Cleveland Clinic Journal of Medicine

Stopping dual antiplatelet therapy (DAPT) (eg, clopidogrel plus aspirin) after 3 months is reasonable in patients with stable ischemic heart disease who have a second-generation drug-eluting stent and a high bleeding risk, with stable ischemic disease defined as at least 1 year free of acute coronary syndromes. However, these patients should continue lifelong aspirin monotherapy. Current guidelines suggest that in stable ischemic disease, the risk-benefit ratio may favor an even shorter duration of DAPT than the 6 months currently recommended.¹

STABLE ISCHEMIC HEART DISEASE VS ACUTE CORONARY SYNDROME

Percutaneous coronary intervention for stable ischemic heart disease is indicated primarily in patients with angina that persists despite optimal antianginal therapy.

The prognostic implications of DAPT are different in stable ischemic disease than in acute coronary syndromes. The substrate treated by percutaneous intervention in stable ischemic disease is primarily fibrofatty plaque, as opposed to thrombus in acute coronary syndromes.

Percutaneous intervention significantly improves the prognosis in acute coronary syndromes, whereas its impact on overall survival in stable ischemic heart disease is not well documented. Given these differences, our discussion about DAPT in stable ischemic disease cannot be extrapolated to acute coronary syndromes.

BENEFITS OF DAPT

DAPT is mandatory early after drug-eluting stent placement, when the stent continuously releases medication, inhibiting tissue growth within the lumen of the stent.

Endothelialization of the stent normally occurs during the first 7 to 30 days after placement. During this period, the nonendothelialized stent poses a risk of thrombosis, a life-threatening, catastrophic condition with a mortality rate between 9% and 45%.¹

THERAPY BEYOND 12 MONTHS

Although guidelines have traditionally recommended 12 months of DAPT, the optimal duration is still debated.

A duration beyond 12 months in patients with a history of myocardial infarction was shown to be reasonable in 2 large trials,^2,3 while a 2016 review by Bittl et al⁴ suggested that therapy beyond 12 months in patients with a newer-generation drug-eluting stent could increase the incidence of major bleeding. A detailed discussion of DAPT longer than 12 months is beyond the scope of this article.

EVIDENCE FOR SHORTER DURATION

The results of 5 major trials support shorter duration of DAPT in stable ischemic disease.

The OPTIMIZE⁵ and RESET⁶ trials found that 3 months of DAPT was not inferior to 12 months in terms of ischemic and safety end points.

The ISAR-SAFE,⁷ EXCELLENT,⁸ and SECURITY⁹ trials also reported that 6 months of DAPT was not inferior to 12 months for the primary composite end point of death, stent thrombosis, myocardial infarction, stroke, or major bleeding.

However, these trials may have been underpowered to detect a difference in rates of stent thrombosis with shorter-duration DAPT.

CURRENT GUIDELINES

For patients at high bleeding risk, the current guidelines of the American College of Cardiology and American Heart Association, updated in 2016, suggest that it may be reasonable to discontinue DAPT 3 months after drug-eluting stent placement in patients with stable ischemic heart disease, and at 6 months in patients with acute coronary syndrome (class IIb recommendation, level of evidence C).¹ These recommendations are based on results of randomized controlled trials showing no difference in the rate of stent thrombosis and composite ischemic events with a shorter duration than with 12 months of therapy.^5–10

The evidence for DAPT in stable ischemic disease is based on clopidogrel, with only limited data on ticagrelor.¹ To our knowledge, no study to date has evaluated DAPT in this setting for less than 3 months, and further study is needed to address shorter-duration approaches with current-generation drug-eluting stents Since 2017, all coronary stents implanted in the United States have been second-generation stents.

The decision to stop DAPT in a patient at high risk of bleeding requires a careful assessment of the risks and benefits. Risk factors for bleeding include advanced age, history of major bleeding, anticoagulation, chronic kidney disease (serum creatinine level ≥ 2 mg/dL), platelet count 100 × 10⁹/L or lower, and history of stroke.¹¹

• Age 75 or older: −2 points
• Ages 65 to 74: −1
• Age under 65: 0
• Diabetes mellitus: 1
• Myocardial infarction at presentation: 1
• History of percutaneous coronary intervention or myocardial infarction: 1
• Stent diameter less than 3 mm: 1
• Paclitaxel drug-eluting stent: 1
• Current smoker: 2
• Percutaneous coronary intervention with saphenous vein graft: 2
• Congestive heart failure or left ventricular ejection fraction less than 30%: 2.

A score of 2 or greater favors continuing DAPT, as it indicates higher ischemic risk. A score less than 2 favors discontinuing DAPT, as it indicates higher bleeding risk.^1,2

IF BLEEDING RISK IS HIGH

Preventing and controlling bleeding associated with DAPT is important. The gastrointestinal tract is the most common site of bleeding.

Aspirin inhibits prostaglandin synthesis, leading to disruption of the protective mucous membrane. Therefore, a proton pump inhibitor should be started along with DAPT in patients at high risk of gastrointestinal bleeding.

If a patient’s bleeding risk significantly outweighs the risk of stent thrombosis, or if active hemorrhage makes a patient hemodynamically unstable, antiplatelet therapy must be stopped.¹

FACING SURGERY

For patients with a drug-eluting stent who are on DAPT and are to undergo elective noncardiac surgery, 3 considerations must be kept in mind:

• The risk of stent thrombosis if DAPT needs to be interrupted
• The consequences of delaying the surgical procedure
• The risk and consequences of periprocedural and intraprocedural bleeding if DAPT is continued.

Because clinical evidence for bridging therapy with intravenous antiplatelet or anticoagulant agents is limited, it is difficult to make recommendations about stopping DAPT. However, once bleeding risk is stabilized, DAPT should be restarted as soon as possible.¹

CURRENT RESEARCH

Several trials are under way to further evaluate ways to minimize bleeding risk and shorten the duration of DAPT.

A prospective multicenter trial is evaluating 3-month DAPT in patients at high bleeding risk who undergo placement of an everolimus-eluting stent.¹¹ This study is expected to be completed in August 2019.

Another strategy for patients at high bleeding risk is use of a polymer-free drug-coated coronary stent. In a 2015 trial comparing a biolimus A9-coated stent vs a bare-metal stent, patients received DAPT for 1 month after stent placement. The drug-coated stent was found to be superior in terms of the primary safety end point (cardiac death, myocardial infarction, or stent thrombosis).¹² This stent is not yet approved by the US Food and Drug Administration at the time of this writing.

Further study is needed to evaluate DAPT durations of less than 3 months and to establish the proper timing for safely discontinuing DAPT in difficult clinical scenarios.

WHEN STOPPING MAY BE REASONABLE

According to current guidelines, in patients at high bleeding risk with a second-generation or newer drug-eluting stent for stable ischemic heart disease, discontinuing DAPT 3 months after stent placement may be reasonable.¹ The decision to stop DAPT in these patients requires a careful assessment of the risks and benefits and may be aided by a tool such as the DAPT risk score. However, these recommendations cannot be extrapolated to patients with an acute coronary syndrome within the past year, as they are at higher risk.

TAKE-HOME MESSAGES

• A cardiologist should be consulted before discontinuing DAPT in patients with a drug-eluting stent, especially if the stent was recently placed.
• The duration of therapy depends on the indication for stent placement (stable ischemic heart disease vs acute coronary syndrome) and on stent location.
• Based on the 2016 American College of Cardiology/American Heart Association guidelines,¹ in patients at high bleeding risk with a second-generation drug-eluting stent, discontinuing DAPT is safe after 3 months in patients with stable ischemic heart disease, and after 6 months in patients with an acute coronary syndrome.
• When prescribing DAPT, available evidence favors clopidogrel in patients with stable ischemic heart disease who have a second-generation drug-eluting stent and are at high bleeding risk.
• In these patients, the risk-benefit ratio based on the DAPT score may be useful when considering stopping clopidogrel.       

Stopping dual antiplatelet therapy (DAPT) (eg, clopidogrel plus aspirin) after 3 months is reasonable in patients with stable ischemic heart disease who have a second-generation drug-eluting stent and a high bleeding risk, with stable ischemic disease defined as at least 1 year free of acute coronary syndromes. However, these patients should continue lifelong aspirin monotherapy. Current guidelines suggest that in stable ischemic disease, the risk-benefit ratio may favor an even shorter duration of DAPT than the 6 months currently recommended.¹

STABLE ISCHEMIC HEART DISEASE VS ACUTE CORONARY SYNDROME

Percutaneous coronary intervention for stable ischemic heart disease is indicated primarily in patients with angina that persists despite optimal antianginal therapy.

The prognostic implications of DAPT are different in stable ischemic disease than in acute coronary syndromes. The substrate treated by percutaneous intervention in stable ischemic disease is primarily fibrofatty plaque, as opposed to thrombus in acute coronary syndromes.

Percutaneous intervention significantly improves the prognosis in acute coronary syndromes, whereas its impact on overall survival in stable ischemic heart disease is not well documented. Given these differences, our discussion about DAPT in stable ischemic disease cannot be extrapolated to acute coronary syndromes.

BENEFITS OF DAPT

DAPT is mandatory early after drug-eluting stent placement, when the stent continuously releases medication, inhibiting tissue growth within the lumen of the stent.

Endothelialization of the stent normally occurs during the first 7 to 30 days after placement. During this period, the nonendothelialized stent poses a risk of thrombosis, a life-threatening, catastrophic condition with a mortality rate between 9% and 45%.¹

THERAPY BEYOND 12 MONTHS

Although guidelines have traditionally recommended 12 months of DAPT, the optimal duration is still debated.

A duration beyond 12 months in patients with a history of myocardial infarction was shown to be reasonable in 2 large trials,^2,3 while a 2016 review by Bittl et al⁴ suggested that therapy beyond 12 months in patients with a newer-generation drug-eluting stent could increase the incidence of major bleeding. A detailed discussion of DAPT longer than 12 months is beyond the scope of this article.

EVIDENCE FOR SHORTER DURATION

The results of 5 major trials support shorter duration of DAPT in stable ischemic disease.

The OPTIMIZE⁵ and RESET⁶ trials found that 3 months of DAPT was not inferior to 12 months in terms of ischemic and safety end points.

The ISAR-SAFE,⁷ EXCELLENT,⁸ and SECURITY⁹ trials also reported that 6 months of DAPT was not inferior to 12 months for the primary composite end point of death, stent thrombosis, myocardial infarction, stroke, or major bleeding.

However, these trials may have been underpowered to detect a difference in rates of stent thrombosis with shorter-duration DAPT.

