels).^3,5–7

Although the level of attenuation on CT may help distinguish subarachnoid from pseudosubarachnoid hemorrhage, its accuracy has not been defined. Inspecting the CT images may clarify whether areas with high attenuation look like blood vessels vs subarachnoid hemorrhage.

Our patient recovered and had an uneventful follow-up. The cause of his elevated hematocrit was likely chronic hypoxia from COPD.

Acknowledgment: We thank Dr. Saeide Khanbagi and Dr. Azade Nasr-lari for their cooperation.

Christopher Columbus, age 41, returned to Europe from his first voyage to the New World suffering from what would turn out to be a chronic illness that included recurrent febrile bouts of severe lower-extremity arthritis. For many years he was thought to have had gout, but careful reanalysis led Allison¹ and then Arnett et al² to propose an alternative diagnosis. Based on the pattern of Columbus’s arthritis and the accompanying symptoms, which these clinicians linked to the arthritis, they proposed the diagnosis of reactive arthritis—actually a subset of reactive arthritis, which at the time of their publications was called Reiter’s syndrome. Arnett discussed this extensively at a historic clinicopathologic conference, noting that the bouts of arthritis were prolonged (too long for typical gout) and that the historically described recurrent episodes of red (“bleeding”) eyes with intermittent “blindness” and ultimate immobility due to spine pain (arthritis) would not be typical of gout. Arnett et al recognized the pattern of this arthritis—lower-extremity-predominant with prolonged episodes, associated inflammatory eye disease, spine involvement, and the protracted course of nearly a decade—as far more typical of a reactive arthritis than gout (or ongoing bacterial infection), occurring in a likely HLA-B27-positive individual. They proposed that the probable trigger for the arthritis was an episode of food-borne bacterial infection acquired during the extensive transatlantic journey.

Fast forward about 470 years to an epidemic aboard a US Navy ship of Shigella-associated dysentery that was accompanied by readily diagnosed reactive arthritis.³ Several diarrheal epidemics with associated reactive arthritis aboard cruise ships have been described, and the association is well documented following Shigella, Salmonella, Campylobacter, and nondiarrheal chlamydial infections.

In this issue of the Journal, Gómez-Moyano et al present images of a patient with dermatologic features of reactive arthritis. I have two points to make in introducing this historical background. First, I want to highlight some features of this syndrome that are distinctive enough as a clinical pattern to enable a diagnosis by appearance alone or, as in the case of Columbus, by historical description alone. But second and more important, I wonder, as perhaps you do, why similar inflammatory features occur in patients of seemingly diverse backgrounds, triggered by different organisms that may have infected different mucosal areas. Why does this rose look like a rose and not a gardenia?

Reactive arthritis is classically thought of as self-limited, lasting less than 6 months. But a significant minority of patients may have chronic disease, particularly with spondylitis, which may be more common in patients who have the HLA-B27 haplotype. The peripheral arthritis generally affects relatively few joints, with the larger lower-extremity joints a common target. Enthesitis, especially at the Achilles tendon heel insertion, is common, and dactylitis or “sausage digits” can occur. These features may also be seen in patients with psoriatic or enteropathic arthritis. Inflammation of the skin (as shown by Gómez-Moyano et al), the eye (conjunctivitis, uveitis, episcleritis), oral mucosa, and the genitourinary tract (urethritis, prostatitis) can also occur. Urethritis can occur in patients with enteric diarrhea as the trigger; thus, it is not just associated with genitourinary infections like chlamydia. What all these sites have in common to be targeted following an infection is not known with certainty; relevant bacterial antigens cannot always be detected in the involved tissues. It is intriguing that transgenic rats engineered to contain many copies of the human HLA-B27 gene develop arthritis along with mucosal, eye, and skin inflammation, which can be avoided if the animals are raised in a germ-free environment. But probably fewer than 50% of patients with reactive arthritis have the B27 gene, so other factors must contribute to this uncommon syndrome. B27 is thus not a generally useful diagnostic test.

When a patient presents with acute inflammatory asymmetric oligoarthritis (affecting < 4 joints), infectious arthritis and crystal-induced arthritis need to be excluded. But looking for and finding other features more typical of reactive arthritis may spare the patient a more extensive and expensive inpatient evaluation.

Recognizing a rose can provide an aesthetic moment, even if we can’t define exactly what makes it a rose. Pattern recognition matters in clinical practice, even without full understanding of the molecular backdrop.

Christopher Columbus, age 41, returned to Europe from his first voyage to the New World suffering from what would turn out to be a chronic illness that included recurrent febrile bouts of severe lower-extremity arthritis. For many years he was thought to have had gout, but careful reanalysis led Allison¹ and then Arnett et al² to propose an alternative diagnosis. Based on the pattern of Columbus’s arthritis and the accompanying symptoms, which these clinicians linked to the arthritis, they proposed the diagnosis of reactive arthritis—actually a subset of reactive arthritis, which at the time of their publications was called Reiter’s syndrome. Arnett discussed this extensively at a historic clinicopathologic conference, noting that the bouts of arthritis were prolonged (too long for typical gout) and that the historically described recurrent episodes of red (“bleeding”) eyes with intermittent “blindness” and ultimate immobility due to spine pain (arthritis) would not be typical of gout. Arnett et al recognized the pattern of this arthritis—lower-extremity-predominant with prolonged episodes, associated inflammatory eye disease, spine involvement, and the protracted course of nearly a decade—as far more typical of a reactive arthritis than gout (or ongoing bacterial infection), occurring in a likely HLA-B27-positive individual. They proposed that the probable trigger for the arthritis was an episode of food-borne bacterial infection acquired during the extensive transatlantic journey.

Fast forward about 470 years to an epidemic aboard a US Navy ship of Shigella-associated dysentery that was accompanied by readily diagnosed reactive arthritis.³ Several diarrheal epidemics with associated reactive arthritis aboard cruise ships have been described, and the association is well documented following Shigella, Salmonella, Campylobacter, and nondiarrheal chlamydial infections.

In this issue of the Journal, Gómez-Moyano et al present images of a patient with dermatologic features of reactive arthritis. I have two points to make in introducing this historical background. First, I want to highlight some features of this syndrome that are distinctive enough as a clinical pattern to enable a diagnosis by appearance alone or, as in the case of Columbus, by historical description alone. But second and more important, I wonder, as perhaps you do, why similar inflammatory features occur in patients of seemingly diverse backgrounds, triggered by different organisms that may have infected different mucosal areas. Why does this rose look like a rose and not a gardenia?

Reactive arthritis is classically thought of as self-limited, lasting less than 6 months. But a significant minority of patients may have chronic disease, particularly with spondylitis, which may be more common in patients who have the HLA-B27 haplotype. The peripheral arthritis generally affects relatively few joints, with the larger lower-extremity joints a common target. Enthesitis, especially at the Achilles tendon heel insertion, is common, and dactylitis or “sausage digits” can occur. These features may also be seen in patients with psoriatic or enteropathic arthritis. Inflammation of the skin (as shown by Gómez-Moyano et al), the eye (conjunctivitis, uveitis, episcleritis), oral mucosa, and the genitourinary tract (urethritis, prostatitis) can also occur. Urethritis can occur in patients with enteric diarrhea as the trigger; thus, it is not just associated with genitourinary infections like chlamydia. What all these sites have in common to be targeted following an infection is not known with certainty; relevant bacterial antigens cannot always be detected in the involved tissues. It is intriguing that transgenic rats engineered to contain many copies of the human HLA-B27 gene develop arthritis along with mucosal, eye, and skin inflammation, which can be avoided if the animals are raised in a germ-free environment. But probably fewer than 50% of patients with reactive arthritis have the B27 gene, so other factors must contribute to this uncommon syndrome. B27 is thus not a generally useful diagnostic test.

When a patient presents with acute inflammatory asymmetric oligoarthritis (affecting < 4 joints), infectious arthritis and crystal-induced arthritis need to be excluded. But looking for and finding other features more typical of reactive arthritis may spare the patient a more extensive and expensive inpatient evaluation.

Recognizing a rose can provide an aesthetic moment, even if we can’t define exactly what makes it a rose. Pattern recognition matters in clinical practice, even without full understanding of the molecular backdrop.

Christopher Columbus, age 41, returned to Europe from his first voyage to the New World suffering from what would turn out to be a chronic illness that included recurrent febrile bouts of severe lower-extremity arthritis. For many years he was thought to have had gout, but careful reanalysis led Allison¹ and then Arnett et al² to propose an alternative diagnosis. Based on the pattern of Columbus’s arthritis and the accompanying symptoms, which these clinicians linked to the arthritis, they proposed the diagnosis of reactive arthritis—actually a subset of reactive arthritis, which at the time of their publications was called Reiter’s syndrome. Arnett discussed this extensively at a historic clinicopathologic conference, noting that the bouts of arthritis were prolonged (too long for typical gout) and that the historically described recurrent episodes of red (“bleeding”) eyes with intermittent “blindness” and ultimate immobility due to spine pain (arthritis) would not be typical of gout. Arnett et al recognized the pattern of this arthritis—lower-extremity-predominant with prolonged episodes, associated inflammatory eye disease, spine involvement, and the protracted course of nearly a decade—as far more typical of a reactive arthritis than gout (or ongoing bacterial infection), occurring in a likely HLA-B27-positive individual. They proposed that the probable trigger for the arthritis was an episode of food-borne bacterial infection acquired during the extensive transatlantic journey.

Fast forward about 470 years to an epidemic aboard a US Navy ship of Shigella-associated dysentery that was accompanied by readily diagnosed reactive arthritis.³ Several diarrheal epidemics with associated reactive arthritis aboard cruise ships have been described, and the association is well documented following Shigella, Salmonella, Campylobacter, and nondiarrheal chlamydial infections.

In this issue of the Journal, Gómez-Moyano et al present images of a patient with dermatologic features of reactive arthritis. I have two points to make in introducing this historical background. First, I want to highlight some features of this syndrome that are distinctive enough as a clinical pattern to enable a diagnosis by appearance alone or, as in the case of Columbus, by historical description alone. But second and more important, I wonder, as perhaps you do, why similar inflammatory features occur in patients of seemingly diverse backgrounds, triggered by different organisms that may have infected different mucosal areas. Why does this rose look like a rose and not a gardenia?

Reactive arthritis is classically thought of as self-limited, lasting less than 6 months. But a significant minority of patients may have chronic disease, particularly with spondylitis, which may be more common in patients who have the HLA-B27 haplotype. The peripheral arthritis generally affects relatively few joints, with the larger lower-extremity joints a common target. Enthesitis, especially at the Achilles tendon heel insertion, is common, and dactylitis or “sausage digits” can occur. These features may also be seen in patients with psoriatic or enteropathic arthritis. Inflammation of the skin (as shown by Gómez-Moyano et al), the eye (conjunctivitis, uveitis, episcleritis), oral mucosa, and the genitourinary tract (urethritis, prostatitis) can also occur. Urethritis can occur in patients with enteric diarrhea as the trigger; thus, it is not just associated with genitourinary infections like chlamydia. What all these sites have in common to be targeted following an infection is not known with certainty; relevant bacterial antigens cannot always be detected in the involved tissues. It is intriguing that transgenic rats engineered to contain many copies of the human HLA-B27 gene develop arthritis along with mucosal, eye, and skin inflammation, which can be avoided if the animals are raised in a germ-free environment. But probably fewer than 50% of patients with reactive arthritis have the B27 gene, so other factors must contribute to this uncommon syndrome. B27 is thus not a generally useful diagnostic test.

When a patient presents with acute inflammatory asymmetric oligoarthritis (affecting < 4 joints), infectious arthritis and crystal-induced arthritis need to be excluded. But looking for and finding other features more typical of reactive arthritis may spare the patient a more extensive and expensive inpatient evaluation.

Recognizing a rose can provide an aesthetic moment, even if we can’t define exactly what makes it a rose. Pattern recognition matters in clinical practice, even without full understanding of the molecular backdrop.

Primary care physicians are uniquely positioned to screen for benign prostatic hyperplasia (BPH) and lower urinary tract symptoms, to perform the initial diagnostic workup, and to start medical therapy in uncomplicated cases. Effective medical therapy is available but underutilized in the primary care setting.¹

This overview covers how to identify and evaluate patients with lower urinary tract symptoms, initiate therapy, and identify factors warranting timely urology referral.

TWO MECHANISMS: STATIC, DYNAMIC

BPH is a histologic diagnosis of proliferation of smooth muscle, epithelium, and stromal cells within the transition zone of the prostate,² which surrounds the proximal urethra.

Symptoms arise through two mechanisms: static, in which the hyperplastic prostatic tissue compresses the urethra (Figure 1); and dynamic, with increased adrenergic nervous system and prostatic smooth muscle tone (Figure 2).³ Both mechanisms increase resistance to urinary flow at the level of the bladder outlet.

As an adaptive change to overcome outlet resistance and maintain urinary flow, the detrusor muscles undergo hypertrophy. However, over time the bladder may develop diminished compliance and increased detrusor activity, causing symptoms such as urinary frequency and urgency. Chronic bladder outlet obstruction can lead to bladder decompensation and detrusor underactivity, manifesting as incomplete emptying, urinary hesitancy, intermittency (starting and stopping while voiding), a weakened urinary stream, and urinary retention.

MOST MEN EVENTUALLY DEVELOP BPH

Autopsy studies have shown that BPH increases in prevalence with age beginning around age 30 and reaching a peak prevalence of 88% in men in their 80s.⁴ This trend parallels those of the incidence and severity of lower urinary tract symptoms.⁵

In the year 2000 alone, BPH was responsible for 4.5 million physician visits at an estimated direct cost of $1.1 billion, not including the cost of pharmacotherapy.⁶

OFFICE WORKUP

BPH can cause lower urinary tract symptoms that fall into two categories: storage and emptying. Storage symptoms include urinary frequency, urgency, and nocturia, whereas emptying symptoms include weak stream, hesitancy, intermittency, incomplete emptying, straining, and postvoid dribbling.

History and differential diagnosis

Assessment begins with characterizing the patient’s symptoms and determining those that are most bothersome. Because BPH is just one of many possible causes of lower urinary tract symptoms, a detailed medical history is necessary to evaluate for other conditions that may cause lower urinary tract dysfunction or complicate its treatment.

Obstructive urinary symptoms can arise from BPH or from other conditions, including ureth­ral stricture disease and neurogenic voiding dysfunction.

Irritative voiding symptoms such as urinary urgency and frequency can result from detrusor overactivity secondary to BPH, but can also be caused by neurologic disease, malignancy, initiation of diuretic therapy, high fluid intake, or consumption of bladder irritants such as caffeine, alcohol, and spicy foods.