CURRENT GUIDELINES

For patients at high bleeding risk, the current guidelines of the American College of Cardiology and American Heart Association, updated in 2016, suggest that it may be reasonable to discontinue DAPT 3 months after drug-eluting stent placement in patients with stable ischemic heart disease, and at 6 months in patients with acute coronary syndrome (class IIb recommendation, level of evidence C).¹ These recommendations are based on results of randomized controlled trials showing no difference in the rate of stent thrombosis and composite ischemic events with a shorter duration than with 12 months of therapy.^5–10

The evidence for DAPT in stable ischemic disease is based on clopidogrel, with only limited data on ticagrelor.¹ To our knowledge, no study to date has evaluated DAPT in this setting for less than 3 months, and further study is needed to address shorter-duration approaches with current-generation drug-eluting stents Since 2017, all coronary stents implanted in the United States have been second-generation stents.

The decision to stop DAPT in a patient at high risk of bleeding requires a careful assessment of the risks and benefits. Risk factors for bleeding include advanced age, history of major bleeding, anticoagulation, chronic kidney disease (serum creatinine level ≥ 2 mg/dL), platelet count 100 × 10⁹/L or lower, and history of stroke.¹¹

• Age 75 or older: −2 points
• Ages 65 to 74: −1
• Age under 65: 0
• Diabetes mellitus: 1
• Myocardial infarction at presentation: 1
• History of percutaneous coronary intervention or myocardial infarction: 1
• Stent diameter less than 3 mm: 1
• Paclitaxel drug-eluting stent: 1
• Current smoker: 2
• Percutaneous coronary intervention with saphenous vein graft: 2
• Congestive heart failure or left ventricular ejection fraction less than 30%: 2.

A score of 2 or greater favors continuing DAPT, as it indicates higher ischemic risk. A score less than 2 favors discontinuing DAPT, as it indicates higher bleeding risk.^1,2

IF BLEEDING RISK IS HIGH

Preventing and controlling bleeding associated with DAPT is important. The gastrointestinal tract is the most common site of bleeding.

Aspirin inhibits prostaglandin synthesis, leading to disruption of the protective mucous membrane. Therefore, a proton pump inhibitor should be started along with DAPT in patients at high risk of gastrointestinal bleeding.

If a patient’s bleeding risk significantly outweighs the risk of stent thrombosis, or if active hemorrhage makes a patient hemodynamically unstable, antiplatelet therapy must be stopped.¹

FACING SURGERY

For patients with a drug-eluting stent who are on DAPT and are to undergo elective noncardiac surgery, 3 considerations must be kept in mind:

• The risk of stent thrombosis if DAPT needs to be interrupted
• The consequences of delaying the surgical procedure
• The risk and consequences of periprocedural and intraprocedural bleeding if DAPT is continued.

Because clinical evidence for bridging therapy with intravenous antiplatelet or anticoagulant agents is limited, it is difficult to make recommendations about stopping DAPT. However, once bleeding risk is stabilized, DAPT should be restarted as soon as possible.¹

CURRENT RESEARCH

Several trials are under way to further evaluate ways to minimize bleeding risk and shorten the duration of DAPT.

A prospective multicenter trial is evaluating 3-month DAPT in patients at high bleeding risk who undergo placement of an everolimus-eluting stent.¹¹ This study is expected to be completed in August 2019.

Another strategy for patients at high bleeding risk is use of a polymer-free drug-coated coronary stent. In a 2015 trial comparing a biolimus A9-coated stent vs a bare-metal stent, patients received DAPT for 1 month after stent placement. The drug-coated stent was found to be superior in terms of the primary safety end point (cardiac death, myocardial infarction, or stent thrombosis).¹² This stent is not yet approved by the US Food and Drug Administration at the time of this writing.

Further study is needed to evaluate DAPT durations of less than 3 months and to establish the proper timing for safely discontinuing DAPT in difficult clinical scenarios.

WHEN STOPPING MAY BE REASONABLE

According to current guidelines, in patients at high bleeding risk with a second-generation or newer drug-eluting stent for stable ischemic heart disease, discontinuing DAPT 3 months after stent placement may be reasonable.¹ The decision to stop DAPT in these patients requires a careful assessment of the risks and benefits and may be aided by a tool such as the DAPT risk score. However, these recommendations cannot be extrapolated to patients with an acute coronary syndrome within the past year, as they are at higher risk.

TAKE-HOME MESSAGES

• A cardiologist should be consulted before discontinuing DAPT in patients with a drug-eluting stent, especially if the stent was recently placed.
• The duration of therapy depends on the indication for stent placement (stable ischemic heart disease vs acute coronary syndrome) and on stent location.
• Based on the 2016 American College of Cardiology/American Heart Association guidelines,¹ in patients at high bleeding risk with a second-generation drug-eluting stent, discontinuing DAPT is safe after 3 months in patients with stable ischemic heart disease, and after 6 months in patients with an acute coronary syndrome.
• When prescribing DAPT, available evidence favors clopidogrel in patients with stable ischemic heart disease who have a second-generation drug-eluting stent and are at high bleeding risk.
• In these patients, the risk-benefit ratio based on the DAPT score may be useful when considering stopping clopidogrel.       

Stopping dual antiplatelet therapy (DAPT) (eg, clopidogrel plus aspirin) after 3 months is reasonable in patients with stable ischemic heart disease who have a second-generation drug-eluting stent and a high bleeding risk, with stable ischemic disease defined as at least 1 year free of acute coronary syndromes. However, these patients should continue lifelong aspirin monotherapy. Current guidelines suggest that in stable ischemic disease, the risk-benefit ratio may favor an even shorter duration of DAPT than the 6 months currently recommended.¹

STABLE ISCHEMIC HEART DISEASE VS ACUTE CORONARY SYNDROME

Percutaneous coronary intervention for stable ischemic heart disease is indicated primarily in patients with angina that persists despite optimal antianginal therapy.

The prognostic implications of DAPT are different in stable ischemic disease than in acute coronary syndromes. The substrate treated by percutaneous intervention in stable ischemic disease is primarily fibrofatty plaque, as opposed to thrombus in acute coronary syndromes.

Percutaneous intervention significantly improves the prognosis in acute coronary syndromes, whereas its impact on overall survival in stable ischemic heart disease is not well documented. Given these differences, our discussion about DAPT in stable ischemic disease cannot be extrapolated to acute coronary syndromes.

BENEFITS OF DAPT

DAPT is mandatory early after drug-eluting stent placement, when the stent continuously releases medication, inhibiting tissue growth within the lumen of the stent.

Endothelialization of the stent normally occurs during the first 7 to 30 days after placement. During this period, the nonendothelialized stent poses a risk of thrombosis, a life-threatening, catastrophic condition with a mortality rate between 9% and 45%.¹

THERAPY BEYOND 12 MONTHS

Although guidelines have traditionally recommended 12 months of DAPT, the optimal duration is still debated.

A duration beyond 12 months in patients with a history of myocardial infarction was shown to be reasonable in 2 large trials,^2,3 while a 2016 review by Bittl et al⁴ suggested that therapy beyond 12 months in patients with a newer-generation drug-eluting stent could increase the incidence of major bleeding. A detailed discussion of DAPT longer than 12 months is beyond the scope of this article.

EVIDENCE FOR SHORTER DURATION

The results of 5 major trials support shorter duration of DAPT in stable ischemic disease.

The OPTIMIZE⁵ and RESET⁶ trials found that 3 months of DAPT was not inferior to 12 months in terms of ischemic and safety end points.

The ISAR-SAFE,⁷ EXCELLENT,⁸ and SECURITY⁹ trials also reported that 6 months of DAPT was not inferior to 12 months for the primary composite end point of death, stent thrombosis, myocardial infarction, stroke, or major bleeding.

However, these trials may have been underpowered to detect a difference in rates of stent thrombosis with shorter-duration DAPT.

CURRENT GUIDELINES

For patients at high bleeding risk, the current guidelines of the American College of Cardiology and American Heart Association, updated in 2016, suggest that it may be reasonable to discontinue DAPT 3 months after drug-eluting stent placement in patients with stable ischemic heart disease, and at 6 months in patients with acute coronary syndrome (class IIb recommendation, level of evidence C).¹ These recommendations are based on results of randomized controlled trials showing no difference in the rate of stent thrombosis and composite ischemic events with a shorter duration than with 12 months of therapy.^5–10

The evidence for DAPT in stable ischemic disease is based on clopidogrel, with only limited data on ticagrelor.¹ To our knowledge, no study to date has evaluated DAPT in this setting for less than 3 months, and further study is needed to address shorter-duration approaches with current-generation drug-eluting stents Since 2017, all coronary stents implanted in the United States have been second-generation stents.

The decision to stop DAPT in a patient at high risk of bleeding requires a careful assessment of the risks and benefits. Risk factors for bleeding include advanced age, history of major bleeding, anticoagulation, chronic kidney disease (serum creatinine level ≥ 2 mg/dL), platelet count 100 × 10⁹/L or lower, and history of stroke.¹¹

• Age 75 or older: −2 points
• Ages 65 to 74: −1
• Age under 65: 0
• Diabetes mellitus: 1
• Myocardial infarction at presentation: 1
• History of percutaneous coronary intervention or myocardial infarction: 1
• Stent diameter less than 3 mm: 1
• Paclitaxel drug-eluting stent: 1
• Current smoker: 2
• Percutaneous coronary intervention with saphenous vein graft: 2
• Congestive heart failure or left ventricular ejection fraction less than 30%: 2.

A score of 2 or greater favors continuing DAPT, as it indicates higher ischemic risk. A score less than 2 favors discontinuing DAPT, as it indicates higher bleeding risk.^1,2

IF BLEEDING RISK IS HIGH

Preventing and controlling bleeding associated with DAPT is important. The gastrointestinal tract is the most common site of bleeding.

Aspirin inhibits prostaglandin synthesis, leading to disruption of the protective mucous membrane. Therefore, a proton pump inhibitor should be started along with DAPT in patients at high risk of gastrointestinal bleeding.

If a patient’s bleeding risk significantly outweighs the risk of stent thrombosis, or if active hemorrhage makes a patient hemodynamically unstable, antiplatelet therapy must be stopped.¹

FACING SURGERY

For patients with a drug-eluting stent who are on DAPT and are to undergo elective noncardiac surgery, 3 considerations must be kept in mind:

• The risk of stent thrombosis if DAPT needs to be interrupted
• The consequences of delaying the surgical procedure
• The risk and consequences of periprocedural and intraprocedural bleeding if DAPT is continued.

Because clinical evidence for bridging therapy with intravenous antiplatelet or anticoagulant agents is limited, it is difficult to make recommendations about stopping DAPT. However, once bleeding risk is stabilized, DAPT should be restarted as soon as possible.¹

CURRENT RESEARCH

Several trials are under way to further evaluate ways to minimize bleeding risk and shorten the duration of DAPT.

A prospective multicenter trial is evaluating 3-month DAPT in patients at high bleeding risk who undergo placement of an everolimus-eluting stent.¹¹ This study is expected to be completed in August 2019.

Another strategy for patients at high bleeding risk is use of a polymer-free drug-coated coronary stent. In a 2015 trial comparing a biolimus A9-coated stent vs a bare-metal stent, patients received DAPT for 1 month after stent placement. The drug-coated stent was found to be superior in terms of the primary safety end point (cardiac death, myocardial infarction, or stent thrombosis).¹² This stent is not yet approved by the US Food and Drug Administration at the time of this writing.

Further study is needed to evaluate DAPT durations of less than 3 months and to establish the proper timing for safely discontinuing DAPT in difficult clinical scenarios.

WHEN STOPPING MAY BE REASONABLE

According to current guidelines, in patients at high bleeding risk with a second-generation or newer drug-eluting stent for stable ischemic heart disease, discontinuing DAPT 3 months after stent placement may be reasonable.¹ The decision to stop DAPT in these patients requires a careful assessment of the risks and benefits and may be aided by a tool such as the DAPT risk score. However, these recommendations cannot be extrapolated to patients with an acute coronary syndrome within the past year, as they are at higher risk.

TAKE-HOME MESSAGES

• A cardiologist should be consulted before discontinuing DAPT in patients with a drug-eluting stent, especially if the stent was recently placed.
• The duration of therapy depends on the indication for stent placement (stable ischemic heart disease vs acute coronary syndrome) and on stent location.
• Based on the 2016 American College of Cardiology/American Heart Association guidelines,¹ in patients at high bleeding risk with a second-generation drug-eluting stent, discontinuing DAPT is safe after 3 months in patients with stable ischemic heart disease, and after 6 months in patients with an acute coronary syndrome.
• When prescribing DAPT, available evidence favors clopidogrel in patients with stable ischemic heart disease who have a second-generation drug-eluting stent and are at high bleeding risk.
• In these patients, the risk-benefit ratio based on the DAPT score may be useful when considering stopping clopidogrel.       

Most patients should receive it, with exceptions as noted below. Metformin is the cornerstone of diabetes therapy and should be considered in all patients with type 2 diabetes. Both the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists (AACE)^1,2 recommend it as first-line treatment for type 2 diabetes. It lowers blood glucose levels by inhibiting hepatic glucose production, and it does not tend to cause hypoglycemia.

However, metformin is underused. A 2012 study showed that only 50% to 70% of patients with type 2 diabetes treated with a sulfonylurea, dipeptidyl peptidase-4 (DPP-4) inhibitor, thiazolidinedione, or glucagon-like peptide-1 analogue also received metformin.³ This occurred despite guidelines recommending continuing metformin when starting other diabetes drugs.⁴

EVIDENCE METFORMIN IS EFFECTIVE

The United Kingdom Prospective Diabetes Study (UKPDS)⁵ found that metformin significantly reduced the incidence of:

• Any diabetes-related end point (hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.53–0.87)
• Myocardial infarction (HR 0.61, 95% CI 0.41–0.89)
• Diabetes-related death (HR 0.58, 95% CI 0.37–0.91)
• All-cause mortality (HR 0.64; 95% CI 0.45–0.91).

The Hyperinsulinemia: Outcomes of Its Metabolic Effects (HOME) trial,⁶ a multicenter trial conducted in the Netherlands, evaluated the effect of adding  metformin (vs placebo) to existing insulin regimens. Metformin recipients had a significantly lower rate of macrovascular mortality (HR 0.61, 95% CI 0.40–0.94, P = .02), but not of the primary end point, an aggregate of microvascular and macrovascular morbidity and mortality.

The Study on the Prognosis and Effect of Antidiabetic Drugs on Type 2 Diabetes Mellitus With Coronary Artery Disease trial,⁷ a multicenter trial conducted in China, compared the effects of metformin vs glipizide on cardiovascular outcomes. At about 3 years of treatment, the metformin group had a significantly lower rate of the composite primary end point of recurrent cardiovascular events (HR 0.54, 95% CI 0.30–0.90). This end point included nonfatal myocardial infarction, nonfatal stroke, arterial revascularization by percutaneous transluminal coronary angioplasty or by coronary artery bypass graft, death from a cardiovascular cause, and death from any cause.

These studies prompted the ADA to emphasize that metformin can reduce the risk of cardiovascular events or death. Metformin also has been shown to be weight-neutral or to induce slight weight loss. Furthermore, it is inexpensive.

WHAT ABOUT THE RENAL EFFECTS?

Because metformin is renally cleared, it has caused some concern about nephrotoxicity, especially lactic acidosis, in patients with impaired renal function. But the most recent guidelines have relaxed the criteria for metformin use in this patient population.

Revised labeling

Metformin’s labeling,⁸ revised in 2016, states the following:

• If the estimated glomerular filtration rate (eGFR) is below 30 mL/min/1.73 m², metformin is contraindicated
• If the eGFR is between 30 and 45 mL/min/1.73 m², metformin is not recommended
• If the eGFR is below 45 mL/min/1.73 m² in a patient taking metformin, the risks and benefits of continuing treatment should be assessed, the dosage may need to be adjusted, and renal function should be monitored more frequently.⁸

These labeling revisions were based on a systematic review by Inzucchi et al⁹ that found metformin is not associated with increased rates of lactic acidosis in patients with mild to moderate kidney disease. Subsequently, an observational study published in 2018 by Lazarus et al¹⁰ showed that metformin increases the risk of acidosis only at eGFR levels below 30 mL/min/1.73 m². Also, a Cochrane review published in 2003 did not find a single case of lactic acidosis in 347 trials with 70,490 patient-years of metformin treatment.¹¹

Previous guidelines used serum creatinine levels, with metformin contraindicated at levels of 1.5 mg/dL or above for men and 1.4 mg/dL for women, or with abnormal creatinine clearance. The ADA and the AACE now use the eGFR^1,2 instead of the serum creatinine level to measure kidney function because it better accounts for factors such as the patient’s age, sex, race, and weight.

Despite the evidence, the common patient perception is that metformin is nephrotoxic, and it is important for practitioners to dispel this myth during clinic visits.

What about metformin use with contrast agents?

Labeling has a precautionary note stating that metformin should be held at the time of, or prior to, any imaging procedure involving iodinated contrast agents in patients with an eGFR between 30 and 60 mL/min/1.73 m²; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will receive intra-arterial iodinated contrast. The eGFR should be reevaluated 48 hours after the imaging procedure.⁸

Additionally, if the iodinated contrast agent causes acute kidney injury, metformin could accumulate, with resultant lactate accumulation.

The American College of Radiology (ACR) has proposed less stringent guidelines for metformin during radiocontrast imaging studies. This change is based on evidence that lactic acidosis is rare­—about 10 cases per 100,000 patient-years—and that there are no reports of lactic acidosis after intravenously administered iodinated contrast in properly selected patients.^12,13

The ACR divides patients taking metformin into 2 categories:

• No evidence of acute kidney injury and eGFR greater than 30 mL/min/1.73 m²
• Either acute kidney injury or chronic kidney disease with eGFR below 30 mL/min/1.73 m² or undergoing arterial catheter studies with a high chance of embolization to the renal arteries.¹⁴

For the first group, they recommend against discontinuing metformin before or after giving iodinated contrast or checking kidney function after the procedure.

For the second group, they recommend holding metformin before and 48 hours after the procedure. It should not be restarted until renal function is confirmed to be normal.

The ADA recommends¹ continuing metformin after initiating insulin. However, in clinical practice, it is often not done.

Clinical trials have shown that combining metformin with insulin significantly improves glycemic control, prevents weight gain, and decreases insulin requirements.^15,16 One trial¹⁶ also looked at cardiovascular end points during a 4-year follow-up period;  combining metformin with insulin decreased the macrovascular disease-related event rate compared with insulin alone.

In the HOME trial,⁶ which added metformin to the existing insulin regimen, both groups gained weight, but the metformin group had gained about 3 kg less than the placebo group at the end of the 4.3-year trial. Metformin did not increase the risk of hypoglycemia, but it also did not reduce the risk of microvascular disease.

Concomitant metformin reduces costs

These days, practitioners can choose from a large selection of diabetes drugs. These include insulins with better pharmacokinetic profiles, as well as newer classes of noninsulin agents such as sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 analogues.

Metformin is less expensive than these newer drugs, and using it concomitantly with other diabetes drugs can decrease their dosage requirements, which in turn decreases their monthly costs.

GASTROINTESTINAL EFFECTS

Metformin’s gastrointestinal adverse effects such as diarrhea, flatulence, nausea, and vomiting are a barrier to its use. The actual incidence rate of diarrhea varies widely in randomized trials and observational studies, and gastrointestinal effects are worse in metformin-naive patients, as well as those who have chronic gastritis or Helicobacter pylori infection.¹⁷

We have found that starting metformin at a low dose and up-titrating it over several weeks increases tolerability. We often start patients at 500 mg/day and increase the dosage by 1 500-mg tablet every 1 to 2 weeks. Also, we have noticed that intolerance is more likely in patients who eat a high-carbohydrate diet, but there is no high-level evidence to back this up because patients in clinical trials all undergo nutrition counseling and are therefore more likely to adhere to the low-carbohydrate diet.

Also, the extended-release formulation is more tolerable than the immediate-release formulation and has similar glycemic efficacy. It may be an option as first-line therapy or for patients who have significant adverse effects from immediate-release metformin.¹⁸ For patients on the immediate-release formulation, taking it with meals helps lessen some gastrointestinal effects, and this should be emphasized at every visit.

Finally, we limit the metformin dose to 2,000 mg/day, rather than the 2,550 mg/day allowed on labeling. Garber et al¹⁹ found that the lower dosage still provides the maximum clinical efficacy.

OTHER CAUTIONS

Metformin should be avoided in patients with acute or unstable heart failure because of the increased risk of lactic acidosis.

It also should be avoided in patients with hepatic impairment, according to the labeling. But this remains controversial in practice. Zhang et al²⁰ showed that continuing metformin in patients with diabetes and cirrhosis decreases the mortality risk by 57% compared with those taken off metformin.

Diet and lifestyle measures need to be emphasized at each visit. Wing et al²¹ showed that calorie restriction regardless of weight loss is beneficial for glycemic control and insulin sensitivity in obese patients with diabetes.

TAKE-HOME POINTS

Metformin improves glycemic control without tending to cause weight gain or hypoglycemia. It may also have cardiovascular benefits. Metformin is an inexpensive agent that should be continued, if tolerated, in those who need additional agents for glycemic control. It should be considered in all adult patients with type 2 diabetes.   

Most patients should receive it, with exceptions as noted below. Metformin is the cornerstone of diabetes therapy and should be considered in all patients with type 2 diabetes. Both the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists (AACE)^1,2 recommend it as first-line treatment for type 2 diabetes. It lowers blood glucose levels by inhibiting hepatic glucose production, and it does not tend to cause hypoglycemia.