Urinary frequency is sometimes a presenting symptom of undiagnosed or poorly controlled diabetes mellitus resulting from glucosuria and polyuria. Iatrogenic causes of polyuria include the new hypoglycemic agents canagliflozin and dapagliflozin, which block renal glucose reabsorption, improving glycemic control by inducing urinary
glucose loss.⁷

Nocturia has many possible nonurologic causes including heart failure (in which excess extravascular fluid shifts to the intravascular space when the patient lies down, resulting in polyuria), obstructive sleep apnea, and behavioral factors such as high evening fluid intake. In these cases, patients usually have nocturnal polyuria (greater than one-third of 24-hour urine output at night) rather than only nocturia (waking at night to void). A fluid diary is a simple tool that can differentiate these two conditions.

Hematuria can develop in patients with BPH with bleeding from congested prostatic or bladder neck vessels; however, hematuria may indicate an underlying malignancy or urolithiasis, for which a urologic workup is indicated.

The broad differential diagnosis for the different lower urinary tract symptoms highlights the importance of obtaining a thorough history.

Physical examination

A general examination should include the following:

Body mass index. Obese patients are at risk of obstructive sleep apnea, which can cause nocturnal polyuria.

Gait. Abnormal gait may suggest a neurologic condition such as Parkinson disease or stroke that can also affect lower urinary tract function.

Lower abdomen. A palpable bladder suggests urinary retention.

External genitalia. Penile causes of urinary obstruction include urethral meatal stenosis or a palpable urethral mass.

Digital rectal examination can reveal benign prostatic enlargement or nodules or firmness, which suggest malignancy and warrant urologic referral.

Neurologic examination, including evaluation of anal sphincter tone and lower extremity sensorimotor function.

Feet. Bilateral lower-extremity edema may be due to heart failure or venous insufficiency.

The International Prostate Symptom Score

All men with lower urinary tract symptoms should complete the International Prostate Symptom Score (IPSS) survey, consisting of seven questions about urinary symptoms plus one about quality of life.⁸ Specifically, it asks the patient, “Over the past month, how often have you…”

• Had a sensation of not emptying your bladder completely after you finish urinating?
• Had to urinate again less than 2 hours after you finished urinating?
• Found you stopped and started again several times when you urinated?
• Found it difficult to postpone urination?
• Had a weak urinary stream?
• Had to push or strain to begin urination?

Each question above is scored as 0 (not at all), 1 (less than 1 time in 5), 2 (less than half the time), 3 (about half the time), 4 (more than half the time, or 5 (almost always).

• Over the past month, how many times did you most typically get up to urinate from the time you went to bed until the time you got up in the morning?

This question is scored from 0 (none) to 5 (5 times or more).

• If you were to spend the rest of your life with your urinary condition the way it is now, how would you feel about that?

This question is scored as 0 (delighted), 1 (pleased), 2 (mostly satisfied), 3 (mixed: equally satisfied and dissatisfied), 4 (mostly dissatisfied), 5 (unhappy), or 6 (terrible).

A total score of 1 to 7 is categorized as mild, 8 to 19 moderate, and 20 to 35 severe.

The questionnaire can also be used to evaluate for disease progression and response to treatment over time. A change of 3 points is clinically significant, as patients are unable to discern a difference below this threshold.⁹

Urinalysis

Urinalysis is recommended to assess for urinary tract infection, hematuria, proteinuria, or glucosuria.

Fluid diary

A fluid diary is useful for patients complaining of frequency or nocturia and can help quantify the volume of fluid intake, frequency of urination, and volumes voided. The patient should complete the diary over a 24-hour period, recording the time and volume of fluid intake and each void. This aids in diagnosing polyuria (> 3 L of urine output per 24 hours), nocturnal polyuria, and behavioral causes of symptoms, including excessive total fluid intake or high evening fluid intake contributing to nocturia.

Serum creatinine not recommended

Measuring serum creatinine is not recommended in the initial BPH workup, as men with lower urinary tract symptoms are not at higher risk of renal failure than those without these symptoms.¹⁰

Prostate-specific antigen

Prostate-specific antigen (PSA) is a glycoprotein primarily produced by prostatic luminal epithelial cells. It is most commonly discussed in the setting of prostate cancer screening, but its utility extends to guiding the management of BPH.

PSA levels correlate with prostate volume and subsequent growth.¹¹ In addition, the risks of developing acute urinary retention or needing surgical intervention rise with increasing PSA.¹² Among men in the Proscar Long-Term Efficacy and Safety Study, the risk of acute urinary retention or BPH-related surgery after 4 years in the watchful-waiting arm was 7.8% in men with a PSA of 1.3 ng/dL or less, compared with 19.9% in men with a PSA greater than 3.2 ng/dL.¹¹ Therefore, men with BPH and an elevated PSA are at higher risk with watchful waiting and may be better served with medical therapy.

In addition, American Urological Association guidelines recommend measuring serum PSA levels in men with a life expectancy greater than 10 years in whom the diagnosis of prostate cancer would alter management.¹⁰

Urologic referral

If the initial evaluation reveals hematuria, recurrent urinary tract infection, a palpable bladder, abnormal findings on digital rectal examination suggesting prostate cancer, or a history of or risk factors for urethral stricture or neurologic disease, the patient should be referred to a urologist for further evaluation (Table 1).¹⁰ Other patients who should undergo urologic evaluation are those with persistent bothersome symptoms after basic management and those who desire referral.

Adjunctive tests

Patients referred for urologic evaluation may require additional tests for diagnosis and to guide management.

Postvoid residual volume is easily measured with either abdominal ultrasonography or catheterization and is often included in the urologic evaluation of BPH. Patients vary considerably in their residual volume, which correlates poorly with BPH, symptom severity, or surgical success. However, those with a residual volume of more than 100 mL have a slightly higher rate of failure with watchful waiting.¹³ Postvoid residual volume is not routinely monitored in patients with a low residual volume unless there is a significant change in urinary symptoms. Conversely, patients with a volume greater than 200 mL should be monitored closely for worsening urinary retention, especially if considering anticholinergic therapy.

There is no absolute threshold postvoid residual volume above which therapy is mandatory. Rather, the decision to intervene is based on symptom severity and whether sequelae of urinary retention (eg, incontinence, urinary tract infection, hematuria, hydronephrosis, renal dysfunction) are present.

Uroflowmetry is a noninvasive test measuring the urinary flow rate during voiding and is recommended during specialist evaluation of men with lower urinary tract symptoms and suspected BPH.¹⁰ Though a diminished urinary flow rate may be detected in men with bladder outlet obstruction from BPH, it cannot differentiate obstruction from detrusor underactivity, both of which may result in reduced urinary flow. Urodynamic studies can help differentiate between these two mechanisms of lower urinary tract symptoms. Uroflowmetry may be useful in selecting surgical candidates, as patients with a maximum urinary flow rate of 15 mL/second or greater have been shown to have lower rates of surgical success.¹⁴

Urodynamic studies. If the diagnosis of bladder outlet obstruction remains in doubt, urodynamic studies can differentiate obstruction from detrusor underactivity. Urodynamic studies allow simultaneous measurement of urinary flow and detrusor pressure, differentiating between obstruction (manifesting as diminished urinary flow with normal or elevated detrusor pressure) and detrusor underactivity (diminished urinary flow with diminished detrusor pressure). Nomograms¹⁵ and the easily calculated bladder outlet obstruction index¹⁶ are simple tools used to differentiate these two causes of diminished urinary flow.

Cystourethroscopy is not recommended for routine evaluation of BPH. Indications for cystourethroscopy include hematuria and the presence of a risk factor for urethral stricture disease such as urethritis, prior urethral instrumentation, or perineal trauma. Cystourethroscopy can also aid in surgical planning when intervention is considered.

An algorithm for diagnostic workup and management of BPH and lower urinary tract symptoms is shown in Figure 3.¹⁷

MANAGEMENT STRATEGIES FOR BPH

While BPH is rarely life-threatening, it can significantly detract from a patient’s quality of life. The goal of treatment is not only to alleviate bothersome symptoms, but also to prevent disease progression and disease-related complications.

BPH tends to progress

Understanding the natural history of BPH is imperative to appropriately counsel patients on management options, which include watchful waiting, behavioral modification, pharmacologic therapy, and surgery.

In a randomized trial,¹⁸ men with moderately symptomatic BPH underwent either surgery or, in the control group, watchful waiting. At 5 years, the failure rate was 21% with watchful waiting vs 10% with surgery (P < .0004). (Failure was defined as a composite of death, repeated or intractable urinary retention, residual urine volume > 350 mL, development of bladder calculus, new persistent incontinence requiring use of a pad or other incontinence device, symptom score in the severe range [> 24 at 1 visit or score of 21 or higher at two consecutive visits, with 27 being the maximum score], or a doubling of baseline serum creatinine.) In the watchful-waiting group, 36% of the men crossed over to surgery. Men with more bothersome symptoms at enrollment were at higher risk of progressing to surgery.

In a longitudinal study of men with BPH and mild symptoms (IPSS < 8), the risk of progression to moderate or severe symptoms (IPPS ≥ 8) was 31% at 4 years.¹⁹

The Olmsted County Study of Urinary Symptoms and Health Status Among Men²⁰ found that the peak urinary flow rate decreased by a mean of 2.1% per year, declining faster in older men who had a lower peak flow at baseline. In this cohort, the IPSS increased by a mean of 0.18 points per year, with a greater increase in older men.²¹

Though men managed with watchful waiting are at no higher risk of death or renal failure than men managed surgically,¹⁷ population-based studies have demonstrated an overall risk of acute urinary retention of 6.8/1,000 person-years with watchful waiting. Older men with a larger prostate, higher symptom score, and lower peak urinary flow rate are at higher risk of acute urinary retention and progression to needing BPH treatment.^22,23

There is evidence that patients progressing to needing surgery after an initial period of watchful waiting have worse surgical outcomes than men managed surgically at the onset.¹⁸ This observation must be considered in counseling and selecting patients for watchful waiting. Ideal candidates include patients who have mild or moderate symptoms that cause little bother.¹⁰ Patients electing watchful waiting warrant annual follow-up including history, physical examination, and symptom assessment with the IPSS.

Behavioral modification

Behavioral modification should be incorporated into whichever management strategy a patient elects. Such modifications include:

• Reducing total or evening fluid intake for patients with urinary frequency or nocturia.
• Minimizing consumption of bladder irritants such as alcohol and caffeine, which exacerbate storage symptoms.
• Smoking cessation counseling.
• For patients with lower extremity edema who complain of nocturia, using compression stockings or elevating their legs in the afternoon to mobilize lower extremity edema and promote diuresis before going to sleep. If these measures fail, initiating or increasing the dose of a diuretic should be considered. Patients on diuretic therapy with nocturnal lower urinary tract symptoms should be instructed to take diuretics in the morning and early afternoon to avoid diuresis just before bed.

MEDICAL MANAGEMENT

Drugs for BPH include alpha-adrenergic blockers, 5-alpha reductase inhibitors, anticholinergics, beta-3 agonists, and phosphodiesterase-5 inhibitors. Costs of selected agents in these classes are listed in Table 2.

Alpha-adrenergic receptor blockers

Alpha-adrenergic receptors are found throughout the body and modulate smooth muscle tone.²⁴ The alpha-1a receptor is the predominant subtype found in the bladder neck and prostate²⁵ (Figure 2) and is a target of therapy. By antagonizing the alpha-1a receptor, alpha-blockers relax the smooth muscle in the prostate and bladder neck, reduce bladder outlet resistance, and improve urinary flow.²⁶

In clinical trials in BPH, alpha-blockers improved the symptom score by 30% to 45% and increased the peak urinary flow rate by 15% to 30% from baseline values.²⁷ These agents have a rapid onset (within a few days) and result in significant symptom improvement. They are all about the same in efficacy (Table 3),^28–36 with no strong evidence that any one of them is superior to another; thus, decisions about which agent to use must consider differences in receptor subtype specificity, adverse-effect profile, and tolerability.

In the Medical Therapy of Prostatic Symptoms (MTOPS) trial,³⁷ men randomized to the alpha-blocker doxazosin had a 39% lower risk of BPH progression than with placebo, largely due to symptom score reduction. However, doxazosin failed to reduce the risk of progressing to acute urinary retention or surgical intervention. Though rapidly effective in reducing symptoms, alpha-blocker monotherapy may not be the best option in men at higher risk of BPH progression, as discussed below.

Before starting this therapy, patients must be counseled about common side effects such as dizziness, fatigue, peripheral edema, orthostatic hypotension, and ejaculatory dysfunction. The incidence of adverse effects varies among  agents (Table 4).^{28–30,34,35,38,39}

To maximize efficacy of alpha-blocker therapy, it is imperative to understand dosing variations among agents.

Alpha-blockers are classified as uroselective or non-uroselective based on alpha-1a receptor subtype specificity. The non-uroselective alpha-blockers doxazosin and terazosin need to be titrated because the higher the dose the greater the efficacy, but also the greater the blood pressure-lowering effect and other side effects.²⁵ Though non-uroselective, alfuzosin does not affect blood pressure and does not require dose titration. Similarly, the uroselective alpha-blockers tamsulosin and silodosin can be initiated at a therapeutic dose.

Terazosin, a non-uroselective agent, can lower blood pressure and often causes dizziness. It should be started at 2 mg and titrated to side effects, efficacy, or maximum therapeutic dose (10 mg daily).²⁸

Doxazosin has a high, dose-related incidence of dizziness (up to 20%) and must be titrated, starting at 1 mg to a maximum 8 mg.³⁰

Alfuzosin, tamsulosin, and silodosin do not require titration and can be initiated at the therapeutic doses listed in Table 3. Of note, obese patients often require 0.8 mg tamsulosin for maximum efficacy due to a higher volume of distribution.

Before initiating an alpha-blocker, a physician must determine whether a patient plans to undergo cataract surgery, as the use of alpha-blockers is associated with intraoperative floppy iris syndrome. This condition is marked by poor intraoperative pupil dilation, increasing the risk of surgical complications.⁴⁰ It is unclear whether discontinuing alpha-blockers before cataract surgery reduces the risk of intraoperative floppy iris syndrome. As such, alpha-blocker therapy should be delayed in patients planning to undergo cataract surgery.

5-Alpha reductase inhibitors

Prostate growth is androgen-dependent and mediated predominantly by dihydrotestosterone, which is generated from testosterone by the action of 5-alpha reductase. There are two 5-alpha reductase isoenzymes: type 1, expressed in the liver and skin, and type 2, expressed primarily in the prostate.