However, metformin is underused. A 2012 study showed that only 50% to 70% of patients with type 2 diabetes treated with a sulfonylurea, dipeptidyl peptidase-4 (DPP-4) inhibitor, thiazolidinedione, or glucagon-like peptide-1 analogue also received metformin.³ This occurred despite guidelines recommending continuing metformin when starting other diabetes drugs.⁴

EVIDENCE METFORMIN IS EFFECTIVE

The United Kingdom Prospective Diabetes Study (UKPDS)⁵ found that metformin significantly reduced the incidence of:

• Any diabetes-related end point (hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.53–0.87)
• Myocardial infarction (HR 0.61, 95% CI 0.41–0.89)
• Diabetes-related death (HR 0.58, 95% CI 0.37–0.91)
• All-cause mortality (HR 0.64; 95% CI 0.45–0.91).

The Hyperinsulinemia: Outcomes of Its Metabolic Effects (HOME) trial,⁶ a multicenter trial conducted in the Netherlands, evaluated the effect of adding  metformin (vs placebo) to existing insulin regimens. Metformin recipients had a significantly lower rate of macrovascular mortality (HR 0.61, 95% CI 0.40–0.94, P = .02), but not of the primary end point, an aggregate of microvascular and macrovascular morbidity and mortality.

The Study on the Prognosis and Effect of Antidiabetic Drugs on Type 2 Diabetes Mellitus With Coronary Artery Disease trial,⁷ a multicenter trial conducted in China, compared the effects of metformin vs glipizide on cardiovascular outcomes. At about 3 years of treatment, the metformin group had a significantly lower rate of the composite primary end point of recurrent cardiovascular events (HR 0.54, 95% CI 0.30–0.90). This end point included nonfatal myocardial infarction, nonfatal stroke, arterial revascularization by percutaneous transluminal coronary angioplasty or by coronary artery bypass graft, death from a cardiovascular cause, and death from any cause.

These studies prompted the ADA to emphasize that metformin can reduce the risk of cardiovascular events or death. Metformin also has been shown to be weight-neutral or to induce slight weight loss. Furthermore, it is inexpensive.

WHAT ABOUT THE RENAL EFFECTS?

Because metformin is renally cleared, it has caused some concern about nephrotoxicity, especially lactic acidosis, in patients with impaired renal function. But the most recent guidelines have relaxed the criteria for metformin use in this patient population.

Revised labeling

Metformin’s labeling,⁸ revised in 2016, states the following:

• If the estimated glomerular filtration rate (eGFR) is below 30 mL/min/1.73 m², metformin is contraindicated
• If the eGFR is between 30 and 45 mL/min/1.73 m², metformin is not recommended
• If the eGFR is below 45 mL/min/1.73 m² in a patient taking metformin, the risks and benefits of continuing treatment should be assessed, the dosage may need to be adjusted, and renal function should be monitored more frequently.⁸

These labeling revisions were based on a systematic review by Inzucchi et al⁹ that found metformin is not associated with increased rates of lactic acidosis in patients with mild to moderate kidney disease. Subsequently, an observational study published in 2018 by Lazarus et al¹⁰ showed that metformin increases the risk of acidosis only at eGFR levels below 30 mL/min/1.73 m². Also, a Cochrane review published in 2003 did not find a single case of lactic acidosis in 347 trials with 70,490 patient-years of metformin treatment.¹¹

Previous guidelines used serum creatinine levels, with metformin contraindicated at levels of 1.5 mg/dL or above for men and 1.4 mg/dL for women, or with abnormal creatinine clearance. The ADA and the AACE now use the eGFR^1,2 instead of the serum creatinine level to measure kidney function because it better accounts for factors such as the patient’s age, sex, race, and weight.

Despite the evidence, the common patient perception is that metformin is nephrotoxic, and it is important for practitioners to dispel this myth during clinic visits.

What about metformin use with contrast agents?

Labeling has a precautionary note stating that metformin should be held at the time of, or prior to, any imaging procedure involving iodinated contrast agents in patients with an eGFR between 30 and 60 mL/min/1.73 m²; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will receive intra-arterial iodinated contrast. The eGFR should be reevaluated 48 hours after the imaging procedure.⁸

Additionally, if the iodinated contrast agent causes acute kidney injury, metformin could accumulate, with resultant lactate accumulation.

The American College of Radiology (ACR) has proposed less stringent guidelines for metformin during radiocontrast imaging studies. This change is based on evidence that lactic acidosis is rare­—about 10 cases per 100,000 patient-years—and that there are no reports of lactic acidosis after intravenously administered iodinated contrast in properly selected patients.^12,13

The ACR divides patients taking metformin into 2 categories:

• No evidence of acute kidney injury and eGFR greater than 30 mL/min/1.73 m²
• Either acute kidney injury or chronic kidney disease with eGFR below 30 mL/min/1.73 m² or undergoing arterial catheter studies with a high chance of embolization to the renal arteries.¹⁴

For the first group, they recommend against discontinuing metformin before or after giving iodinated contrast or checking kidney function after the procedure.

For the second group, they recommend holding metformin before and 48 hours after the procedure. It should not be restarted until renal function is confirmed to be normal.

The ADA recommends¹ continuing metformin after initiating insulin. However, in clinical practice, it is often not done.

Clinical trials have shown that combining metformin with insulin significantly improves glycemic control, prevents weight gain, and decreases insulin requirements.^15,16 One trial¹⁶ also looked at cardiovascular end points during a 4-year follow-up period;  combining metformin with insulin decreased the macrovascular disease-related event rate compared with insulin alone.

In the HOME trial,⁶ which added metformin to the existing insulin regimen, both groups gained weight, but the metformin group had gained about 3 kg less than the placebo group at the end of the 4.3-year trial. Metformin did not increase the risk of hypoglycemia, but it also did not reduce the risk of microvascular disease.

Concomitant metformin reduces costs

These days, practitioners can choose from a large selection of diabetes drugs. These include insulins with better pharmacokinetic profiles, as well as newer classes of noninsulin agents such as sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 analogues.

Metformin is less expensive than these newer drugs, and using it concomitantly with other diabetes drugs can decrease their dosage requirements, which in turn decreases their monthly costs.

GASTROINTESTINAL EFFECTS

Metformin’s gastrointestinal adverse effects such as diarrhea, flatulence, nausea, and vomiting are a barrier to its use. The actual incidence rate of diarrhea varies widely in randomized trials and observational studies, and gastrointestinal effects are worse in metformin-naive patients, as well as those who have chronic gastritis or Helicobacter pylori infection.¹⁷

We have found that starting metformin at a low dose and up-titrating it over several weeks increases tolerability. We often start patients at 500 mg/day and increase the dosage by 1 500-mg tablet every 1 to 2 weeks. Also, we have noticed that intolerance is more likely in patients who eat a high-carbohydrate diet, but there is no high-level evidence to back this up because patients in clinical trials all undergo nutrition counseling and are therefore more likely to adhere to the low-carbohydrate diet.

Also, the extended-release formulation is more tolerable than the immediate-release formulation and has similar glycemic efficacy. It may be an option as first-line therapy or for patients who have significant adverse effects from immediate-release metformin.¹⁸ For patients on the immediate-release formulation, taking it with meals helps lessen some gastrointestinal effects, and this should be emphasized at every visit.

Finally, we limit the metformin dose to 2,000 mg/day, rather than the 2,550 mg/day allowed on labeling. Garber et al¹⁹ found that the lower dosage still provides the maximum clinical efficacy.

OTHER CAUTIONS

Metformin should be avoided in patients with acute or unstable heart failure because of the increased risk of lactic acidosis.

It also should be avoided in patients with hepatic impairment, according to the labeling. But this remains controversial in practice. Zhang et al²⁰ showed that continuing metformin in patients with diabetes and cirrhosis decreases the mortality risk by 57% compared with those taken off metformin.

Diet and lifestyle measures need to be emphasized at each visit. Wing et al²¹ showed that calorie restriction regardless of weight loss is beneficial for glycemic control and insulin sensitivity in obese patients with diabetes.

TAKE-HOME POINTS

Metformin improves glycemic control without tending to cause weight gain or hypoglycemia. It may also have cardiovascular benefits. Metformin is an inexpensive agent that should be continued, if tolerated, in those who need additional agents for glycemic control. It should be considered in all adult patients with type 2 diabetes.   

Most patients should receive it, with exceptions as noted below. Metformin is the cornerstone of diabetes therapy and should be considered in all patients with type 2 diabetes. Both the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists (AACE)^1,2 recommend it as first-line treatment for type 2 diabetes. It lowers blood glucose levels by inhibiting hepatic glucose production, and it does not tend to cause hypoglycemia.

However, metformin is underused. A 2012 study showed that only 50% to 70% of patients with type 2 diabetes treated with a sulfonylurea, dipeptidyl peptidase-4 (DPP-4) inhibitor, thiazolidinedione, or glucagon-like peptide-1 analogue also received metformin.³ This occurred despite guidelines recommending continuing metformin when starting other diabetes drugs.⁴

EVIDENCE METFORMIN IS EFFECTIVE

The United Kingdom Prospective Diabetes Study (UKPDS)⁵ found that metformin significantly reduced the incidence of:

• Any diabetes-related end point (hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.53–0.87)
• Myocardial infarction (HR 0.61, 95% CI 0.41–0.89)
• Diabetes-related death (HR 0.58, 95% CI 0.37–0.91)
• All-cause mortality (HR 0.64; 95% CI 0.45–0.91).

The Hyperinsulinemia: Outcomes of Its Metabolic Effects (HOME) trial,⁶ a multicenter trial conducted in the Netherlands, evaluated the effect of adding  metformin (vs placebo) to existing insulin regimens. Metformin recipients had a significantly lower rate of macrovascular mortality (HR 0.61, 95% CI 0.40–0.94, P = .02), but not of the primary end point, an aggregate of microvascular and macrovascular morbidity and mortality.

The Study on the Prognosis and Effect of Antidiabetic Drugs on Type 2 Diabetes Mellitus With Coronary Artery Disease trial,⁷ a multicenter trial conducted in China, compared the effects of metformin vs glipizide on cardiovascular outcomes. At about 3 years of treatment, the metformin group had a significantly lower rate of the composite primary end point of recurrent cardiovascular events (HR 0.54, 95% CI 0.30–0.90). This end point included nonfatal myocardial infarction, nonfatal stroke, arterial revascularization by percutaneous transluminal coronary angioplasty or by coronary artery bypass graft, death from a cardiovascular cause, and death from any cause.

These studies prompted the ADA to emphasize that metformin can reduce the risk of cardiovascular events or death. Metformin also has been shown to be weight-neutral or to induce slight weight loss. Furthermore, it is inexpensive.

WHAT ABOUT THE RENAL EFFECTS?

Because metformin is renally cleared, it has caused some concern about nephrotoxicity, especially lactic acidosis, in patients with impaired renal function. But the most recent guidelines have relaxed the criteria for metformin use in this patient population.