There are also two 5-alpha reductase inhibitors: dutasteride and finasteride. Dutasteride inhibits both isoenzymes, while finasteride is selective for type 2. By inhibiting both isoenzymes, dutasteride reduces the serum dihydrotestosterone concentration more than finasteride does (by 95% vs 70%), and also reduces the intraprostatic dihydrotestosterone concentration more (by 94% vs 80%).^41–43 Both agents induce apoptosis of prostatic stroma, with a resultant 20% to 25% mean reduction in prostate volume.^41,42

Finasteride and dutasteride are believed to mitigate the static obstructive component of BPH, with similar improvements in urinary flow rate (1.6–2.2 mL/sec) and symptom score (–2.7 to – 4.5 points) in men with an enlarged prostate.^41,42 Indeed, data from the MTOPS trial showed that men with a prostate volume of 30 grams or greater or a PSA level of 1.5 ng/mL or greater are most likely to benefit from 5-alpha reductase inhibitors.³⁷ Maximum symptomatic improvement is seen after 3 to 6 months of 5-alpha reductase inhibitor therapy.

In addition to improving urinary flow and lower urinary tract symptoms, finasteride has been shown to reduce the risk of disease progression in men with prostates greater than 30 grams.⁴⁴ Compared with placebo, these drugs significantly reduce the risk of developing acute urinary retention or requiring BPH-related surgery, a benefit not seen with alpha-blockers.³⁷ To estimate prostate volume, most practitioners rely on digital rectal examination. Though less precise than transrectal ultrasonography, digital rectal examination can identify men with significant prostatic enlargement likely to benefit from this therapy.

Before starting 5-alpha reductase inhibitor therapy, patients should be counseled about common adverse effects such as erectile dysfunction (occurring in 5%–8%), decreased libido (5%), ejaculatory dysfunction (1%–5%), and gynecomastia (1%).

Combination therapy

The MTOPS trial³⁷ randomized patients to receive doxazosin, finasteride, both, or placebo. The combination of doxazosin (an alpha-blocker) and finasteride (a 5-alpha reductase inhibitor) reduced the risk of disease progression to a greater extent than doxazosin or finasteride alone. It also reduced the IPSS more and increased the peak urinary flow rate more. Similar results have been seen with the combination of dutasteride and tamsulosin.⁴⁵

Given its superior efficacy and benefits in preventing disease progression, combination therapy should be considered for men with an enlarged prostate and moderate to severe lower urinary tract symptoms.

Anticholinergic agents

Anticholinergic agents block muscarinic receptors within the detrusor muscle, resulting in relaxation. They are used in the treatment of overactive bladder for symptoms of urinary urgency, frequency, and urge incontinence.

Anticholinergics were historically contraindicated in men with BPH because of concern about urinary retention. However, in men with a postvoid residual volume less than 200 mL, anticholinergics do not increase the risk of urinary retention.⁴⁶ Further, greater symptom improvement has been demonstrated with the addition of anticholinergics to alpha-blocker therapy for men with BPH, irritative lower urinary tract symptoms, and a low postvoid residual volume.⁴⁷

Beta-3 agonists

Anticholinergic side effects often limit the use of anticholinergic agents. An alternative in such instances is the beta-3 agonist mirabegron. By activating beta-3 adrenergic receptors in the bladder wall, mirabegron promotes detrusor relaxation and inhibits detrusor overactivity.⁴⁸ Mirabegron does not have anticholinergic side effects and is generally well tolerated, though poorly controlled hypertension is a contraindication to its use.

Phosphodiesterase-5 inhibitors

Phosphodiesterase-5 (PDE5) inhibitors are a mainstay in the treatment of erectile dysfunction. These agents act within penile corporal smooth muscle cells and antagonize PDE5, resulting in cyclic guanosine monophosphate accumulation and smooth muscle relaxation. PDE5 is also found within the prostate and its inhibition is believed to reduce prostatic smooth muscle tone. Randomized studies have demonstrated significant improvement in lower urinary tract symptoms with PDE5 inhibitors, with an average 2-point IPSS improvement on a PDE5 inhibitor compared with placebo.⁴⁹

Tadalafil is the only drug of this class approved by the FDA for the treatment of lower urinary tract symptoms, though other agents have demonstrated similar efficacy.

Dual therapy with a PDE5 inhibitor and an alpha-blocker has greater efficacy than either monotherapy alone; however, caution must be exercised as these agents are titrated to avoid symptomatic hypotension. Lower urinary tract symptoms and sexual dysfunction often coexist; PDE5 inhibitors are appropriate in the management of such cases.

SURGERY FOR BPH

Even with effective medical therapy, the disease will progress in some men. In the MTOPS trial,³⁷ the 4-year incidence of disease progression was 10% for men on alpha-blocker or 5-alpha reductase inhibitor monotherapy and 5% for men on combination therapy; from 1% to 3% of those in the various treatment groups needed surgery. With this in mind, patients whose symptoms do not improve with medical therapy, whose symptoms progress, or who simply are interested in surgery should be referred for urologic evaluation.

A number of effective surgical therapies are available for men with BPH (Table 5), providing excellent 1-year outcomes including a mean 70% reduction in IPSS and a mean 12 mL/sec improvement in peak urinary flow.⁵⁰ Given the efficacy of surgical therapy, men who do not improve with medical therapy who demonstrate any of the findings outlined in Table 1 warrant urologic evaluation.

Acknowledgments: We would like to thank Mary Ellen Amos, PharmD, and Kara Sink, BS, RPh, for their assistance in obtaining the suggested wholesale pricing information included in Table 2.

Primary care physicians are uniquely positioned to screen for benign prostatic hyperplasia (BPH) and lower urinary tract symptoms, to perform the initial diagnostic workup, and to start medical therapy in uncomplicated cases. Effective medical therapy is available but underutilized in the primary care setting.¹

This overview covers how to identify and evaluate patients with lower urinary tract symptoms, initiate therapy, and identify factors warranting timely urology referral.

TWO MECHANISMS: STATIC, DYNAMIC

BPH is a histologic diagnosis of proliferation of smooth muscle, epithelium, and stromal cells within the transition zone of the prostate,² which surrounds the proximal urethra.

Symptoms arise through two mechanisms: static, in which the hyperplastic prostatic tissue compresses the urethra (Figure 1); and dynamic, with increased adrenergic nervous system and prostatic smooth muscle tone (Figure 2).³ Both mechanisms increase resistance to urinary flow at the level of the bladder outlet.

As an adaptive change to overcome outlet resistance and maintain urinary flow, the detrusor muscles undergo hypertrophy. However, over time the bladder may develop diminished compliance and increased detrusor activity, causing symptoms such as urinary frequency and urgency. Chronic bladder outlet obstruction can lead to bladder decompensation and detrusor underactivity, manifesting as incomplete emptying, urinary hesitancy, intermittency (starting and stopping while voiding), a weakened urinary stream, and urinary retention.

MOST MEN EVENTUALLY DEVELOP BPH

Autopsy studies have shown that BPH increases in prevalence with age beginning around age 30 and reaching a peak prevalence of 88% in men in their 80s.⁴ This trend parallels those of the incidence and severity of lower urinary tract symptoms.⁵

In the year 2000 alone, BPH was responsible for 4.5 million physician visits at an estimated direct cost of $1.1 billion, not including the cost of pharmacotherapy.⁶

OFFICE WORKUP

BPH can cause lower urinary tract symptoms that fall into two categories: storage and emptying. Storage symptoms include urinary frequency, urgency, and nocturia, whereas emptying symptoms include weak stream, hesitancy, intermittency, incomplete emptying, straining, and postvoid dribbling.

History and differential diagnosis

Assessment begins with characterizing the patient’s symptoms and determining those that are most bothersome. Because BPH is just one of many possible causes of lower urinary tract symptoms, a detailed medical history is necessary to evaluate for other conditions that may cause lower urinary tract dysfunction or complicate its treatment.

Obstructive urinary symptoms can arise from BPH or from other conditions, including ureth­ral stricture disease and neurogenic voiding dysfunction.

Irritative voiding symptoms such as urinary urgency and frequency can result from detrusor overactivity secondary to BPH, but can also be caused by neurologic disease, malignancy, initiation of diuretic therapy, high fluid intake, or consumption of bladder irritants such as caffeine, alcohol, and spicy foods.

Urinary frequency is sometimes a presenting symptom of undiagnosed or poorly controlled diabetes mellitus resulting from glucosuria and polyuria. Iatrogenic causes of polyuria include the new hypoglycemic agents canagliflozin and dapagliflozin, which block renal glucose reabsorption, improving glycemic control by inducing urinary
glucose loss.⁷

Nocturia has many possible nonurologic causes including heart failure (in which excess extravascular fluid shifts to the intravascular space when the patient lies down, resulting in polyuria), obstructive sleep apnea, and behavioral factors such as high evening fluid intake. In these cases, patients usually have nocturnal polyuria (greater than one-third of 24-hour urine output at night) rather than only nocturia (waking at night to void). A fluid diary is a simple tool that can differentiate these two conditions.

Hematuria can develop in patients with BPH with bleeding from congested prostatic or bladder neck vessels; however, hematuria may indicate an underlying malignancy or urolithiasis, for which a urologic workup is indicated.

The broad differential diagnosis for the different lower urinary tract symptoms highlights the importance of obtaining a thorough history.

Physical examination

A general examination should include the following:

Body mass index. Obese patients are at risk of obstructive sleep apnea, which can cause nocturnal polyuria.

Gait. Abnormal gait may suggest a neurologic condition such as Parkinson disease or stroke that can also affect lower urinary tract function.

Lower abdomen. A palpable bladder suggests urinary retention.

External genitalia. Penile causes of urinary obstruction include urethral meatal stenosis or a palpable urethral mass.

Digital rectal examination can reveal benign prostatic enlargement or nodules or firmness, which suggest malignancy and warrant urologic referral.

Neurologic examination, including evaluation of anal sphincter tone and lower extremity sensorimotor function.

Feet. Bilateral lower-extremity edema may be due to heart failure or venous insufficiency.

The International Prostate Symptom Score

All men with lower urinary tract symptoms should complete the International Prostate Symptom Score (IPSS) survey, consisting of seven questions about urinary symptoms plus one about quality of life.⁸ Specifically, it asks the patient, “Over the past month, how often have you…”

• Had a sensation of not emptying your bladder completely after you finish urinating?
• Had to urinate again less than 2 hours after you finished urinating?
• Found you stopped and started again several times when you urinated?
• Found it difficult to postpone urination?
• Had a weak urinary stream?
• Had to push or strain to begin urination?

Each question above is scored as 0 (not at all), 1 (less than 1 time in 5), 2 (less than half the time), 3 (about half the time), 4 (more than half the time, or 5 (almost always).

• Over the past month, how many times did you most typically get up to urinate from the time you went to bed until the time you got up in the morning?

This question is scored from 0 (none) to 5 (5 times or more).

• If you were to spend the rest of your life with your urinary condition the way it is now, how would you feel about that?

This question is scored as 0 (delighted), 1 (pleased), 2 (mostly satisfied), 3 (mixed: equally satisfied and dissatisfied), 4 (mostly dissatisfied), 5 (unhappy), or 6 (terrible).

A total score of 1 to 7 is categorized as mild, 8 to 19 moderate, and 20 to 35 severe.

The questionnaire can also be used to evaluate for disease progression and response to treatment over time. A change of 3 points is clinically significant, as patients are unable to discern a difference below this threshold.⁹

Urinalysis

Urinalysis is recommended to assess for urinary tract infection, hematuria, proteinuria, or glucosuria.

Fluid diary

A fluid diary is useful for patients complaining of frequency or nocturia and can help quantify the volume of fluid intake, frequency of urination, and volumes voided. The patient should complete the diary over a 24-hour period, recording the time and volume of fluid intake and each void. This aids in diagnosing polyuria (> 3 L of urine output per 24 hours), nocturnal polyuria, and behavioral causes of symptoms, including excessive total fluid intake or high evening fluid intake contributing to nocturia.

Serum creatinine not recommended

Measuring serum creatinine is not recommended in the initial BPH workup, as men with lower urinary tract symptoms are not at higher risk of renal failure than those without these symptoms.¹⁰

Prostate-specific antigen

Prostate-specific antigen (PSA) is a glycoprotein primarily produced by prostatic luminal epithelial cells. It is most commonly discussed in the setting of prostate cancer screening, but its utility extends to guiding the management of BPH.

PSA levels correlate with prostate volume and subsequent growth.¹¹ In addition, the risks of developing acute urinary retention or needing surgical intervention rise with increasing PSA.¹² Among men in the Proscar Long-Term Efficacy and Safety Study, the risk of acute urinary retention or BPH-related surgery after 4 years in the watchful-waiting arm was 7.8% in men with a PSA of 1.3 ng/dL or less, compared with 19.9% in men with a PSA greater than 3.2 ng/dL.¹¹ Therefore, men with BPH and an elevated PSA are at higher risk with watchful waiting and may be better served with medical therapy.

In addition, American Urological Association guidelines recommend measuring serum PSA levels in men with a life expectancy greater than 10 years in whom the diagnosis of prostate cancer would alter management.¹⁰

Urologic referral

If the initial evaluation reveals hematuria, recurrent urinary tract infection, a palpable bladder, abnormal findings on digital rectal examination suggesting prostate cancer, or a history of or risk factors for urethral stricture or neurologic disease, the patient should be referred to a urologist for further evaluation (Table 1).¹⁰ Other patients who should undergo urologic evaluation are those with persistent bothersome symptoms after basic management and those who desire referral.

Adjunctive tests

Patients referred for urologic evaluation may require additional tests for diagnosis and to guide management.

Postvoid residual volume is easily measured with either abdominal ultrasonography or catheterization and is often included in the urologic evaluation of BPH. Patients vary considerably in their residual volume, which correlates poorly with BPH, symptom severity, or surgical success. However, those with a residual volume of more than 100 mL have a slightly higher rate of failure with watchful waiting.¹³ Postvoid residual volume is not routinely monitored in patients with a low residual volume unless there is a significant change in urinary symptoms. Conversely, patients with a volume greater than 200 mL should be monitored closely for worsening urinary retention, especially if considering anticholinergic therapy.

There is no absolute threshold postvoid residual volume above which therapy is mandatory. Rather, the decision to intervene is based on symptom severity and whether sequelae of urinary retention (eg, incontinence, urinary tract infection, hematuria, hydronephrosis, renal dysfunction) are present.

Uroflowmetry is a noninvasive test measuring the urinary flow rate during voiding and is recommended during specialist evaluation of men with lower urinary tract symptoms and suspected BPH.¹⁰ Though a diminished urinary flow rate may be detected in men with bladder outlet obstruction from BPH, it cannot differentiate obstruction from detrusor underactivity, both of which may result in reduced urinary flow. Urodynamic studies can help differentiate between these two mechanisms of lower urinary tract symptoms. Uroflowmetry may be useful in selecting surgical candidates, as patients with a maximum urinary flow rate of 15 mL/second or greater have been shown to have lower rates of surgical success.¹⁴

Urodynamic studies. If the diagnosis of bladder outlet obstruction remains in doubt, urodynamic studies can differentiate obstruction from detrusor underactivity. Urodynamic studies allow simultaneous measurement of urinary flow and detrusor pressure, differentiating between obstruction (manifesting as diminished urinary flow with normal or elevated detrusor pressure) and detrusor underactivity (diminished urinary flow with diminished detrusor pressure). Nomograms¹⁵ and the easily calculated bladder outlet obstruction index¹⁶ are simple tools used to differentiate these two causes of diminished urinary flow.

Cystourethroscopy is not recommended for routine evaluation of BPH. Indications for cystourethroscopy include hematuria and the presence of a risk factor for urethral stricture disease such as urethritis, prior urethral instrumentation, or perineal trauma. Cystourethroscopy can also aid in surgical planning when intervention is considered.

An algorithm for diagnostic workup and management of BPH and lower urinary tract symptoms is shown in Figure 3.¹⁷

MANAGEMENT STRATEGIES FOR BPH

While BPH is rarely life-threatening, it can significantly detract from a patient’s quality of life. The goal of treatment is not only to alleviate bothersome symptoms, but also to prevent disease progression and disease-related complications.

BPH tends to progress

Understanding the natural history of BPH is imperative to appropriately counsel patients on management options, which include watchful waiting, behavioral modification, pharmacologic therapy, and surgery.

In a randomized trial,¹⁸ men with moderately symptomatic BPH underwent either surgery or, in the control group, watchful waiting. At 5 years, the failure rate was 21% with watchful waiting vs 10% with surgery (P < .0004). (Failure was defined as a composite of death, repeated or intractable urinary retention, residual urine volume > 350 mL, development of bladder calculus, new persistent incontinence requiring use of a pad or other incontinence device, symptom score in the severe range [> 24 at 1 visit or score of 21 or higher at two consecutive visits, with 27 being the maximum score], or a doubling of baseline serum creatinine.) In the watchful-waiting group, 36% of the men crossed over to surgery. Men with more bothersome symptoms at enrollment were at higher risk of progressing to surgery.

In a longitudinal study of men with BPH and mild symptoms (IPSS < 8), the risk of progression to moderate or severe symptoms (IPPS ≥ 8) was 31% at 4 years.¹⁹

The Olmsted County Study of Urinary Symptoms and Health Status Among Men²⁰ found that the peak urinary flow rate decreased by a mean of 2.1% per year, declining faster in older men who had a lower peak flow at baseline. In this cohort, the IPSS increased by a mean of 0.18 points per year, with a greater increase in older men.²¹

Though men managed with watchful waiting are at no higher risk of death or renal failure than men managed surgically,¹⁷ population-based studies have demonstrated an overall risk of acute urinary retention of 6.8/1,000 person-years with watchful waiting. Older men with a larger prostate, higher symptom score, and lower peak urinary flow rate are at higher risk of acute urinary retention and progression to needing BPH treatment.^22,23

There is evidence that patients progressing to needing surgery after an initial period of watchful waiting have worse surgical outcomes than men managed surgically at the onset.¹⁸ This observation must be considered in counseling and selecting patients for watchful waiting. Ideal candidates include patients who have mild or moderate symptoms that cause little bother.¹⁰ Patients electing watchful waiting warrant annual follow-up including history, physical examination, and symptom assessment with the IPSS.

Behavioral modification

Behavioral modification should be incorporated into whichever management strategy a patient elects. Such modifications include:

• Reducing total or evening fluid intake for patients with urinary frequency or nocturia.
• Minimizing consumption of bladder irritants such as alcohol and caffeine, which exacerbate storage symptoms.
• Smoking cessation counseling.
• For patients with lower extremity edema who complain of nocturia, using compression stockings or elevating their legs in the afternoon to mobilize lower extremity edema and promote diuresis before going to sleep. If these measures fail, initiating or increasing the dose of a diuretic should be considered. Patients on diuretic therapy with nocturnal lower urinary tract symptoms should be instructed to take diuretics in the morning and early afternoon to avoid diuresis just before bed.

MEDICAL MANAGEMENT

Drugs for BPH include alpha-adrenergic blockers, 5-alpha reductase inhibitors, anticholinergics, beta-3 agonists, and phosphodiesterase-5 inhibitors. Costs of selected agents in these classes are listed in Table 2.

Alpha-adrenergic receptor blockers

Alpha-adrenergic receptors are found throughout the body and modulate smooth muscle tone.²⁴ The alpha-1a receptor is the predominant subtype found in the bladder neck and prostate²⁵ (Figure 2) and is a target of therapy. By antagonizing the alpha-1a receptor, alpha-blockers relax the smooth muscle in the prostate and bladder neck, reduce bladder outlet resistance, and improve urinary flow.²⁶

In clinical trials in BPH, alpha-blockers improved the symptom score by 30% to 45% and increased the peak urinary flow rate by 15% to 30% from baseline values.²⁷ These agents have a rapid onset (within a few days) and result in significant symptom improvement. They are all about the same in efficacy (Table 3),^28–36 with no strong evidence that any one of them is superior to another; thus, decisions about which agent to use must consider differences in receptor subtype specificity, adverse-effect profile, and tolerability.

In the Medical Therapy of Prostatic Symptoms (MTOPS) trial,³⁷ men randomized to the alpha-blocker doxazosin had a 39% lower risk of BPH progression than with placebo, largely due to symptom score reduction. However, doxazosin failed to reduce the risk of progressing to acute urinary retention or surgical intervention. Though rapidly effective in reducing symptoms, alpha-blocker monotherapy may not be the best option in men at higher risk of BPH progression, as discussed below.

Before starting this therapy, patients must be counseled about common side effects such as dizziness, fatigue, peripheral edema, orthostatic hypotension, and ejaculatory dysfunction. The incidence of adverse effects varies among  agents (Table 4).^{28–30,34,35,38,39}

To maximize efficacy of alpha-blocker therapy, it is imperative to understand dosing variations among agents.

Alpha-blockers are classified as uroselective or non-uroselective based on alpha-1a receptor subtype specificity. The non-uroselective alpha-blockers doxazosin and terazosin need to be titrated because the higher the dose the greater the efficacy, but also the greater the blood pressure-lowering effect and other side effects.²⁵ Though non-uroselective, alfuzosin does not affect blood pressure and does not require dose titration. Similarly, the uroselective alpha-blockers tamsulosin and silodosin can be initiated at a therapeutic dose.

Terazosin, a non-uroselective agent, can lower blood pressure and often causes dizziness. It should be started at 2 mg and titrated to side effects, efficacy, or maximum therapeutic dose (10 mg daily).²⁸

Doxazosin has a high, dose-related incidence of dizziness (up to 20%) and must be titrated, starting at 1 mg to a maximum 8 mg.³⁰

Alfuzosin, tamsulosin, and silodosin do not require titration and can be initiated at the therapeutic doses listed in Table 3. Of note, obese patients often require 0.8 mg tamsulosin for maximum efficacy due to a higher volume of distribution.

Before initiating an alpha-blocker, a physician must determine whether a patient plans to undergo cataract surgery, as the use of alpha-blockers is associated with intraoperative floppy iris syndrome. This condition is marked by poor intraoperative pupil dilation, increasing the risk of surgical complications.⁴⁰ It is unclear whether discontinuing alpha-blockers before cataract surgery reduces the risk of intraoperative floppy iris syndrome. As such, alpha-blocker therapy should be delayed in patients planning to undergo cataract surgery.

5-Alpha reductase inhibitors

Prostate growth is androgen-dependent and mediated predominantly by dihydrotestosterone, which is generated from testosterone by the action of 5-alpha reductase. There are two 5-alpha reductase isoenzymes: type 1, expressed in the liver and skin, and type 2, expressed primarily in the prostate.

There are also two 5-alpha reductase inhibitors: dutasteride and finasteride. Dutasteride inhibits both isoenzymes, while finasteride is selective for type 2. By inhibiting both isoenzymes, dutasteride reduces the serum dihydrotestosterone concentration more than finasteride does (by 95% vs 70%), and also reduces the intraprostatic dihydrotestosterone concentration more (by 94% vs 80%).^41–43 Both agents induce apoptosis of prostatic stroma, with a resultant 20% to 25% mean reduction in prostate volume.^41,42

Finasteride and dutasteride are believed to mitigate the static obstructive component of BPH, with similar improvements in urinary flow rate (1.6–2.2 mL/sec) and symptom score (–2.7 to – 4.5 points) in men with an enlarged prostate.^41,42 Indeed, data from the MTOPS trial showed that men with a prostate volume of 30 grams or greater or a PSA level of 1.5 ng/mL or greater are most likely to benefit from 5-alpha reductase inhibitors.³⁷ Maximum symptomatic improvement is seen after 3 to 6 months of 5-alpha reductase inhibitor therapy.

In addition to improving urinary flow and lower urinary tract symptoms, finasteride has been shown to reduce the risk of disease progression in men with prostates greater than 30 grams.⁴⁴ Compared with placebo, these drugs significantly reduce the risk of developing acute urinary retention or requiring BPH-related surgery, a benefit not seen with alpha-blockers.³⁷ To estimate prostate volume, most practitioners rely on digital rectal examination. Though less precise than transrectal ultrasonography, digital rectal examination can identify men with significant prostatic enlargement likely to benefit from this therapy.

Before starting 5-alpha reductase inhibitor therapy, patients should be counseled about common adverse effects such as erectile dysfunction (occurring in 5%–8%), decreased libido (5%), ejaculatory dysfunction (1%–5%), and gynecomastia (1%).

Combination therapy

The MTOPS trial³⁷ randomized patients to receive doxazosin, finasteride, both, or placebo. The combination of doxazosin (an alpha-blocker) and finasteride (a 5-alpha reductase inhibitor) reduced the risk of disease progression to a greater extent than doxazosin or finasteride alone. It also reduced the IPSS more and increased the peak urinary flow rate more. Similar results have been seen with the combination of dutasteride and tamsulosin.⁴⁵

Given its superior efficacy and benefits in preventing disease progression, combination therapy should be considered for men with an enlarged prostate and moderate to severe lower urinary tract symptoms.

Anticholinergic agents

Anticholinergic agents block muscarinic receptors within the detrusor muscle, resulting in relaxation. They are used in the treatment of overactive bladder for symptoms of urinary urgency, frequency, and urge incontinence.

Anticholinergics were historically contraindicated in men with BPH because of concern about urinary retention. However, in men with a postvoid residual volume less than 200 mL, anticholinergics do not increase the risk of urinary retention.⁴⁶ Further, greater symptom improvement has been demonstrated with the addition of anticholinergics to alpha-blocker therapy for men with BPH, irritative lower urinary tract symptoms, and a low postvoid residual volume.⁴⁷

Beta-3 agonists

Anticholinergic side effects often limit the use of anticholinergic agents. An alternative in such instances is the beta-3 agonist mirabegron. By activating beta-3 adrenergic receptors in the bladder wall, mirabegron promotes detrusor relaxation and inhibits detrusor overactivity.⁴⁸ Mirabegron does not have anticholinergic side effects and is generally well tolerated, though poorly controlled hypertension is a contraindication to its use.

Phosphodiesterase-5 inhibitors

Phosphodiesterase-5 (PDE5) inhibitors are a mainstay in the treatment of erectile dysfunction. These agents act within penile corporal smooth muscle cells and antagonize PDE5, resulting in cyclic guanosine monophosphate accumulation and smooth muscle relaxation. PDE5 is also found within the prostate and its inhibition is believed to reduce prostatic smooth muscle tone. Randomized studies have demonstrated significant improvement in lower urinary tract symptoms with PDE5 inhibitors, with an average 2-point IPSS improvement on a PDE5 inhibitor compared with placebo.⁴⁹

Tadalafil is the only drug of this class approved by the FDA for the treatment of lower urinary tract symptoms, though other agents have demonstrated similar efficacy.

Dual therapy with a PDE5 inhibitor and an alpha-blocker has greater efficacy than either monotherapy alone; however, caution must be exercised as these agents are titrated to avoid symptomatic hypotension. Lower urinary tract symptoms and sexual dysfunction often coexist; PDE5 inhibitors are appropriate in the management of such cases.

SURGERY FOR BPH

Even with effective medical therapy, the disease will progress in some men. In the MTOPS trial,³⁷ the 4-year incidence of disease progression was 10% for men on alpha-blocker or 5-alpha reductase inhibitor monotherapy and 5% for men on combination therapy; from 1% to 3% of those in the various treatment groups needed surgery. With this in mind, patients whose symptoms do not improve with medical therapy, whose symptoms progress, or who simply are interested in surgery should be referred for urologic evaluation.

A number of effective surgical therapies are available for men with BPH (Table 5), providing excellent 1-year outcomes including a mean 70% reduction in IPSS and a mean 12 mL/sec improvement in peak urinary flow.⁵⁰ Given the efficacy of surgical therapy, men who do not improve with medical therapy who demonstrate any of the findings outlined in Table 1 warrant urologic evaluation.

Acknowledgments: We would like to thank Mary Ellen Amos, PharmD, and Kara Sink, BS, RPh, for their assistance in obtaining the suggested wholesale pricing information included in Table 2.

Primary care physicians are uniquely positioned to screen for benign prostatic hyperplasia (BPH) and lower urinary tract symptoms, to perform the initial diagnostic workup, and to start medical therapy in uncomplicated cases. Effective medical therapy is available but underutilized in the primary care setting.¹

This overview covers how to identify and evaluate patients with lower urinary tract symptoms, initiate therapy, and identify factors warranting timely urology referral.

TWO MECHANISMS: STATIC, DYNAMIC

BPH is a histologic diagnosis of proliferation of smooth muscle, epithelium, and stromal cells within the transition zone of the prostate,² which surrounds the proximal urethra.

Symptoms arise through two mechanisms: static, in which the hyperplastic prostatic tissue compresses the urethra (Figure 1); and dynamic, with increased adrenergic nervous system and prostatic smooth muscle tone (Figure 2).³ Both mechanisms increase resistance to urinary flow at the level of the bladder outlet.

As an adaptive change to overcome outlet resistance and maintain urinary flow, the detrusor muscles undergo hypertrophy. However, over time the bladder may develop diminished compliance and increased detrusor activity, causing symptoms such as urinary frequency and urgency. Chronic bladder outlet obstruction can lead to bladder decompensation and detrusor underactivity, manifesting as incomplete emptying, urinary hesitancy, intermittency (starting and stopping while voiding), a weakened urinary stream, and urinary retention.