Revised labeling

Metformin’s labeling,⁸ revised in 2016, states the following:

• If the estimated glomerular filtration rate (eGFR) is below 30 mL/min/1.73 m², metformin is contraindicated
• If the eGFR is between 30 and 45 mL/min/1.73 m², metformin is not recommended
• If the eGFR is below 45 mL/min/1.73 m² in a patient taking metformin, the risks and benefits of continuing treatment should be assessed, the dosage may need to be adjusted, and renal function should be monitored more frequently.⁸

These labeling revisions were based on a systematic review by Inzucchi et al⁹ that found metformin is not associated with increased rates of lactic acidosis in patients with mild to moderate kidney disease. Subsequently, an observational study published in 2018 by Lazarus et al¹⁰ showed that metformin increases the risk of acidosis only at eGFR levels below 30 mL/min/1.73 m². Also, a Cochrane review published in 2003 did not find a single case of lactic acidosis in 347 trials with 70,490 patient-years of metformin treatment.¹¹

Previous guidelines used serum creatinine levels, with metformin contraindicated at levels of 1.5 mg/dL or above for men and 1.4 mg/dL for women, or with abnormal creatinine clearance. The ADA and the AACE now use the eGFR^1,2 instead of the serum creatinine level to measure kidney function because it better accounts for factors such as the patient’s age, sex, race, and weight.

Despite the evidence, the common patient perception is that metformin is nephrotoxic, and it is important for practitioners to dispel this myth during clinic visits.

What about metformin use with contrast agents?

Labeling has a precautionary note stating that metformin should be held at the time of, or prior to, any imaging procedure involving iodinated contrast agents in patients with an eGFR between 30 and 60 mL/min/1.73 m²; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will receive intra-arterial iodinated contrast. The eGFR should be reevaluated 48 hours after the imaging procedure.⁸

Additionally, if the iodinated contrast agent causes acute kidney injury, metformin could accumulate, with resultant lactate accumulation.

The American College of Radiology (ACR) has proposed less stringent guidelines for metformin during radiocontrast imaging studies. This change is based on evidence that lactic acidosis is rare­—about 10 cases per 100,000 patient-years—and that there are no reports of lactic acidosis after intravenously administered iodinated contrast in properly selected patients.^12,13

The ACR divides patients taking metformin into 2 categories:

• No evidence of acute kidney injury and eGFR greater than 30 mL/min/1.73 m²
• Either acute kidney injury or chronic kidney disease with eGFR below 30 mL/min/1.73 m² or undergoing arterial catheter studies with a high chance of embolization to the renal arteries.¹⁴

For the first group, they recommend against discontinuing metformin before or after giving iodinated contrast or checking kidney function after the procedure.

For the second group, they recommend holding metformin before and 48 hours after the procedure. It should not be restarted until renal function is confirmed to be normal.

The ADA recommends¹ continuing metformin after initiating insulin. However, in clinical practice, it is often not done.

Clinical trials have shown that combining metformin with insulin significantly improves glycemic control, prevents weight gain, and decreases insulin requirements.^15,16 One trial¹⁶ also looked at cardiovascular end points during a 4-year follow-up period;  combining metformin with insulin decreased the macrovascular disease-related event rate compared with insulin alone.

In the HOME trial,⁶ which added metformin to the existing insulin regimen, both groups gained weight, but the metformin group had gained about 3 kg less than the placebo group at the end of the 4.3-year trial. Metformin did not increase the risk of hypoglycemia, but it also did not reduce the risk of microvascular disease.

Concomitant metformin reduces costs

These days, practitioners can choose from a large selection of diabetes drugs. These include insulins with better pharmacokinetic profiles, as well as newer classes of noninsulin agents such as sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 analogues.

Metformin is less expensive than these newer drugs, and using it concomitantly with other diabetes drugs can decrease their dosage requirements, which in turn decreases their monthly costs.

GASTROINTESTINAL EFFECTS

Metformin’s gastrointestinal adverse effects such as diarrhea, flatulence, nausea, and vomiting are a barrier to its use. The actual incidence rate of diarrhea varies widely in randomized trials and observational studies, and gastrointestinal effects are worse in metformin-naive patients, as well as those who have chronic gastritis or Helicobacter pylori infection.¹⁷

We have found that starting metformin at a low dose and up-titrating it over several weeks increases tolerability. We often start patients at 500 mg/day and increase the dosage by 1 500-mg tablet every 1 to 2 weeks. Also, we have noticed that intolerance is more likely in patients who eat a high-carbohydrate diet, but there is no high-level evidence to back this up because patients in clinical trials all undergo nutrition counseling and are therefore more likely to adhere to the low-carbohydrate diet.

Also, the extended-release formulation is more tolerable than the immediate-release formulation and has similar glycemic efficacy. It may be an option as first-line therapy or for patients who have significant adverse effects from immediate-release metformin.¹⁸ For patients on the immediate-release formulation, taking it with meals helps lessen some gastrointestinal effects, and this should be emphasized at every visit.

Finally, we limit the metformin dose to 2,000 mg/day, rather than the 2,550 mg/day allowed on labeling. Garber et al¹⁹ found that the lower dosage still provides the maximum clinical efficacy.

OTHER CAUTIONS

Metformin should be avoided in patients with acute or unstable heart failure because of the increased risk of lactic acidosis.

It also should be avoided in patients with hepatic impairment, according to the labeling. But this remains controversial in practice. Zhang et al²⁰ showed that continuing metformin in patients with diabetes and cirrhosis decreases the mortality risk by 57% compared with those taken off metformin.

Diet and lifestyle measures need to be emphasized at each visit. Wing et al²¹ showed that calorie restriction regardless of weight loss is beneficial for glycemic control and insulin sensitivity in obese patients with diabetes.

TAKE-HOME POINTS

Metformin improves glycemic control without tending to cause weight gain or hypoglycemia. It may also have cardiovascular benefits. Metformin is an inexpensive agent that should be continued, if tolerated, in those who need additional agents for glycemic control. It should be considered in all adult patients with type 2 diabetes.   

A 33-year-old male nonsmoker with no significant medical history presented to the pulmonary clinic with severe left-sided pleuritic chest pain and mild breathlessness for the past 5 days. He denied fever, chills, cough, phlegm, runny nose, or congestion.

Five days before this visit, he had been seen in the emergency department with mild left-sided pleuritic chest pain. His vital signs at that time had been as follows:

• Blood pressure 141/77 mm Hg
• Heart rate 77 beats/minute
• Respiratory rate 17 breaths/minute
• Temperature 36.8°C (98.2°F)
• Oxygen saturation 98% on room air.

• White blood cell count 6.89 × 10⁹/L (reference range 3.70–11.00)
• Neutrophils 58% (40%–70%)
• Lymphocytes 29.6% (22%–44%)
• Monocytes 10.7% (0–11%)
• Eosinophils 1% (0–4%)
• Basophils 0.6% (0–1%)
• Troponin T and D-dimer levels normal.

DIFFERENTIAL DIAGNOSIS OF PLEURITIC CHEST PAIN

1. What is the most likely cause of his pleuritic chest pain?

• Pleuritis
• Pneumonia
• Pulmonary embolism
• Malignancy

The differential diagnosis of pleuritic chest pain is broad.

The patient’s symptoms at presentation to the emergency department did not suggest an infectious process. There was no fever, cough, or phlegm, and his white blood cell count was normal. Nonetheless, pneumonia could not be ruled out, as the lung parenchyma was not normal on radiography, and the findings could have been consistent with an early or resolving infectious process.

Pulmonary embolism was a possibility, but his normal D-dimer level argued against it. Further, the patient subsequently underwent CT angiography, which ruled out pulmonary embolism.

Malignancy was unlikely in a young nonsmoker, but follow-up imaging would be needed to ensure resolution and rule this out.

The emergency department physician diagnosed inflammatory pleuritis and discharged him home on a nonsteroidal anti-inflammatory drug.

CLINIC VISIT 5 DAYS LATER

At his pulmonary clinic visit 5 days later, the patient reported persistent but stable left-sided pleuritic chest pain and mild breathlessness on exertion. His blood pressure was 137/81 mm Hg, heart rate 109 beats per minute, temperature 37.1°C (98.8°F), and oxygen saturation 97% on room air.

Auscultation of the lungs revealed rales and slightly decreased breath sounds at the left base. No dullness to percussion could be detected.

Because the patient had developed mild tachycardia and breathlessness along with clinical signs that suggested worsening infiltrates, consolidation, or the development of pleural effusion, he underwent further investigation with chest radiography, a complete blood cell count, and measurement of serum inflammatory markers.

• White blood cell count 13.08 × 10⁹/L
• Neutrophils 81%
• Lymphocytes 7.4%
• Monocytes 7.2%
• Eeosinophils 0.2%
• Basophils 0.2%
• Procalcitonin 0.34 µg/L (reference range < 0.09).

Bedside ultrasonography to assess the effusion’s size and characteristics and the need for thoracentesis indicated that the effusion was too small to tap, and there were no fibrinous strands or loculations to suggest empyema.

2. What was the best management strategy for this patient at this time?

• Admit to the hospital for thoracentesis and intravenous antibiotics
• Give oral antibiotics with close follow-up
• Perform thoracentesis on an outpatient basis and give oral antibiotics
• Repeat chest CT

The patient had worsening pleuritic pain with development of a small left pleural effusion. His symptoms had not improved on a nonsteroidal anti-inflammatory drug. He now had an elevated white blood cell count with a “left shift” (ie, an increase in neutrophils, indicating more immature cells in circulation) and elevated procalcitonin. The most likely diagnosis was pneumonia with a resulting pleural effusion, ie, parapneumonic effusion, requiring appropriate antibiotic therapy. Ideally, the pleural effusion should be sampled by thoracentesis, with management on an outpatient or inpatient basis.

5 DAYS LATER, THE EFFUSION HAD BECOME MASSIVE

On follow-up 5 days later, the patient’s chest pain was better, but he was significantly more short of breath. His blood pressure was 137/90 mm Hg, heart rate 117 beats/minute, respiratory rate 16 breaths/minute, oxygen saturation 97% on room air, and temperature 36.9°C (98.4°F). Chest auscultation revealed decreased breath sounds over the left hemithorax, with dullness to percussion and decreased fremitus.

RAPIDLY PROGRESSIVE PLEURAL EFFUSIONS

A rapidly progressive pleural effusion in a healthy patient suggests parapneumonic effusion. The most likely organism is streptococcal.²

Explosive pleuritis is defined as a pleural effusion that increases in size in less than 24 hours. It was first described by Braman and Donat³ in 1986 as an effusion that develops within hours of admission. In 2001, Sharma and Marrie⁴ refined the definition as rapid development of pleural effusion involving more than 90% of the hemithorax within 24 hours, causing compression of pulmonary tissue and a mediastinal shift. It is a medical emergency that requires prompt investigation and treatment with drainage and antibiotics. All reported cases of explosive pleuritis have been parapneumonic effusion.