MOST MEN EVENTUALLY DEVELOP BPH

Autopsy studies have shown that BPH increases in prevalence with age beginning around age 30 and reaching a peak prevalence of 88% in men in their 80s.⁴ This trend parallels those of the incidence and severity of lower urinary tract symptoms.⁵

In the year 2000 alone, BPH was responsible for 4.5 million physician visits at an estimated direct cost of $1.1 billion, not including the cost of pharmacotherapy.⁶

OFFICE WORKUP

BPH can cause lower urinary tract symptoms that fall into two categories: storage and emptying. Storage symptoms include urinary frequency, urgency, and nocturia, whereas emptying symptoms include weak stream, hesitancy, intermittency, incomplete emptying, straining, and postvoid dribbling.

History and differential diagnosis

Assessment begins with characterizing the patient’s symptoms and determining those that are most bothersome. Because BPH is just one of many possible causes of lower urinary tract symptoms, a detailed medical history is necessary to evaluate for other conditions that may cause lower urinary tract dysfunction or complicate its treatment.

Obstructive urinary symptoms can arise from BPH or from other conditions, including ureth­ral stricture disease and neurogenic voiding dysfunction.

Irritative voiding symptoms such as urinary urgency and frequency can result from detrusor overactivity secondary to BPH, but can also be caused by neurologic disease, malignancy, initiation of diuretic therapy, high fluid intake, or consumption of bladder irritants such as caffeine, alcohol, and spicy foods.

Urinary frequency is sometimes a presenting symptom of undiagnosed or poorly controlled diabetes mellitus resulting from glucosuria and polyuria. Iatrogenic causes of polyuria include the new hypoglycemic agents canagliflozin and dapagliflozin, which block renal glucose reabsorption, improving glycemic control by inducing urinary
glucose loss.⁷

Nocturia has many possible nonurologic causes including heart failure (in which excess extravascular fluid shifts to the intravascular space when the patient lies down, resulting in polyuria), obstructive sleep apnea, and behavioral factors such as high evening fluid intake. In these cases, patients usually have nocturnal polyuria (greater than one-third of 24-hour urine output at night) rather than only nocturia (waking at night to void). A fluid diary is a simple tool that can differentiate these two conditions.

Hematuria can develop in patients with BPH with bleeding from congested prostatic or bladder neck vessels; however, hematuria may indicate an underlying malignancy or urolithiasis, for which a urologic workup is indicated.

The broad differential diagnosis for the different lower urinary tract symptoms highlights the importance of obtaining a thorough history.

Physical examination

A general examination should include the following:

Body mass index. Obese patients are at risk of obstructive sleep apnea, which can cause nocturnal polyuria.

Gait. Abnormal gait may suggest a neurologic condition such as Parkinson disease or stroke that can also affect lower urinary tract function.

Lower abdomen. A palpable bladder suggests urinary retention.

External genitalia. Penile causes of urinary obstruction include urethral meatal stenosis or a palpable urethral mass.

Digital rectal examination can reveal benign prostatic enlargement or nodules or firmness, which suggest malignancy and warrant urologic referral.

Neurologic examination, including evaluation of anal sphincter tone and lower extremity sensorimotor function.

Feet. Bilateral lower-extremity edema may be due to heart failure or venous insufficiency.

The International Prostate Symptom Score

All men with lower urinary tract symptoms should complete the International Prostate Symptom Score (IPSS) survey, consisting of seven questions about urinary symptoms plus one about quality of life.⁸ Specifically, it asks the patient, “Over the past month, how often have you…”

• Had a sensation of not emptying your bladder completely after you finish urinating?
• Had to urinate again less than 2 hours after you finished urinating?
• Found you stopped and started again several times when you urinated?
• Found it difficult to postpone urination?
• Had a weak urinary stream?
• Had to push or strain to begin urination?

Each question above is scored as 0 (not at all), 1 (less than 1 time in 5), 2 (less than half the time), 3 (about half the time), 4 (more than half the time, or 5 (almost always).

• Over the past month, how many times did you most typically get up to urinate from the time you went to bed until the time you got up in the morning?

This question is scored from 0 (none) to 5 (5 times or more).

• If you were to spend the rest of your life with your urinary condition the way it is now, how would you feel about that?

This question is scored as 0 (delighted), 1 (pleased), 2 (mostly satisfied), 3 (mixed: equally satisfied and dissatisfied), 4 (mostly dissatisfied), 5 (unhappy), or 6 (terrible).

A total score of 1 to 7 is categorized as mild, 8 to 19 moderate, and 20 to 35 severe.

The questionnaire can also be used to evaluate for disease progression and response to treatment over time. A change of 3 points is clinically significant, as patients are unable to discern a difference below this threshold.⁹

Urinalysis

Urinalysis is recommended to assess for urinary tract infection, hematuria, proteinuria, or glucosuria.

Fluid diary

A fluid diary is useful for patients complaining of frequency or nocturia and can help quantify the volume of fluid intake, frequency of urination, and volumes voided. The patient should complete the diary over a 24-hour period, recording the time and volume of fluid intake and each void. This aids in diagnosing polyuria (> 3 L of urine output per 24 hours), nocturnal polyuria, and behavioral causes of symptoms, including excessive total fluid intake or high evening fluid intake contributing to nocturia.

Serum creatinine not recommended

Measuring serum creatinine is not recommended in the initial BPH workup, as men with lower urinary tract symptoms are not at higher risk of renal failure than those without these symptoms.¹⁰

Prostate-specific antigen

Prostate-specific antigen (PSA) is a glycoprotein primarily produced by prostatic luminal epithelial cells. It is most commonly discussed in the setting of prostate cancer screening, but its utility extends to guiding the management of BPH.

PSA levels correlate with prostate volume and subsequent growth.¹¹ In addition, the risks of developing acute urinary retention or needing surgical intervention rise with increasing PSA.¹² Among men in the Proscar Long-Term Efficacy and Safety Study, the risk of acute urinary retention or BPH-related surgery after 4 years in the watchful-waiting arm was 7.8% in men with a PSA of 1.3 ng/dL or less, compared with 19.9% in men with a PSA greater than 3.2 ng/dL.¹¹ Therefore, men with BPH and an elevated PSA are at higher risk with watchful waiting and may be better served with medical therapy.

In addition, American Urological Association guidelines recommend measuring serum PSA levels in men with a life expectancy greater than 10 years in whom the diagnosis of prostate cancer would alter management.¹⁰

Urologic referral

If the initial evaluation reveals hematuria, recurrent urinary tract infection, a palpable bladder, abnormal findings on digital rectal examination suggesting prostate cancer, or a history of or risk factors for urethral stricture or neurologic disease, the patient should be referred to a urologist for further evaluation (Table 1).¹⁰ Other patients who should undergo urologic evaluation are those with persistent bothersome symptoms after basic management and those who desire referral.

Adjunctive tests

Patients referred for urologic evaluation may require additional tests for diagnosis and to guide management.

Postvoid residual volume is easily measured with either abdominal ultrasonography or catheterization and is often included in the urologic evaluation of BPH. Patients vary considerably in their residual volume, which correlates poorly with BPH, symptom severity, or surgical success. However, those with a residual volume of more than 100 mL have a slightly higher rate of failure with watchful waiting.¹³ Postvoid residual volume is not routinely monitored in patients with a low residual volume unless there is a significant change in urinary symptoms. Conversely, patients with a volume greater than 200 mL should be monitored closely for worsening urinary retention, especially if considering anticholinergic therapy.

There is no absolute threshold postvoid residual volume above which therapy is mandatory. Rather, the decision to intervene is based on symptom severity and whether sequelae of urinary retention (eg, incontinence, urinary tract infection, hematuria, hydronephrosis, renal dysfunction) are present.

Uroflowmetry is a noninvasive test measuring the urinary flow rate during voiding and is recommended during specialist evaluation of men with lower urinary tract symptoms and suspected BPH.¹⁰ Though a diminished urinary flow rate may be detected in men with bladder outlet obstruction from BPH, it cannot differentiate obstruction from detrusor underactivity, both of which may result in reduced urinary flow. Urodynamic studies can help differentiate between these two mechanisms of lower urinary tract symptoms. Uroflowmetry may be useful in selecting surgical candidates, as patients with a maximum urinary flow rate of 15 mL/second or greater have been shown to have lower rates of surgical success.¹⁴

Urodynamic studies. If the diagnosis of bladder outlet obstruction remains in doubt, urodynamic studies can differentiate obstruction from detrusor underactivity. Urodynamic studies allow simultaneous measurement of urinary flow and detrusor pressure, differentiating between obstruction (manifesting as diminished urinary flow with normal or elevated detrusor pressure) and detrusor underactivity (diminished urinary flow with diminished detrusor pressure). Nomograms¹⁵ and the easily calculated bladder outlet obstruction index¹⁶ are simple tools used to differentiate these two causes of diminished urinary flow.

Cystourethroscopy is not recommended for routine evaluation of BPH. Indications for cystourethroscopy include hematuria and the presence of a risk factor for urethral stricture disease such as urethritis, prior urethral instrumentation, or perineal trauma. Cystourethroscopy can also aid in surgical planning when intervention is considered.

An algorithm for diagnostic workup and management of BPH and lower urinary tract symptoms is shown in Figure 3.¹⁷

MANAGEMENT STRATEGIES FOR BPH

While BPH is rarely life-threatening, it can significantly detract from a patient’s quality of life. The goal of treatment is not only to alleviate bothersome symptoms, but also to prevent disease progression and disease-related complications.

BPH tends to progress

Understanding the natural history of BPH is imperative to appropriately counsel patients on management options, which include watchful waiting, behavioral modification, pharmacologic therapy, and surgery.

In a randomized trial,¹⁸ men with moderately symptomatic BPH underwent either surgery or, in the control group, watchful waiting. At 5 years, the failure rate was 21% with watchful waiting vs 10% with surgery (P < .0004). (Failure was defined as a composite of death, repeated or intractable urinary retention, residual urine volume > 350 mL, development of bladder calculus, new persistent incontinence requiring use of a pad or other incontinence device, symptom score in the severe range [> 24 at 1 visit or score of 21 or higher at two consecutive visits, with 27 being the maximum score], or a doubling of baseline serum creatinine.) In the watchful-waiting group, 36% of the men crossed over to surgery. Men with more bothersome symptoms at enrollment were at higher risk of progressing to surgery.

In a longitudinal study of men with BPH and mild symptoms (IPSS < 8), the risk of progression to moderate or severe symptoms (IPPS ≥ 8) was 31% at 4 years.¹⁹

The Olmsted County Study of Urinary Symptoms and Health Status Among Men²⁰ found that the peak urinary flow rate decreased by a mean of 2.1% per year, declining faster in older men who had a lower peak flow at baseline. In this cohort, the IPSS increased by a mean of 0.18 points per year, with a greater increase in older men.²¹

Though men managed with watchful waiting are at no higher risk of death or renal failure than men managed surgically,¹⁷ population-based studies have demonstrated an overall risk of acute urinary retention of 6.8/1,000 person-years with watchful waiting. Older men with a larger prostate, higher symptom score, and lower peak urinary flow rate are at higher risk of acute urinary retention and progression to needing BPH treatment.^22,23

There is evidence that patients progressing to needing surgery after an initial period of watchful waiting have worse surgical outcomes than men managed surgically at the onset.¹⁸ This observation must be considered in counseling and selecting patients for watchful waiting. Ideal candidates include patients who have mild or moderate symptoms that cause little bother.¹⁰ Patients electing watchful waiting warrant annual follow-up including history, physical examination, and symptom assessment with the IPSS.

Behavioral modification

Behavioral modification should be incorporated into whichever management strategy a patient elects. Such modifications include:

• Reducing total or evening fluid intake for patients with urinary frequency or nocturia.
• Minimizing consumption of bladder irritants such as alcohol and caffeine, which exacerbate storage symptoms.
• Smoking cessation counseling.
• For patients with lower extremity edema who complain of nocturia, using compression stockings or elevating their legs in the afternoon to mobilize lower extremity edema and promote diuresis before going to sleep. If these measures fail, initiating or increasing the dose of a diuretic should be considered. Patients on diuretic therapy with nocturnal lower urinary tract symptoms should be instructed to take diuretics in the morning and early afternoon to avoid diuresis just before bed.

MEDICAL MANAGEMENT

Drugs for BPH include alpha-adrenergic blockers, 5-alpha reductase inhibitors, anticholinergics, beta-3 agonists, and phosphodiesterase-5 inhibitors. Costs of selected agents in these classes are listed in Table 2.

Alpha-adrenergic receptor blockers

Alpha-adrenergic receptors are found throughout the body and modulate smooth muscle tone.²⁴ The alpha-1a receptor is the predominant subtype found in the bladder neck and prostate²⁵ (Figure 2) and is a target of therapy. By antagonizing the alpha-1a receptor, alpha-blockers relax the smooth muscle in the prostate and bladder neck, reduce bladder outlet resistance, and improve urinary flow.²⁶

In clinical trials in BPH, alpha-blockers improved the symptom score by 30% to 45% and increased the peak urinary flow rate by 15% to 30% from baseline values.²⁷ These agents have a rapid onset (within a few days) and result in significant symptom improvement. They are all about the same in efficacy (Table 3),^28–36 with no strong evidence that any one of them is superior to another; thus, decisions about which agent to use must consider differences in receptor subtype specificity, adverse-effect profile, and tolerability.

In the Medical Therapy of Prostatic Symptoms (MTOPS) trial,³⁷ men randomized to the alpha-blocker doxazosin had a 39% lower risk of BPH progression than with placebo, largely due to symptom score reduction. However, doxazosin failed to reduce the risk of progressing to acute urinary retention or surgical intervention. Though rapidly effective in reducing symptoms, alpha-blocker monotherapy may not be the best option in men at higher risk of BPH progression, as discussed below.

Before starting this therapy, patients must be counseled about common side effects such as dizziness, fatigue, peripheral edema, orthostatic hypotension, and ejaculatory dysfunction. The incidence of adverse effects varies among  agents (Table 4).^{28–30,34,35,38,39}

To maximize efficacy of alpha-blocker therapy, it is imperative to understand dosing variations among agents.

Alpha-blockers are classified as uroselective or non-uroselective based on alpha-1a receptor subtype specificity. The non-uroselective alpha-blockers doxazosin and terazosin need to be titrated because the higher the dose the greater the efficacy, but also the greater the blood pressure-lowering effect and other side effects.²⁵ Though non-uroselective, alfuzosin does not affect blood pressure and does not require dose titration. Similarly, the uroselective alpha-blockers tamsulosin and silodosin can be initiated at a therapeutic dose.

Terazosin, a non-uroselective agent, can lower blood pressure and often causes dizziness. It should be started at 2 mg and titrated to side effects, efficacy, or maximum therapeutic dose (10 mg daily).²⁸

Doxazosin has a high, dose-related incidence of dizziness (up to 20%) and must be titrated, starting at 1 mg to a maximum 8 mg.³⁰

Alfuzosin, tamsulosin, and silodosin do not require titration and can be initiated at the therapeutic doses listed in Table 3. Of note, obese patients often require 0.8 mg tamsulosin for maximum efficacy due to a higher volume of distribution.

Before initiating an alpha-blocker, a physician must determine whether a patient plans to undergo cataract surgery, as the use of alpha-blockers is associated with intraoperative floppy iris syndrome. This condition is marked by poor intraoperative pupil dilation, increasing the risk of surgical complications.⁴⁰ It is unclear whether discontinuing alpha-blockers before cataract surgery reduces the risk of intraoperative floppy iris syndrome. As such, alpha-blocker therapy should be delayed in patients planning to undergo cataract surgery.

5-Alpha reductase inhibitors

Prostate growth is androgen-dependent and mediated predominantly by dihydrotestosterone, which is generated from testosterone by the action of 5-alpha reductase. There are two 5-alpha reductase isoenzymes: type 1, expressed in the liver and skin, and type 2, expressed primarily in the prostate.

There are also two 5-alpha reductase inhibitors: dutasteride and finasteride. Dutasteride inhibits both isoenzymes, while finasteride is selective for type 2. By inhibiting both isoenzymes, dutasteride reduces the serum dihydrotestosterone concentration more than finasteride does (by 95% vs 70%), and also reduces the intraprostatic dihydrotestosterone concentration more (by 94% vs 80%).^41–43 Both agents induce apoptosis of prostatic stroma, with a resultant 20% to 25% mean reduction in prostate volume.^41,42

Finasteride and dutasteride are believed to mitigate the static obstructive component of BPH, with similar improvements in urinary flow rate (1.6–2.2 mL/sec) and symptom score (–2.7 to – 4.5 points) in men with an enlarged prostate.^41,42 Indeed, data from the MTOPS trial showed that men with a prostate volume of 30 grams or greater or a PSA level of 1.5 ng/mL or greater are most likely to benefit from 5-alpha reductase inhibitors.³⁷ Maximum symptomatic improvement is seen after 3 to 6 months of 5-alpha reductase inhibitor therapy.

In addition to improving urinary flow and lower urinary tract symptoms, finasteride has been shown to reduce the risk of disease progression in men with prostates greater than 30 grams.⁴⁴ Compared with placebo, these drugs significantly reduce the risk of developing acute urinary retention or requiring BPH-related surgery, a benefit not seen with alpha-blockers.³⁷ To estimate prostate volume, most practitioners rely on digital rectal examination. Though less precise than transrectal ultrasonography, digital rectal examination can identify men with significant prostatic enlargement likely to benefit from this therapy.

Before starting 5-alpha reductase inhibitor therapy, patients should be counseled about common adverse effects such as erectile dysfunction (occurring in 5%–8%), decreased libido (5%), ejaculatory dysfunction (1%–5%), and gynecomastia (1%).

Combination therapy

The MTOPS trial³⁷ randomized patients to receive doxazosin, finasteride, both, or placebo. The combination of doxazosin (an alpha-blocker) and finasteride (a 5-alpha reductase inhibitor) reduced the risk of disease progression to a greater extent than doxazosin or finasteride alone. It also reduced the IPSS more and increased the peak urinary flow rate more. Similar results have been seen with the combination of dutasteride and tamsulosin.⁴⁵

Given its superior efficacy and benefits in preventing disease progression, combination therapy should be considered for men with an enlarged prostate and moderate to severe lower urinary tract symptoms.

Anticholinergic agents

Anticholinergic agents block muscarinic receptors within the detrusor muscle, resulting in relaxation. They are used in the treatment of overactive bladder for symptoms of urinary urgency, frequency, and urge incontinence.

Anticholinergics were historically contraindicated in men with BPH because of concern about urinary retention. However, in men with a postvoid residual volume less than 200 mL, anticholinergics do not increase the risk of urinary retention.⁴⁶ Further, greater symptom improvement has been demonstrated with the addition of anticholinergics to alpha-blocker therapy for men with BPH, irritative lower urinary tract symptoms, and a low postvoid residual volume.⁴⁷

Beta-3 agonists

Anticholinergic side effects often limit the use of anticholinergic agents. An alternative in such instances is the beta-3 agonist mirabegron. By activating beta-3 adrenergic receptors in the bladder wall, mirabegron promotes detrusor relaxation and inhibits detrusor overactivity.⁴⁸ Mirabegron does not have anticholinergic side effects and is generally well tolerated, though poorly controlled hypertension is a contraindication to its use.

Phosphodiesterase-5 inhibitors

Phosphodiesterase-5 (PDE5) inhibitors are a mainstay in the treatment of erectile dysfunction. These agents act within penile corporal smooth muscle cells and antagonize PDE5, resulting in cyclic guanosine monophosphate accumulation and smooth muscle relaxation. PDE5 is also found within the prostate and its inhibition is believed to reduce prostatic smooth muscle tone. Randomized studies have demonstrated significant improvement in lower urinary tract symptoms with PDE5 inhibitors, with an average 2-point IPSS improvement on a PDE5 inhibitor compared with placebo.⁴⁹

Tadalafil is the only drug of this class approved by the FDA for the treatment of lower urinary tract symptoms, though other agents have demonstrated similar efficacy.

Dual therapy with a PDE5 inhibitor and an alpha-blocker has greater efficacy than either monotherapy alone; however, caution must be exercised as these agents are titrated to avoid symptomatic hypotension. Lower urinary tract symptoms and sexual dysfunction often coexist; PDE5 inhibitors are appropriate in the management of such cases.

SURGERY FOR BPH

Even with effective medical therapy, the disease will progress in some men. In the MTOPS trial,³⁷ the 4-year incidence of disease progression was 10% for men on alpha-blocker or 5-alpha reductase inhibitor monotherapy and 5% for men on combination therapy; from 1% to 3% of those in the various treatment groups needed surgery. With this in mind, patients whose symptoms do not improve with medical therapy, whose symptoms progress, or who simply are interested in surgery should be referred for urologic evaluation.

A number of effective surgical therapies are available for men with BPH (Table 5), providing excellent 1-year outcomes including a mean 70% reduction in IPSS and a mean 12 mL/sec improvement in peak urinary flow.⁵⁰ Given the efficacy of surgical therapy, men who do not improve with medical therapy who demonstrate any of the findings outlined in Table 1 warrant urologic evaluation.

Acknowledgments: We would like to thank Mary Ellen Amos, PharmD, and Kara Sink, BS, RPh, for their assistance in obtaining the suggested wholesale pricing information included in Table 2.

An 86-year-old woman with hypertension, osteoporosis, and mild cognitive impairment presents with episodes of palpitations and heart “fluttering.” These episodes occur 1 to 2 times per week, last for up to several hours, and are associated with mild shortness of breath and reduced activity tolerance. She is widowed and lives in a retirement facility, but she is independent in activities of daily living. She has fallen twice in the past year without significant injury.

See related editorial

Physical examination is unremarkable. An electrocardiogram demonstrates sinus rhythm with left ventricular hypertrophy. A 30-day event monitor reveals several episodes of paroxysmal atrial fibrillation that correspond with her symptoms. A subsequent echocardiogram shows normal left ventricular systolic function, mild diastolic dysfunction, and no significant valvular abnormalities. Laboratory studies, including thyroid-stimulating hormone, are normal.

What is this patient’s risk of stroke? What is her risk of major bleeding from anticoagulation? How should fall risk be addressed in the decision-making process? What other factors should be considered?

AGE, ATRIAL FIBRILLATION, AND STROKE RISK

The prevalence of atrial fibrillation increases with age, and nearly half of patients with atrial fibrillation in the United States are 75 or older.¹ In addition, older age is an independent risk factor for stroke in patients with atrial fibrillation, and the proportion of strokes attributable to atrial fibrillation increases exponentially with age:

• 1.5% at age 50 to 59
• 2.8% at age 60 to 69
• 9.9% at age 70 to 79
• 23.5% at age 80 to 89.²

Numerous large randomized trials have shown that anticoagulation with warfarin reduces the risk of stroke by about two-thirds in patients with atrial fibrillation, and that this benefit extends to the elderly.

In the Birmingham Atrial Fibrillation Treatment of the Aged trial,³ 973 patients at least 75 years old (mean age 81.5, 55% male) were randomized to receive either warfarin with a target international normalized ratio of 2.0 to 3.0 or aspirin 75 mg/day. Over an average follow-up of 2.7 years, the composite outcome of fatal or disabling stroke, arterial embolism, or intracranial hemorrhage occurred in 24 (4.9%) of the 488 patients in the warfarin group and 48 (9.9%) of the 485 patients in the aspirin group (absolute yearly risk reduction 2%, 95% confidence interval 0.7–3.2, number needed to treat 50 for 1 year). Importantly, the benefit of warfarin was similar in men and women, and in patients ages 75 to 79, 80 to 84, and 85 and older.

More recently, the oral anticoagulants dabigatran, rivaroxaban, apixaban, and edoxaban have been shown to be at least as effective as warfarin with respect to both stroke prevention and major bleeding complications, and subgroup analyses have confirmed similar outcomes in older and younger patients.^4,5

But despite the proven value of anticoagulation for stroke prevention in older adults, only 40% to 60% of older patients who are suitable candidates for anticoagulation actually receive it.⁶ Moreover, the proportion of patients who are treated declines progressively with age. The most frequently cited reason for nontreatment is perception of a high risk of falls and associated concerns about bleeding, especially intracranial hemorrhage.^7–10

BALANCING STROKE RISK VS BLEEDING RISK

Balancing the risk of stroke against the risk of bleeding related to falls is a commonly encountered conundrum in older patients with atrial fibrillation.

Stroke risk

The CHADS₂ score was, until recently, the most widely used method for assessing stroke risk in patients with nonvalvular atrial fibrillation. CHADS₂ assigns 1 point each for congestive heart failure, hypertension, age ≥ 75, and diabetes, and 2 points for prior stroke or transient ischemic attack (range 0–6 points). Annual stroke risk based on the CHADS₂ score ranges from about 2% to about 18%
(Table 1).¹¹

The CHA₂DS₂-VASc score,¹² a modification of CHADS₂, appears to assess the risk of stroke more accurately, especially at the lower end of the scale, and recent guidelines for managing atrial fibrillation recommend using the CHA₂DS₂-VASc algorithm.¹³ CHA₂DS₂-VASc is similar to CHADS₂, except that it assigns 1 point for ages 65 to 74, 2 points for ages 75 and older, 1 point for vascular disease (coronary artery disease, peripheral arterial disease, aortic aneurysm), and 1 point for female sex (Table 1).^11,12

For both CHADS₂ and CHA₂DS₂-VASc, systemic anticoagulation is recommended for patients who have a score of 2 or higher. Our patient’s CHADS₂ score is 2, and her CHA₂DS₂-VASc score is 4, corresponding to an annual estimated stroke risk of 4% with both scores (Table 1). Note, however, that the CHA₂DS₂-VASc score provides more information at the lower end of the spectrum.

Bleeding risk

Several scoring systems for assessing bleeding risk have also been developed (Table 2).^14–16 Of these, the HAS-BLED score has come to be used more widely in recent years.

Perhaps not surprisingly, some of the same factors associated with risk of stroke also predict increased risk of bleeding (eg, older age, hypertension, prior stroke).¹⁴ Note, however, that history of falling or high risk of falling is only included in one of the bleeding risk models (HEMORR₂HAGES).¹⁵

These tools are somewhat limited by their lack of consideration of concomitant antiplatelet therapy (only included in HAS-BLED) or history of bleeding (only ATRIA¹⁶ considers major and minor bleeding, HEMORR₂HAGES does not specify bleeding severity, and HAS-BLED only considers major bleeding). The models also fail to include medications such as antibiotics or antiarrhythmic agents, which are commonly used by older patients with atrial fibrillation and may increase bleeding risk. In addition, all bleeding risk scores were developed for warfarin, and their applicability to patients treated with the newer oral anticoagulants has not been established.

At the time of presentation, our patient has a HAS-BLED score of 2 (1 point each for age and hypertension), placing her at intermediate risk of bleeding.¹⁴

Fear the clot, not the bleed

So how does one balance the risk of stroke vs the risk of bleeding? An adage from the early days of thrombolytic therapy for acute myocardial infarction was “fear the clot, not the bleed.” In other words, in the present context the consequences of a thrombus embolizing from the heart to the brain are likely to be more devastating and more permanent than the consequences of anticoagulation-associated hemorrhage.

Support for this view is underscored by a 2015 study by Lip et al,¹⁷ who examined stroke and bleeding risks and outcomes in a large real-world population of patients age 75 and older. The analysis included 819 patients ages 85 to 89 and 386 patients age 90 and older. The key finding was that the oldest patients derived the greatest net benefit from anticoagulation.

Moreover, the Canadian stroke registry of 3,197 patients, mean age 79, showed that advanced age was a more potent risk factor for ischemic stroke than it was for hemorrhagic stroke.¹⁸

Thus, the benefit from anticoagulation in patients with atrial fibrillation does not appear to have an upper age limit.

FALLS AND ANTICOAGULATION

Falls are an important source of morbidity, disability, and activity curtailment in older adults and, like atrial fibrillation, the incidence and prevalence of falls increase with age. In community-dwelling adults age 65 and older, the overall proportion with at least 1 fall in the preceding year ranges from about 30% to 40%.¹⁹ However, the rate increases with age and exceeds 50% in nursing home residents.²⁰

Although anticoagulation is associated with a higher risk of bleeding in patients who fall, the absolute risk is small.

In a study of older adults with nonvalvular atrial fibrillation, a history of falls or documented high risk of falling was associated with a risk of intracranial hemorrhage during follow-up that was 1.9 times higher.²¹ Importantly, however, this risk did not differ among patients treated with warfarin, aspirin, or no antithrombotic therapy. In this analysis, patients with a CHADS₂ score of 2 or higher benefited from anticoagulation, whether or not they were considered to be at risk for falls.

In another study,²² it was estimated that an individual would have to fall 295 times in 1 year for the risk of fall-related major bleeding to outweigh the benefit of warfarin in reducing the risk of stroke.

Thus, based on available evidence, perception of a high risk of falling should not be construed as justification for withholding anticoagulation in older patients who are otherwise suitable candidates for such therapy.

AT WHAT POINT DOES BLEEDING RISK OUTWEIGH ANTICOAGULATION BENEFIT?

Absolute contraindications to anticoagulation include an intracranial hemorrhage or neurosurgical procedure with high risk for bleeding within the past 30 days, an intracranial neoplasm or vascular abnormality with high risk of bleeding, recurrent life-threatening gastrointestinal or other bleeding events, and severe bleeding disorders, including severe thrombocytopenia.

In patients with atrial fibrillation at high risk of bleeding as assessed by one of the bleeding risk scores and relatively low risk of ischemic stroke, the risk of anticoagulation may outweigh the benefit, although no studies have specifically addressed this issue.