The organisms implicated in explosive pleuritis include gram-positive cocci such as Streptococcus pneumoniae, S pyogenes, other streptococci, staphylococci, and gram-negative cocci such as Neisseria meningitidis and Moraxella catarrhalis. Gram-negative bacilli include Haemophilus influenzae, Klebsiella pneumoniae, Pseudomonas species, Escherichia coli, Proteus species, Enterobacter species, Bacteroides species, and Legionella species.^4,5 However, malignancy is the most common cause of massive pleural effusion, accounting for 54% of cases; 17% of cases are idiopathic, 13% are parapneumonic, and 12% are hydrothorax related to liver cirrhosis.⁶

CASE CONTINUED

Our patient’s massive effusion needed drainage, and he was admitted to the hospital for further management. Samples of blood and sputum were sent for culture. Intravenous piperacillin-tazobactam was started, and an intercostal chest tube was inserted into the pleural cavity under ultrasonographic guidance to drain turbid fluid.

Multiple pleural fluid samples sent for bacterial, fungal, and acid-fast bacilli culture were negative. Blood and sputum cultures also showed no growth. The administration of oral antibiotics for 5 days on an outpatient basis before pleural fluid culture could have led to sterility of all cultures.

Our patient had inadequate pleural fluid output through his chest tube, and radiography showed that the pleural collections failed to clear. In fact, an apical locule did not appear to be connecting with the lower aspect of the pleural collection. In such cases, instillation of intrapleural agents through the chest tube has become common practice in an attempt to lyse adhesions, to connect various locules or pockets of pleural fluid, and to improve drainage.

3. What was the best management strategy for this loculated empyema?

• Continue intravenous antibiotics and existing chest tube drainage for 5 to 7 days, then reassess
• Continue intravenous antibiotics and instill intrapleural fibrinolytics (eg, tissue plasminogen activator [tPA]) through the existing chest tube
• Continue intravenous antibiotics and instill intrapleural fibrinolytics with deoxyribonuclease (DNase) into the existing chest tube
• Continue intravenous antibiotics, insert a second chest tube into the apical pocket under imaging guidance, and instill tPA and DNase
• Surgical decortication

Continuing antibiotics with existing chest tube drainage and the two options of using single-agent intrapleural fibrinolytics have been shown to be less effective than combining tPA and DNase when managing a loculated empyema. As such, surgical decortication, attempting intrapleural instillation of fibrinolytics and DNase (with or without further chest tube insertion into noncommunicating locules), or both were the most appropriate options at this stage.

MANAGEMENT OF PARAPNEUMONIC PLEURAL EFFUSION IN ADULTS

There are several options for managing parapneumonic effusion, and clinicians can use the classification system in Table 1 to assess the risk of a poor outcome and to plan the management. Based on radiographic findings and pleural fluid sampling, a pleural effusion can be either observed or drained.

Options for drainage of the pleural space include repeat thoracentesis, surgical insertion of a chest tube, or image-guided insertion of a small-bore catheter. Although no randomized trial has been done to compare tube sizes, a large retrospective series showed that small-bore tubes (< 14 F) perform similarly to standard large-bore tubes.⁸ However, in another study, Keeling et al⁹ reported higher failure rates when tubes smaller than 12 F were used. Regular flushing of the chest tube (ideally twice a day) is recommended to keep it patent, particularly with small-bore tubes. Multiloculated empyema may require multiple intercostal chest tubes to drain completely, and therefore small-bore tubes are recommended.

In cases that do not improve radiographically and clinically, one must consider whether the antibiotic choice is adequate, review the position of the chest tube, and assess for loculations. As such, repeating chest CT within 24 to 48 hours of tube insertion and drainage is recommended to confirm adequate tube positioning, assess effective drainage, look for different locules and pockets, and determine the degree of communication between them.

The largest well-powered randomized controlled trials of intrapleural agents in the management of pleural infection, the Multicentre Intrapleural Sepsis Trial (MIST1)¹⁰ and MIST2,¹¹ clearly demonstrated that intrapleural fibrinolytics were not beneficial when used alone compared with placebo. However, in MIST2, the combination of tPA and DNase led to clinically significant benefits including radiologic improvement, shorter hospital stay, and less need for surgical decortication.

At our hospital, we follow the MIST2 protocol using a combination of tPA and DNase given intrapleurally twice daily for 3 days. In our patient, we inserted a chest tube into the apical pocket under ultrasonographic guidance, as 2 instillations of intrapleural tPA and DNase did not result in drainage of the apical locule.

Success rates with intrapleural tPA-DNase for complicated pleural effusion and empyema range from 68% to 92%.^12–15 Pleural thickening and necrotizing pneumonia and abscess are important predictors of failure of tPA-DNase therapy and of the need for surgery.^13,14

Early surgical intervention was another reasonable option in this case. The decision to proceed with surgery is based on need to debride multiloculated empyemas or uniloculated empyemas that fail to resolve with antibiotics and tube thoracostomy drainage. Nonetheless, the decision must be individualized and based on factors such as the patient’s risks vs possible benefit from a surgical procedure under general anesthesia, the patient’s ability to tolerate multiple thoracentesis procedures and chest tubes for a potentially lengthy period, the patient’s pain threshold, the patient’s wishes to avoid a surgical procedure balanced against a longer hospital stay, and cultural norms and beliefs.

Surgical options include video-assisted thoracoscopy, thoracotomy, and open drainage. Decortication can be considered early to control pleural sepsis, or late (after 3 to 6 months) if the lung does not expand. Debate continues on the optimal timing for video-assisted thoracoscopy, with data suggesting that when the procedure is performed later in the course of the disease there is a greater chance of complications and of the need to convert to thoracotomy.

A 2017 Cochrane review¹⁶ of surgical vs nonsurgical management of empyema identified 8 randomized trials, 6 in children and 2 in adults, with a total of 391 patients. The authors compared video-assisted thoracoscopy vs tube thoracotomy, with and without intrapleural fibrinolytics. They noted no difference in rates of mortality or procedural complications. However, the mean length of hospital stay was shorter with video-assisted thoracoscopy than with tube thoracotomy (5.9 vs 15.4 days). They could not assess the impact of fibrinolytic therapy on total cost of treatment in the 2 groups.

A randomized trial is planned to compare early video-assisted thoracoscopy vs treatment with chest tube drainage and t-PA-DNase.¹⁷

At our institution, we use a multidisciplinary approach, discussing cases at weekly meetings with thoracic surgeons, pulmonologists, infectious disease specialists, and interventional radiologists. We generally try conservative management first, with chest tube drainage and intrapleural agents for 5 to 7 days, before considering surgery if the response is unsatisfactory.

THE PATIENT RECOVERED

In our patient, the multiloculated empyema was successfully cleared after intrapleural instillation of 4 doses of tPA and DNAse over 3 days and insertion of a second intercostal chest tube into the noncommunicating apical locule. He completed 14 days of intravenous piperacillin-tazobactam treatment and, after discharge home, completed another 4 weeks of oral amoxicillin-clavulanate. He made a full recovery and was back at work 2 weeks after discharge. Chest radiography 10 weeks after discharge showed normal results.

A 33-year-old male nonsmoker with no significant medical history presented to the pulmonary clinic with severe left-sided pleuritic chest pain and mild breathlessness for the past 5 days. He denied fever, chills, cough, phlegm, runny nose, or congestion.

Five days before this visit, he had been seen in the emergency department with mild left-sided pleuritic chest pain. His vital signs at that time had been as follows:

• Blood pressure 141/77 mm Hg
• Heart rate 77 beats/minute
• Respiratory rate 17 breaths/minute
• Temperature 36.8°C (98.2°F)
• Oxygen saturation 98% on room air.

• White blood cell count 6.89 × 10⁹/L (reference range 3.70–11.00)
• Neutrophils 58% (40%–70%)
• Lymphocytes 29.6% (22%–44%)
• Monocytes 10.7% (0–11%)
• Eosinophils 1% (0–4%)
• Basophils 0.6% (0–1%)
• Troponin T and D-dimer levels normal.

DIFFERENTIAL DIAGNOSIS OF PLEURITIC CHEST PAIN

1. What is the most likely cause of his pleuritic chest pain?

• Pleuritis
• Pneumonia
• Pulmonary embolism
• Malignancy

The differential diagnosis of pleuritic chest pain is broad.

The patient’s symptoms at presentation to the emergency department did not suggest an infectious process. There was no fever, cough, or phlegm, and his white blood cell count was normal. Nonetheless, pneumonia could not be ruled out, as the lung parenchyma was not normal on radiography, and the findings could have been consistent with an early or resolving infectious process.

Pulmonary embolism was a possibility, but his normal D-dimer level argued against it. Further, the patient subsequently underwent CT angiography, which ruled out pulmonary embolism.

Malignancy was unlikely in a young nonsmoker, but follow-up imaging would be needed to ensure resolution and rule this out.

The emergency department physician diagnosed inflammatory pleuritis and discharged him home on a nonsteroidal anti-inflammatory drug.

CLINIC VISIT 5 DAYS LATER

At his pulmonary clinic visit 5 days later, the patient reported persistent but stable left-sided pleuritic chest pain and mild breathlessness on exertion. His blood pressure was 137/81 mm Hg, heart rate 109 beats per minute, temperature 37.1°C (98.8°F), and oxygen saturation 97% on room air.

Auscultation of the lungs revealed rales and slightly decreased breath sounds at the left base. No dullness to percussion could be detected.

Because the patient had developed mild tachycardia and breathlessness along with clinical signs that suggested worsening infiltrates, consolidation, or the development of pleural effusion, he underwent further investigation with chest radiography, a complete blood cell count, and measurement of serum inflammatory markers.

• White blood cell count 13.08 × 10⁹/L
• Neutrophils 81%
• Lymphocytes 7.4%
• Monocytes 7.2%
• Eeosinophils 0.2%
• Basophils 0.2%
• Procalcitonin 0.34 µg/L (reference range < 0.09).

Bedside ultrasonography to assess the effusion’s size and characteristics and the need for thoracentesis indicated that the effusion was too small to tap, and there were no fibrinous strands or loculations to suggest empyema.

2. What was the best management strategy for this patient at this time?

• Admit to the hospital for thoracentesis and intravenous antibiotics
• Give oral antibiotics with close follow-up
• Perform thoracentesis on an outpatient basis and give oral antibiotics
• Repeat chest CT

The patient had worsening pleuritic pain with development of a small left pleural effusion. His symptoms had not improved on a nonsteroidal anti-inflammatory drug. He now had an elevated white blood cell count with a “left shift” (ie, an increase in neutrophils, indicating more immature cells in circulation) and elevated procalcitonin. The most likely diagnosis was pneumonia with a resulting pleural effusion, ie, parapneumonic effusion, requiring appropriate antibiotic therapy. Ideally, the pleural effusion should be sampled by thoracentesis, with management on an outpatient or inpatient basis.