In patients with frequent falls, including injurious falls, the benefits of anticoagulation usually outweigh the risks of bleeding, but management should incorporate interventions designed to mitigate fall risk.

Finally, in patients with a poor prognosis approaching the end of life, the risks and burdens of anticoagulation may exceed the perceived benefits, in which case discontinuation of anticoagulation may be appropriate.

SHOULD OUR PATIENT RECEIVE ANTICOAGULATION?

As noted above, our patient has a high risk of stroke and a moderate risk of bleeding, and multiple lines of evidence indicate that the benefits of anticoagulation (ie, prevention of stroke and systemic embolization) substantially outweigh the risks of bleeding. Although she has a history of falls, which may seem to muddy the waters, this factor should not play a major role in decision-making. Moreover, her advanced age should, if anything, be considered a point in favor of anticoagulation. So from the scientific standpoint, anticoagulation is the clear winner.

A shared decision

But that is not the end of the story. Since there is tension between benefits and risks with either approach (ie, anticoagulation or no anticoagulation), it is important to discuss the issues and options with the patient and relevant caregivers. Most older adults have witnessed the ravages of stroke in a friend or relative, and a recent study showed that most would be willing to accept a modest risk of bleeding to prevent a stroke.²³

However, this is ultimately a personal decision for each patient, and in accordance with the principle of patient autonomy, the patient’s expressed wishes should be honored by using a process of shared decision-making.

Which anticoagulant?

Finally, what about the choice of anticoagulation? The complexities of using warfarin, including its narrow therapeutic range and myriad interactions with other medications and foods, can make it a less appealing option for both patient and provider.

We recommend a novel oral anticoagulant as first-line therapy in the absence of contraindications such as severe renal insufficiency, and prefer apixaban because it is the only agent shown to be superior to warfarin with respect to both stroke prevention and bleeding risk.²⁴

Important disadvantages of the novel oral anticoagulants include their higher cost and lack of an effective antidote in the event of clinically significant bleeding (with the exception of idarucizumab, which was recently approved for reversal of serious bleeding associated with dabigatran), issues that may be of particular concern to older adults. While there is no therapeutic range to monitor for the newer agents, more frequent monitoring for occult anemia may be needed.

Thus, selection of an anticoagulant should also be individualized through shared decision-making.

Is aspirin alone an alternative?

And what if the patient chooses to forgo anticoagulation? In that case, aspirin 75 to 325 mg/day may seem reasonable, but there is scant evidence that aspirin is beneficial for stroke prevention in patients with atrial fibrillation in this age group, and aspirin, too, is associated with an increased risk of bleeding.²⁵

As a result, current US and European guidelines recommend a very limited role for aspirin as a single agent in the management of atrial fibrillation.²⁶ The joint 2014 guidelines of the American Heart Association, American College of Cardiology, and Heart Rhythm Society give aspirin a class IIB recommendation (ie, it “may” be considered), level of evidence C (ie, very limited) for use as an alternative to no antithrombotic therapy or systemic anticoagulation only in patients with a CHA₂DS₂-VASc score of 1, thereby excluding all patients age 75 and older.¹³

In most cases, aspirin as sole prophylaxis against stroke in atrial fibrillation should be avoided in the absence of another indication for its use, such as coexisting coronary artery disease or peripheral arterial disease.

A COMPLEX DECISION

In summary, the decisions surrounding anticoagulation of elderly patients with nonvalvular atrial fibrillation are complex. Accurate assessment of stroke risk is key, and although bleeding risk is also an essential consideration, it is important not to overemphasize bleeding and fall risks in the decision-making process.

An 86-year-old woman with hypertension, osteoporosis, and mild cognitive impairment presents with episodes of palpitations and heart “fluttering.” These episodes occur 1 to 2 times per week, last for up to several hours, and are associated with mild shortness of breath and reduced activity tolerance. She is widowed and lives in a retirement facility, but she is independent in activities of daily living. She has fallen twice in the past year without significant injury.

See related editorial

Physical examination is unremarkable. An electrocardiogram demonstrates sinus rhythm with left ventricular hypertrophy. A 30-day event monitor reveals several episodes of paroxysmal atrial fibrillation that correspond with her symptoms. A subsequent echocardiogram shows normal left ventricular systolic function, mild diastolic dysfunction, and no significant valvular abnormalities. Laboratory studies, including thyroid-stimulating hormone, are normal.

What is this patient’s risk of stroke? What is her risk of major bleeding from anticoagulation? How should fall risk be addressed in the decision-making process? What other factors should be considered?

AGE, ATRIAL FIBRILLATION, AND STROKE RISK

The prevalence of atrial fibrillation increases with age, and nearly half of patients with atrial fibrillation in the United States are 75 or older.¹ In addition, older age is an independent risk factor for stroke in patients with atrial fibrillation, and the proportion of strokes attributable to atrial fibrillation increases exponentially with age:

• 1.5% at age 50 to 59
• 2.8% at age 60 to 69
• 9.9% at age 70 to 79
• 23.5% at age 80 to 89.²

Numerous large randomized trials have shown that anticoagulation with warfarin reduces the risk of stroke by about two-thirds in patients with atrial fibrillation, and that this benefit extends to the elderly.

In the Birmingham Atrial Fibrillation Treatment of the Aged trial,³ 973 patients at least 75 years old (mean age 81.5, 55% male) were randomized to receive either warfarin with a target international normalized ratio of 2.0 to 3.0 or aspirin 75 mg/day. Over an average follow-up of 2.7 years, the composite outcome of fatal or disabling stroke, arterial embolism, or intracranial hemorrhage occurred in 24 (4.9%) of the 488 patients in the warfarin group and 48 (9.9%) of the 485 patients in the aspirin group (absolute yearly risk reduction 2%, 95% confidence interval 0.7–3.2, number needed to treat 50 for 1 year). Importantly, the benefit of warfarin was similar in men and women, and in patients ages 75 to 79, 80 to 84, and 85 and older.

More recently, the oral anticoagulants dabigatran, rivaroxaban, apixaban, and edoxaban have been shown to be at least as effective as warfarin with respect to both stroke prevention and major bleeding complications, and subgroup analyses have confirmed similar outcomes in older and younger patients.^4,5

But despite the proven value of anticoagulation for stroke prevention in older adults, only 40% to 60% of older patients who are suitable candidates for anticoagulation actually receive it.⁶ Moreover, the proportion of patients who are treated declines progressively with age. The most frequently cited reason for nontreatment is perception of a high risk of falls and associated concerns about bleeding, especially intracranial hemorrhage.^7–10

BALANCING STROKE RISK VS BLEEDING RISK

Balancing the risk of stroke against the risk of bleeding related to falls is a commonly encountered conundrum in older patients with atrial fibrillation.

Stroke risk

The CHADS₂ score was, until recently, the most widely used method for assessing stroke risk in patients with nonvalvular atrial fibrillation. CHADS₂ assigns 1 point each for congestive heart failure, hypertension, age ≥ 75, and diabetes, and 2 points for prior stroke or transient ischemic attack (range 0–6 points). Annual stroke risk based on the CHADS₂ score ranges from about 2% to about 18%
(Table 1).¹¹

The CHA₂DS₂-VASc score,¹² a modification of CHADS₂, appears to assess the risk of stroke more accurately, especially at the lower end of the scale, and recent guidelines for managing atrial fibrillation recommend using the CHA₂DS₂-VASc algorithm.¹³ CHA₂DS₂-VASc is similar to CHADS₂, except that it assigns 1 point for ages 65 to 74, 2 points for ages 75 and older, 1 point for vascular disease (coronary artery disease, peripheral arterial disease, aortic aneurysm), and 1 point for female sex (Table 1).^11,12

For both CHADS₂ and CHA₂DS₂-VASc, systemic anticoagulation is recommended for patients who have a score of 2 or higher. Our patient’s CHADS₂ score is 2, and her CHA₂DS₂-VASc score is 4, corresponding to an annual estimated stroke risk of 4% with both scores (Table 1). Note, however, that the CHA₂DS₂-VASc score provides more information at the lower end of the spectrum.

Bleeding risk

Several scoring systems for assessing bleeding risk have also been developed (Table 2).^14–16 Of these, the HAS-BLED score has come to be used more widely in recent years.

Perhaps not surprisingly, some of the same factors associated with risk of stroke also predict increased risk of bleeding (eg, older age, hypertension, prior stroke).¹⁴ Note, however, that history of falling or high risk of falling is only included in one of the bleeding risk models (HEMORR₂HAGES).¹⁵

These tools are somewhat limited by their lack of consideration of concomitant antiplatelet therapy (only included in HAS-BLED) or history of bleeding (only ATRIA¹⁶ considers major and minor bleeding, HEMORR₂HAGES does not specify bleeding severity, and HAS-BLED only considers major bleeding). The models also fail to include medications such as antibiotics or antiarrhythmic agents, which are commonly used by older patients with atrial fibrillation and may increase bleeding risk. In addition, all bleeding risk scores were developed for warfarin, and their applicability to patients treated with the newer oral anticoagulants has not been established.

At the time of presentation, our patient has a HAS-BLED score of 2 (1 point each for age and hypertension), placing her at intermediate risk of bleeding.¹⁴

Fear the clot, not the bleed

So how does one balance the risk of stroke vs the risk of bleeding? An adage from the early days of thrombolytic therapy for acute myocardial infarction was “fear the clot, not the bleed.” In other words, in the present context the consequences of a thrombus embolizing from the heart to the brain are likely to be more devastating and more permanent than the consequences of anticoagulation-associated hemorrhage.

Support for this view is underscored by a 2015 study by Lip et al,¹⁷ who examined stroke and bleeding risks and outcomes in a large real-world population of patients age 75 and older. The analysis included 819 patients ages 85 to 89 and 386 patients age 90 and older. The key finding was that the oldest patients derived the greatest net benefit from anticoagulation.

Moreover, the Canadian stroke registry of 3,197 patients, mean age 79, showed that advanced age was a more potent risk factor for ischemic stroke than it was for hemorrhagic stroke.¹⁸

Thus, the benefit from anticoagulation in patients with atrial fibrillation does not appear to have an upper age limit.

FALLS AND ANTICOAGULATION

Falls are an important source of morbidity, disability, and activity curtailment in older adults and, like atrial fibrillation, the incidence and prevalence of falls increase with age. In community-dwelling adults age 65 and older, the overall proportion with at least 1 fall in the preceding year ranges from about 30% to 40%.¹⁹ However, the rate increases with age and exceeds 50% in nursing home residents.²⁰

Although anticoagulation is associated with a higher risk of bleeding in patients who fall, the absolute risk is small.

In a study of older adults with nonvalvular atrial fibrillation, a history of falls or documented high risk of falling was associated with a risk of intracranial hemorrhage during follow-up that was 1.9 times higher.²¹ Importantly, however, this risk did not differ among patients treated with warfarin, aspirin, or no antithrombotic therapy. In this analysis, patients with a CHADS₂ score of 2 or higher benefited from anticoagulation, whether or not they were considered to be at risk for falls.

In another study,²² it was estimated that an individual would have to fall 295 times in 1 year for the risk of fall-related major bleeding to outweigh the benefit of warfarin in reducing the risk of stroke.

Thus, based on available evidence, perception of a high risk of falling should not be construed as justification for withholding anticoagulation in older patients who are otherwise suitable candidates for such therapy.

AT WHAT POINT DOES BLEEDING RISK OUTWEIGH ANTICOAGULATION BENEFIT?

Absolute contraindications to anticoagulation include an intracranial hemorrhage or neurosurgical procedure with high risk for bleeding within the past 30 days, an intracranial neoplasm or vascular abnormality with high risk of bleeding, recurrent life-threatening gastrointestinal or other bleeding events, and severe bleeding disorders, including severe thrombocytopenia.

In patients with atrial fibrillation at high risk of bleeding as assessed by one of the bleeding risk scores and relatively low risk of ischemic stroke, the risk of anticoagulation may outweigh the benefit, although no studies have specifically addressed this issue.

In patients with frequent falls, including injurious falls, the benefits of anticoagulation usually outweigh the risks of bleeding, but management should incorporate interventions designed to mitigate fall risk.

Finally, in patients with a poor prognosis approaching the end of life, the risks and burdens of anticoagulation may exceed the perceived benefits, in which case discontinuation of anticoagulation may be appropriate.

SHOULD OUR PATIENT RECEIVE ANTICOAGULATION?

As noted above, our patient has a high risk of stroke and a moderate risk of bleeding, and multiple lines of evidence indicate that the benefits of anticoagulation (ie, prevention of stroke and systemic embolization) substantially outweigh the risks of bleeding. Although she has a history of falls, which may seem to muddy the waters, this factor should not play a major role in decision-making. Moreover, her advanced age should, if anything, be considered a point in favor of anticoagulation. So from the scientific standpoint, anticoagulation is the clear winner.

A shared decision

But that is not the end of the story. Since there is tension between benefits and risks with either approach (ie, anticoagulation or no anticoagulation), it is important to discuss the issues and options with the patient and relevant caregivers. Most older adults have witnessed the ravages of stroke in a friend or relative, and a recent study showed that most would be willing to accept a modest risk of bleeding to prevent a stroke.²³

However, this is ultimately a personal decision for each patient, and in accordance with the principle of patient autonomy, the patient’s expressed wishes should be honored by using a process of shared decision-making.

Which anticoagulant?

Finally, what about the choice of anticoagulation? The complexities of using warfarin, including its narrow therapeutic range and myriad interactions with other medications and foods, can make it a less appealing option for both patient and provider.

We recommend a novel oral anticoagulant as first-line therapy in the absence of contraindications such as severe renal insufficiency, and prefer apixaban because it is the only agent shown to be superior to warfarin with respect to both stroke prevention and bleeding risk.²⁴

Important disadvantages of the novel oral anticoagulants include their higher cost and lack of an effective antidote in the event of clinically significant bleeding (with the exception of idarucizumab, which was recently approved for reversal of serious bleeding associated with dabigatran), issues that may be of particular concern to older adults. While there is no therapeutic range to monitor for the newer agents, more frequent monitoring for occult anemia may be needed.

Thus, selection of an anticoagulant should also be individualized through shared decision-making.

Is aspirin alone an alternative?

And what if the patient chooses to forgo anticoagulation? In that case, aspirin 75 to 325 mg/day may seem reasonable, but there is scant evidence that aspirin is beneficial for stroke prevention in patients with atrial fibrillation in this age group, and aspirin, too, is associated with an increased risk of bleeding.²⁵

As a result, current US and European guidelines recommend a very limited role for aspirin as a single agent in the management of atrial fibrillation.²⁶ The joint 2014 guidelines of the American Heart Association, American College of Cardiology, and Heart Rhythm Society give aspirin a class IIB recommendation (ie, it “may” be considered), level of evidence C (ie, very limited) for use as an alternative to no antithrombotic therapy or systemic anticoagulation only in patients with a CHA₂DS₂-VASc score of 1, thereby excluding all patients age 75 and older.¹³

In most cases, aspirin as sole prophylaxis against stroke in atrial fibrillation should be avoided in the absence of another indication for its use, such as coexisting coronary artery disease or peripheral arterial disease.

A COMPLEX DECISION

In summary, the decisions surrounding anticoagulation of elderly patients with nonvalvular atrial fibrillation are complex. Accurate assessment of stroke risk is key, and although bleeding risk is also an essential consideration, it is important not to overemphasize bleeding and fall risks in the decision-making process.

An 86-year-old woman with hypertension, osteoporosis, and mild cognitive impairment presents with episodes of palpitations and heart “fluttering.” These episodes occur 1 to 2 times per week, last for up to several hours, and are associated with mild shortness of breath and reduced activity tolerance. She is widowed and lives in a retirement facility, but she is independent in activities of daily living. She has fallen twice in the past year without significant injury.

See related editorial

Physical examination is unremarkable. An electrocardiogram demonstrates sinus rhythm with left ventricular hypertrophy. A 30-day event monitor reveals several episodes of paroxysmal atrial fibrillation that correspond with her symptoms. A subsequent echocardiogram shows normal left ventricular systolic function, mild diastolic dysfunction, and no significant valvular abnormalities. Laboratory studies, including thyroid-stimulating hormone, are normal.

What is this patient’s risk of stroke? What is her risk of major bleeding from anticoagulation? How should fall risk be addressed in the decision-making process? What other factors should be considered?

AGE, ATRIAL FIBRILLATION, AND STROKE RISK

The prevalence of atrial fibrillation increases with age, and nearly half of patients with atrial fibrillation in the United States are 75 or older.¹ In addition, older age is an independent risk factor for stroke in patients with atrial fibrillation, and the proportion of strokes attributable to atrial fibrillation increases exponentially with age:

• 1.5% at age 50 to 59
• 2.8% at age 60 to 69
• 9.9% at age 70 to 79
• 23.5% at age 80 to 89.²

Numerous large randomized trials have shown that anticoagulation with warfarin reduces the risk of stroke by about two-thirds in patients with atrial fibrillation, and that this benefit extends to the elderly.

In the Birmingham Atrial Fibrillation Treatment of the Aged trial,³ 973 patients at least 75 years old (mean age 81.5, 55% male) were randomized to receive either warfarin with a target international normalized ratio of 2.0 to 3.0 or aspirin 75 mg/day. Over an average follow-up of 2.7 years, the composite outcome of fatal or disabling stroke, arterial embolism, or intracranial hemorrhage occurred in 24 (4.9%) of the 488 patients in the warfarin group and 48 (9.9%) of the 485 patients in the aspirin group (absolute yearly risk reduction 2%, 95% confidence interval 0.7–3.2, number needed to treat 50 for 1 year). Importantly, the benefit of warfarin was similar in men and women, and in patients ages 75 to 79, 80 to 84, and 85 and older.

More recently, the oral anticoagulants dabigatran, rivaroxaban, apixaban, and edoxaban have been shown to be at least as effective as warfarin with respect to both stroke prevention and major bleeding complications, and subgroup analyses have confirmed similar outcomes in older and younger patients.^4,5

But despite the proven value of anticoagulation for stroke prevention in older adults, only 40% to 60% of older patients who are suitable candidates for anticoagulation actually receive it.⁶ Moreover, the proportion of patients who are treated declines progressively with age. The most frequently cited reason for nontreatment is perception of a high risk of falls and associated concerns about bleeding, especially intracranial hemorrhage.^7–10

BALANCING STROKE RISK VS BLEEDING RISK

Balancing the risk of stroke against the risk of bleeding related to falls is a commonly encountered conundrum in older patients with atrial fibrillation.

Stroke risk

The CHADS₂ score was, until recently, the most widely used method for assessing stroke risk in patients with nonvalvular atrial fibrillation. CHADS₂ assigns 1 point each for congestive heart failure, hypertension, age ≥ 75, and diabetes, and 2 points for prior stroke or transient ischemic attack (range 0–6 points). Annual stroke risk based on the CHADS₂ score ranges from about 2% to about 18%
(Table 1).¹¹

The CHA₂DS₂-VASc score,¹² a modification of CHADS₂, appears to assess the risk of stroke more accurately, especially at the lower end of the scale, and recent guidelines for managing atrial fibrillation recommend using the CHA₂DS₂-VASc algorithm.¹³ CHA₂DS₂-VASc is similar to CHADS₂, except that it assigns 1 point for ages 65 to 74, 2 points for ages 75 and older, 1 point for vascular disease (coronary artery disease, peripheral arterial disease, aortic aneurysm), and 1 point for female sex (Table 1).^11,12

For both CHADS₂ and CHA₂DS₂-VASc, systemic anticoagulation is recommended for patients who have a score of 2 or higher. Our patient’s CHADS₂ score is 2, and her CHA₂DS₂-VASc score is 4, corresponding to an annual estimated stroke risk of 4% with both scores (Table 1). Note, however, that the CHA₂DS₂-VASc score provides more information at the lower end of the spectrum.

Bleeding risk

Several scoring systems for assessing bleeding risk have also been developed (Table 2).^14–16 Of these, the HAS-BLED score has come to be used more widely in recent years.

Perhaps not surprisingly, some of the same factors associated with risk of stroke also predict increased risk of bleeding (eg, older age, hypertension, prior stroke).¹⁴ Note, however, that history of falling or high risk of falling is only included in one of the bleeding risk models (HEMORR₂HAGES).¹⁵

These tools are somewhat limited by their lack of consideration of concomitant antiplatelet therapy (only included in HAS-BLED) or history of bleeding (only ATRIA¹⁶ considers major and minor bleeding, HEMORR₂HAGES does not specify bleeding severity, and HAS-BLED only considers major bleeding). The models also fail to include medications such as antibiotics or antiarrhythmic agents, which are commonly used by older patients with atrial fibrillation and may increase bleeding risk. In addition, all bleeding risk scores were developed for warfarin, and their applicability to patients treated with the newer oral anticoagulants has not been established.

At the time of presentation, our patient has a HAS-BLED score of 2 (1 point each for age and hypertension), placing her at intermediate risk of bleeding.¹⁴

Fear the clot, not the bleed

So how does one balance the risk of stroke vs the risk of bleeding? An adage from the early days of thrombolytic therapy for acute myocardial infarction was “fear the clot, not the bleed.” In other words, in the present context the consequences of a thrombus embolizing from the heart to the brain are likely to be more devastating and more permanent than the consequences of anticoagulation-associated hemorrhage.

Support for this view is underscored by a 2015 study by Lip et al,¹⁷ who examined stroke and bleeding risks and outcomes in a large real-world population of patients age 75 and older. The analysis included 819 patients ages 85 to 89 and 386 patients age 90 and older. The key finding was that the oldest patients derived the greatest net benefit from anticoagulation.

Moreover, the Canadian stroke registry of 3,197 patients, mean age 79, showed that advanced age was a more potent risk factor for ischemic stroke than it was for hemorrhagic stroke.¹⁸

Thus, the benefit from anticoagulation in patients with atrial fibrillation does not appear to have an upper age limit.

FALLS AND ANTICOAGULATION

Falls are an important source of morbidity, disability, and activity curtailment in older adults and, like atrial fibrillation, the incidence and prevalence of falls increase with age. In community-dwelling adults age 65 and older, the overall proportion with at least 1 fall in the preceding year ranges from about 30% to 40%.¹⁹ However, the rate increases with age and exceeds 50% in nursing home residents.²⁰

Although anticoagulation is associated with a higher risk of bleeding in patients who fall, the absolute risk is small.

In a study of older adults with nonvalvular atrial fibrillation, a history of falls or documented high risk of falling was associated with a risk of intracranial hemorrhage during follow-up that was 1.9 times higher.²¹ Importantly, however, this risk did not differ among patients treated with warfarin, aspirin, or no antithrombotic therapy. In this analysis, patients with a CHADS₂ score of 2 or higher benefited from anticoagulation, whether or not they were considered to be at risk for falls.

In another study,²² it was estimated that an individual would have to fall 295 times in 1 year for the risk of fall-related major bleeding to outweigh the benefit of warfarin in reducing the risk of stroke.

Thus, based on available evidence, perception of a high risk of falling should not be construed as justification for withholding anticoagulation in older patients who are otherwise suitable candidates for such therapy.

AT WHAT POINT DOES BLEEDING RISK OUTWEIGH ANTICOAGULATION BENEFIT?

Absolute contraindications to anticoagulation include an intracranial hemorrhage or neurosurgical procedure with high risk for bleeding within the past 30 days, an intracranial neoplasm or vascular abnormality with high risk of bleeding, recurrent life-threatening gastrointestinal or other bleeding events, and severe bleeding disorders, including severe thrombocytopenia.

In patients with atrial fibrillation at high risk of bleeding as assessed by one of the bleeding risk scores and relatively low risk of ischemic stroke, the risk of anticoagulation may outweigh the benefit, although no studies have specifically addressed this issue.

In patients with frequent falls, including injurious falls, the benefits of anticoagulation usually outweigh the risks of bleeding, but management should incorporate interventions designed to mitigate fall risk.

Finally, in patients with a poor prognosis approaching the end of life, the risks and burdens of anticoagulation may exceed the perceived benefits, in which case discontinuation of anticoagulation may be appropriate.

SHOULD OUR PATIENT RECEIVE ANTICOAGULATION?

As noted above, our patient has a high risk of stroke and a moderate risk of bleeding, and multiple lines of evidence indicate that the benefits of anticoagulation (ie, prevention of stroke and systemic embolization) substantially outweigh the risks of bleeding. Although she has a history of falls, which may seem to muddy the waters, this factor should not play a major role in decision-making. Moreover, her advanced age should, if anything, be considered a point in favor of anticoagulation. So from the scientific standpoint, anticoagulation is the clear winner.

A shared decision

But that is not the end of the story. Since there is tension between benefits and risks with either approach (ie, anticoagulation or no anticoagulation), it is important to discuss the issues and options with the patient and relevant caregivers. Most older adults have witnessed the ravages of stroke in a friend or relative, and a recent study showed that most would be willing to accept a modest risk of bleeding to prevent a stroke.²³

However, this is ultimately a personal decision for each patient, and in accordance with the principle of patient autonomy, the patient’s expressed wishes should be honored by using a process of shared decision-making.

Which anticoagulant?

Finally, what about the choice of anticoagulation? The complexities of using warfarin, including its narrow therapeutic range and myriad interactions with other medications and foods, can make it a less appealing option for both patient and provider.

We recommend a novel oral anticoagulant as first-line therapy in the absence of contraindications such as severe renal insufficiency, and prefer apixaban because it is the only agent shown to be superior to warfarin with respect to both stroke prevention and bleeding risk.²⁴

Important disadvantages of the novel oral anticoagulants include their higher cost and lack of an effective antidote in the event of clinically significant bleeding (with the exception of idarucizumab, which was recently approved for reversal of serious bleeding associated with dabigatran), issues that may be of particular concern to older adults. While there is no therapeutic range to monitor for the newer agents, more frequent monitoring for occult anemia may be needed.

Thus, selection of an anticoagulant should also be individualized through shared decision-making.

Is aspirin alone an alternative?

And what if the patient chooses to forgo anticoagulation? In that case, aspirin 75 to 325 mg/day may seem reasonable, but there is scant evidence that aspirin is beneficial for stroke prevention in patients with atrial fibrillation in this age group, and aspirin, too, is associated with an increased risk of bleeding.²⁵

As a result, current US and European guidelines recommend a very limited role for aspirin as a single agent in the management of atrial fibrillation.²⁶ The joint 2014 guidelines of the American Heart Association, American College of Cardiology, and Heart Rhythm Society give aspirin a class IIB recommendation (ie, it “may” be considered), level of evidence C (ie, very limited) for use as an alternative to no antithrombotic therapy or systemic anticoagulation only in patients with a CHA₂DS₂-VASc score of 1, thereby excluding all patients age 75 and older.¹³

In most cases, aspirin as sole prophylaxis against stroke in atrial fibrillation should be avoided in the absence of another indication for its use, such as coexisting coronary artery disease or peripheral arterial disease.

A COMPLEX DECISION

In summary, the decisions surrounding anticoagulation of elderly patients with nonvalvular atrial fibrillation are complex. Accurate assessment of stroke risk is key, and although bleeding risk is also an essential consideration, it is important not to overemphasize bleeding and fall risks in the decision-making process.

Click here to access the January 2017 Digital Edition

Table of Contents

• What’s New for Federal Practitioner in 2017?
• Addressing Sexual Health With Patients
• Leadership Initiatives in Patient-Centered Transgender Care
• Patient Knowledge and Attitudes About Fecal Microbiota Therapy for Clostridium difficile Infection
• Decentralized vs Centralized Pharmacist Treatment of Patients With Atrial Fibrillation Managed With Anticoagulants
• The Importance of Subclavian Angiography in the Evaluation of Chest Pain
• Diabetes: Health Literacy Education Improves Veteran Outcomes
• Torsades de Pointes in Severe Alcohol Withdrawal and Cirrhosis: Implications for Risk Stratification and Management
• Dementia Evaluation, Management, and Outreach

Click here to access the January 2017 Digital Edition

Table of Contents

• What’s New for Federal Practitioner in 2017?
• Addressing Sexual Health With Patients
• Leadership Initiatives in Patient-Centered Transgender Care
• Patient Knowledge and Attitudes About Fecal Microbiota Therapy for Clostridium difficile Infection
• Decentralized vs Centralized Pharmacist Treatment of Patients With Atrial Fibrillation Managed With Anticoagulants
• The Importance of Subclavian Angiography in the Evaluation of Chest Pain
• Diabetes: Health Literacy Education Improves Veteran Outcomes
• Torsades de Pointes in Severe Alcohol Withdrawal and Cirrhosis: Implications for Risk Stratification and Management
• Dementia Evaluation, Management, and Outreach

Click here to access the January 2017 Digital Edition

Table of Contents

• What’s New for Federal Practitioner in 2017?
• Addressing Sexual Health With Patients
• Leadership Initiatives in Patient-Centered Transgender Care
• Patient Knowledge and Attitudes About Fecal Microbiota Therapy for Clostridium difficile Infection
• Decentralized vs Centralized Pharmacist Treatment of Patients With Atrial Fibrillation Managed With Anticoagulants
• The Importance of Subclavian Angiography in the Evaluation of Chest Pain
• Diabetes: Health Literacy Education Improves Veteran Outcomes
• Torsades de Pointes in Severe Alcohol Withdrawal and Cirrhosis: Implications for Risk Stratification and Management
• Dementia Evaluation, Management, and Outreach