5 DAYS LATER, THE EFFUSION HAD BECOME MASSIVE

On follow-up 5 days later, the patient’s chest pain was better, but he was significantly more short of breath. His blood pressure was 137/90 mm Hg, heart rate 117 beats/minute, respiratory rate 16 breaths/minute, oxygen saturation 97% on room air, and temperature 36.9°C (98.4°F). Chest auscultation revealed decreased breath sounds over the left hemithorax, with dullness to percussion and decreased fremitus.

RAPIDLY PROGRESSIVE PLEURAL EFFUSIONS

A rapidly progressive pleural effusion in a healthy patient suggests parapneumonic effusion. The most likely organism is streptococcal.²

Explosive pleuritis is defined as a pleural effusion that increases in size in less than 24 hours. It was first described by Braman and Donat³ in 1986 as an effusion that develops within hours of admission. In 2001, Sharma and Marrie⁴ refined the definition as rapid development of pleural effusion involving more than 90% of the hemithorax within 24 hours, causing compression of pulmonary tissue and a mediastinal shift. It is a medical emergency that requires prompt investigation and treatment with drainage and antibiotics. All reported cases of explosive pleuritis have been parapneumonic effusion.

The organisms implicated in explosive pleuritis include gram-positive cocci such as Streptococcus pneumoniae, S pyogenes, other streptococci, staphylococci, and gram-negative cocci such as Neisseria meningitidis and Moraxella catarrhalis. Gram-negative bacilli include Haemophilus influenzae, Klebsiella pneumoniae, Pseudomonas species, Escherichia coli, Proteus species, Enterobacter species, Bacteroides species, and Legionella species.^4,5 However, malignancy is the most common cause of massive pleural effusion, accounting for 54% of cases; 17% of cases are idiopathic, 13% are parapneumonic, and 12% are hydrothorax related to liver cirrhosis.⁶

CASE CONTINUED

Our patient’s massive effusion needed drainage, and he was admitted to the hospital for further management. Samples of blood and sputum were sent for culture. Intravenous piperacillin-tazobactam was started, and an intercostal chest tube was inserted into the pleural cavity under ultrasonographic guidance to drain turbid fluid.

Multiple pleural fluid samples sent for bacterial, fungal, and acid-fast bacilli culture were negative. Blood and sputum cultures also showed no growth. The administration of oral antibiotics for 5 days on an outpatient basis before pleural fluid culture could have led to sterility of all cultures.

Our patient had inadequate pleural fluid output through his chest tube, and radiography showed that the pleural collections failed to clear. In fact, an apical locule did not appear to be connecting with the lower aspect of the pleural collection. In such cases, instillation of intrapleural agents through the chest tube has become common practice in an attempt to lyse adhesions, to connect various locules or pockets of pleural fluid, and to improve drainage.

3. What was the best management strategy for this loculated empyema?

• Continue intravenous antibiotics and existing chest tube drainage for 5 to 7 days, then reassess
• Continue intravenous antibiotics and instill intrapleural fibrinolytics (eg, tissue plasminogen activator [tPA]) through the existing chest tube
• Continue intravenous antibiotics and instill intrapleural fibrinolytics with deoxyribonuclease (DNase) into the existing chest tube
• Continue intravenous antibiotics, insert a second chest tube into the apical pocket under imaging guidance, and instill tPA and DNase
• Surgical decortication

Continuing antibiotics with existing chest tube drainage and the two options of using single-agent intrapleural fibrinolytics have been shown to be less effective than combining tPA and DNase when managing a loculated empyema. As such, surgical decortication, attempting intrapleural instillation of fibrinolytics and DNase (with or without further chest tube insertion into noncommunicating locules), or both were the most appropriate options at this stage.

MANAGEMENT OF PARAPNEUMONIC PLEURAL EFFUSION IN ADULTS

There are several options for managing parapneumonic effusion, and clinicians can use the classification system in Table 1 to assess the risk of a poor outcome and to plan the management. Based on radiographic findings and pleural fluid sampling, a pleural effusion can be either observed or drained.

Options for drainage of the pleural space include repeat thoracentesis, surgical insertion of a chest tube, or image-guided insertion of a small-bore catheter. Although no randomized trial has been done to compare tube sizes, a large retrospective series showed that small-bore tubes (< 14 F) perform similarly to standard large-bore tubes.⁸ However, in another study, Keeling et al⁹ reported higher failure rates when tubes smaller than 12 F were used. Regular flushing of the chest tube (ideally twice a day) is recommended to keep it patent, particularly with small-bore tubes. Multiloculated empyema may require multiple intercostal chest tubes to drain completely, and therefore small-bore tubes are recommended.

In cases that do not improve radiographically and clinically, one must consider whether the antibiotic choice is adequate, review the position of the chest tube, and assess for loculations. As such, repeating chest CT within 24 to 48 hours of tube insertion and drainage is recommended to confirm adequate tube positioning, assess effective drainage, look for different locules and pockets, and determine the degree of communication between them.

The largest well-powered randomized controlled trials of intrapleural agents in the management of pleural infection, the Multicentre Intrapleural Sepsis Trial (MIST1)¹⁰ and MIST2,¹¹ clearly demonstrated that intrapleural fibrinolytics were not beneficial when used alone compared with placebo. However, in MIST2, the combination of tPA and DNase led to clinically significant benefits including radiologic improvement, shorter hospital stay, and less need for surgical decortication.

At our hospital, we follow the MIST2 protocol using a combination of tPA and DNase given intrapleurally twice daily for 3 days. In our patient, we inserted a chest tube into the apical pocket under ultrasonographic guidance, as 2 instillations of intrapleural tPA and DNase did not result in drainage of the apical locule.

Success rates with intrapleural tPA-DNase for complicated pleural effusion and empyema range from 68% to 92%.^12–15 Pleural thickening and necrotizing pneumonia and abscess are important predictors of failure of tPA-DNase therapy and of the need for surgery.^13,14

Early surgical intervention was another reasonable option in this case. The decision to proceed with surgery is based on need to debride multiloculated empyemas or uniloculated empyemas that fail to resolve with antibiotics and tube thoracostomy drainage. Nonetheless, the decision must be individualized and based on factors such as the patient’s risks vs possible benefit from a surgical procedure under general anesthesia, the patient’s ability to tolerate multiple thoracentesis procedures and chest tubes for a potentially lengthy period, the patient’s pain threshold, the patient’s wishes to avoid a surgical procedure balanced against a longer hospital stay, and cultural norms and beliefs.

Surgical options include video-assisted thoracoscopy, thoracotomy, and open drainage. Decortication can be considered early to control pleural sepsis, or late (after 3 to 6 months) if the lung does not expand. Debate continues on the optimal timing for video-assisted thoracoscopy, with data suggesting that when the procedure is performed later in the course of the disease there is a greater chance of complications and of the need to convert to thoracotomy.

A 2017 Cochrane review¹⁶ of surgical vs nonsurgical management of empyema identified 8 randomized trials, 6 in children and 2 in adults, with a total of 391 patients. The authors compared video-assisted thoracoscopy vs tube thoracotomy, with and without intrapleural fibrinolytics. They noted no difference in rates of mortality or procedural complications. However, the mean length of hospital stay was shorter with video-assisted thoracoscopy than with tube thoracotomy (5.9 vs 15.4 days). They could not assess the impact of fibrinolytic therapy on total cost of treatment in the 2 groups.

A randomized trial is planned to compare early video-assisted thoracoscopy vs treatment with chest tube drainage and t-PA-DNase.¹⁷

At our institution, we use a multidisciplinary approach, discussing cases at weekly meetings with thoracic surgeons, pulmonologists, infectious disease specialists, and interventional radiologists. We generally try conservative management first, with chest tube drainage and intrapleural agents for 5 to 7 days, before considering surgery if the response is unsatisfactory.

THE PATIENT RECOVERED

In our patient, the multiloculated empyema was successfully cleared after intrapleural instillation of 4 doses of tPA and DNAse over 3 days and insertion of a second intercostal chest tube into the noncommunicating apical locule. He completed 14 days of intravenous piperacillin-tazobactam treatment and, after discharge home, completed another 4 weeks of oral amoxicillin-clavulanate. He made a full recovery and was back at work 2 weeks after discharge. Chest radiography 10 weeks after discharge showed normal results.

A 33-year-old male nonsmoker with no significant medical history presented to the pulmonary clinic with severe left-sided pleuritic chest pain and mild breathlessness for the past 5 days. He denied fever, chills, cough, phlegm, runny nose, or congestion.

Five days before this visit, he had been seen in the emergency department with mild left-sided pleuritic chest pain. His vital signs at that time had been as follows:

• Blood pressure 141/77 mm Hg
• Heart rate 77 beats/minute
• Respiratory rate 17 breaths/minute
• Temperature 36.8°C (98.2°F)
• Oxygen saturation 98% on room air.

• White blood cell count 6.89 × 10⁹/L (reference range 3.70–11.00)
• Neutrophils 58% (40%–70%)
• Lymphocytes 29.6% (22%–44%)
• Monocytes 10.7% (0–11%)
• Eosinophils 1% (0–4%)
• Basophils 0.6% (0–1%)
• Troponin T and D-dimer levels normal.

DIFFERENTIAL DIAGNOSIS OF PLEURITIC CHEST PAIN

1. What is the most likely cause of his pleuritic chest pain?

• Pleuritis
• Pneumonia
• Pulmonary embolism
• Malignancy

The differential diagnosis of pleuritic chest pain is broad.

The patient’s symptoms at presentation to the emergency department did not suggest an infectious process. There was no fever, cough, or phlegm, and his white blood cell count was normal. Nonetheless, pneumonia could not be ruled out, as the lung parenchyma was not normal on radiography, and the findings could have been consistent with an early or resolving infectious process.

Pulmonary embolism was a possibility, but his normal D-dimer level argued against it. Further, the patient subsequently underwent CT angiography, which ruled out pulmonary embolism.

Malignancy was unlikely in a young nonsmoker, but follow-up imaging would be needed to ensure resolution and rule this out.

The emergency department physician diagnosed inflammatory pleuritis and discharged him home on a nonsteroidal anti-inflammatory drug.

CLINIC VISIT 5 DAYS LATER

At his pulmonary clinic visit 5 days later, the patient reported persistent but stable left-sided pleuritic chest pain and mild breathlessness on exertion. His blood pressure was 137/81 mm Hg, heart rate 109 beats per minute, temperature 37.1°C (98.8°F), and oxygen saturation 97% on room air.

Auscultation of the lungs revealed rales and slightly decreased breath sounds at the left base. No dullness to percussion could be detected.

Because the patient had developed mild tachycardia and breathlessness along with clinical signs that suggested worsening infiltrates, consolidation, or the development of pleural effusion, he underwent further investigation with chest radiography, a complete blood cell count, and measurement of serum inflammatory markers.

• White blood cell count 13.08 × 10⁹/L
• Neutrophils 81%
• Lymphocytes 7.4%
• Monocytes 7.2%
• Eeosinophils 0.2%
• Basophils 0.2%
• Procalcitonin 0.34 µg/L (reference range < 0.09).

Bedside ultrasonography to assess the effusion’s size and characteristics and the need for thoracentesis indicated that the effusion was too small to tap, and there were no fibrinous strands or loculations to suggest empyema.

2. What was the best management strategy for this patient at this time?

• Admit to the hospital for thoracentesis and intravenous antibiotics
• Give oral antibiotics with close follow-up
• Perform thoracentesis on an outpatient basis and give oral antibiotics
• Repeat chest CT

The patient had worsening pleuritic pain with development of a small left pleural effusion. His symptoms had not improved on a nonsteroidal anti-inflammatory drug. He now had an elevated white blood cell count with a “left shift” (ie, an increase in neutrophils, indicating more immature cells in circulation) and elevated procalcitonin. The most likely diagnosis was pneumonia with a resulting pleural effusion, ie, parapneumonic effusion, requiring appropriate antibiotic therapy. Ideally, the pleural effusion should be sampled by thoracentesis, with management on an outpatient or inpatient basis.

5 DAYS LATER, THE EFFUSION HAD BECOME MASSIVE

On follow-up 5 days later, the patient’s chest pain was better, but he was significantly more short of breath. His blood pressure was 137/90 mm Hg, heart rate 117 beats/minute, respiratory rate 16 breaths/minute, oxygen saturation 97% on room air, and temperature 36.9°C (98.4°F). Chest auscultation revealed decreased breath sounds over the left hemithorax, with dullness to percussion and decreased fremitus.

RAPIDLY PROGRESSIVE PLEURAL EFFUSIONS

A rapidly progressive pleural effusion in a healthy patient suggests parapneumonic effusion. The most likely organism is streptococcal.²

Explosive pleuritis is defined as a pleural effusion that increases in size in less than 24 hours. It was first described by Braman and Donat³ in 1986 as an effusion that develops within hours of admission. In 2001, Sharma and Marrie⁴ refined the definition as rapid development of pleural effusion involving more than 90% of the hemithorax within 24 hours, causing compression of pulmonary tissue and a mediastinal shift. It is a medical emergency that requires prompt investigation and treatment with drainage and antibiotics. All reported cases of explosive pleuritis have been parapneumonic effusion.

The organisms implicated in explosive pleuritis include gram-positive cocci such as Streptococcus pneumoniae, S pyogenes, other streptococci, staphylococci, and gram-negative cocci such as Neisseria meningitidis and Moraxella catarrhalis. Gram-negative bacilli include Haemophilus influenzae, Klebsiella pneumoniae, Pseudomonas species, Escherichia coli, Proteus species, Enterobacter species, Bacteroides species, and Legionella species.^4,5 However, malignancy is the most common cause of massive pleural effusion, accounting for 54% of cases; 17% of cases are idiopathic, 13% are parapneumonic, and 12% are hydrothorax related to liver cirrhosis.⁶

CASE CONTINUED

Our patient’s massive effusion needed drainage, and he was admitted to the hospital for further management. Samples of blood and sputum were sent for culture. Intravenous piperacillin-tazobactam was started, and an intercostal chest tube was inserted into the pleural cavity under ultrasonographic guidance to drain turbid fluid.

Multiple pleural fluid samples sent for bacterial, fungal, and acid-fast bacilli culture were negative. Blood and sputum cultures also showed no growth. The administration of oral antibiotics for 5 days on an outpatient basis before pleural fluid culture could have led to sterility of all cultures.

Our patient had inadequate pleural fluid output through his chest tube, and radiography showed that the pleural collections failed to clear. In fact, an apical locule did not appear to be connecting with the lower aspect of the pleural collection. In such cases, instillation of intrapleural agents through the chest tube has become common practice in an attempt to lyse adhesions, to connect various locules or pockets of pleural fluid, and to improve drainage.

3. What was the best management strategy for this loculated empyema?

• Continue intravenous antibiotics and existing chest tube drainage for 5 to 7 days, then reassess
• Continue intravenous antibiotics and instill intrapleural fibrinolytics (eg, tissue plasminogen activator [tPA]) through the existing chest tube
• Continue intravenous antibiotics and instill intrapleural fibrinolytics with deoxyribonuclease (DNase) into the existing chest tube
• Continue intravenous antibiotics, insert a second chest tube into the apical pocket under imaging guidance, and instill tPA and DNase
• Surgical decortication

Continuing antibiotics with existing chest tube drainage and the two options of using single-agent intrapleural fibrinolytics have been shown to be less effective than combining tPA and DNase when managing a loculated empyema. As such, surgical decortication, attempting intrapleural instillation of fibrinolytics and DNase (with or without further chest tube insertion into noncommunicating locules), or both were the most appropriate options at this stage.

MANAGEMENT OF PARAPNEUMONIC PLEURAL EFFUSION IN ADULTS

There are several options for managing parapneumonic effusion, and clinicians can use the classification system in Table 1 to assess the risk of a poor outcome and to plan the management. Based on radiographic findings and pleural fluid sampling, a pleural effusion can be either observed or drained.

Options for drainage of the pleural space include repeat thoracentesis, surgical insertion of a chest tube, or image-guided insertion of a small-bore catheter. Although no randomized trial has been done to compare tube sizes, a large retrospective series showed that small-bore tubes (< 14 F) perform similarly to standard large-bore tubes.⁸ However, in another study, Keeling et al⁹ reported higher failure rates when tubes smaller than 12 F were used. Regular flushing of the chest tube (ideally twice a day) is recommended to keep it patent, particularly with small-bore tubes. Multiloculated empyema may require multiple intercostal chest tubes to drain completely, and therefore small-bore tubes are recommended.

In cases that do not improve radiographically and clinically, one must consider whether the antibiotic choice is adequate, review the position of the chest tube, and assess for loculations. As such, repeating chest CT within 24 to 48 hours of tube insertion and drainage is recommended to confirm adequate tube positioning, assess effective drainage, look for different locules and pockets, and determine the degree of communication between them.

The largest well-powered randomized controlled trials of intrapleural agents in the management of pleural infection, the Multicentre Intrapleural Sepsis Trial (MIST1)¹⁰ and MIST2,¹¹ clearly demonstrated that intrapleural fibrinolytics were not beneficial when used alone compared with placebo. However, in MIST2, the combination of tPA and DNase led to clinically significant benefits including radiologic improvement, shorter hospital stay, and less need for surgical decortication.

At our hospital, we follow the MIST2 protocol using a combination of tPA and DNase given intrapleurally twice daily for 3 days. In our patient, we inserted a chest tube into the apical pocket under ultrasonographic guidance, as 2 instillations of intrapleural tPA and DNase did not result in drainage of the apical locule.

Success rates with intrapleural tPA-DNase for complicated pleural effusion and empyema range from 68% to 92%.^12–15 Pleural thickening and necrotizing pneumonia and abscess are important predictors of failure of tPA-DNase therapy and of the need for surgery.^13,14

Early surgical intervention was another reasonable option in this case. The decision to proceed with surgery is based on need to debride multiloculated empyemas or uniloculated empyemas that fail to resolve with antibiotics and tube thoracostomy drainage. Nonetheless, the decision must be individualized and based on factors such as the patient’s risks vs possible benefit from a surgical procedure under general anesthesia, the patient’s ability to tolerate multiple thoracentesis procedures and chest tubes for a potentially lengthy period, the patient’s pain threshold, the patient’s wishes to avoid a surgical procedure balanced against a longer hospital stay, and cultural norms and beliefs.

Surgical options include video-assisted thoracoscopy, thoracotomy, and open drainage. Decortication can be considered early to control pleural sepsis, or late (after 3 to 6 months) if the lung does not expand. Debate continues on the optimal timing for video-assisted thoracoscopy, with data suggesting that when the procedure is performed later in the course of the disease there is a greater chance of complications and of the need to convert to thoracotomy.

A 2017 Cochrane review¹⁶ of surgical vs nonsurgical management of empyema identified 8 randomized trials, 6 in children and 2 in adults, with a total of 391 patients. The authors compared video-assisted thoracoscopy vs tube thoracotomy, with and without intrapleural fibrinolytics. They noted no difference in rates of mortality or procedural complications. However, the mean length of hospital stay was shorter with video-assisted thoracoscopy than with tube thoracotomy (5.9 vs 15.4 days). They could not assess the impact of fibrinolytic therapy on total cost of treatment in the 2 groups.

A randomized trial is planned to compare early video-assisted thoracoscopy vs treatment with chest tube drainage and t-PA-DNase.¹⁷

At our institution, we use a multidisciplinary approach, discussing cases at weekly meetings with thoracic surgeons, pulmonologists, infectious disease specialists, and interventional radiologists. We generally try conservative management first, with chest tube drainage and intrapleural agents for 5 to 7 days, before considering surgery if the response is unsatisfactory.

THE PATIENT RECOVERED

In our patient, the multiloculated empyema was successfully cleared after intrapleural instillation of 4 doses of tPA and DNAse over 3 days and insertion of a second intercostal chest tube into the noncommunicating apical locule. He completed 14 days of intravenous piperacillin-tazobactam treatment and, after discharge home, completed another 4 weeks of oral amoxicillin-clavulanate. He made a full recovery and was back at work 2 weeks after discharge. Chest radiography 10 weeks after discharge showed normal results.

From the Cleveland Clinic Journal of Medicine

This article has been removed from the website. The article was prepared by the editorial staff based on a transcript of the proceedings of a conference, and errors occurred during this process that were subsequently published. A clarification of the errors will be published in a future issue.

A review of this topic was published in the December 2017 issue of the Journal (Donnelly JP, Hanna M. Cardiac amyloidosis: An update on diagnosis and treatment. Cleve Clin J Med 2017;84[12suppl 3]:12–26). doi:10.3949/ccjm.84.s3.02

From the Cleveland Clinic Journal of Medicine

This article has been removed from the website. The article was prepared by the editorial staff based on a transcript of the proceedings of a conference, and errors occurred during this process that were subsequently published. A clarification of the errors will be published in a future issue.

A review of this topic was published in the December 2017 issue of the Journal (Donnelly JP, Hanna M. Cardiac amyloidosis: An update on diagnosis and treatment. Cleve Clin J Med 2017;84[12suppl 3]:12–26). doi:10.3949/ccjm.84.s3.02

From the Cleveland Clinic Journal of Medicine

This article has been removed from the website. The article was prepared by the editorial staff based on a transcript of the proceedings of a conference, and errors occurred during this process that were subsequently published. A clarification of the errors will be published in a future issue.

A review of this topic was published in the December 2017 issue of the Journal (Donnelly JP, Hanna M. Cardiac amyloidosis: An update on diagnosis and treatment. Cleve Clin J Med 2017;84[12suppl 3]:12–26). doi:10.3949/ccjm.84.s3.02

Recent years have seen dramatic increases in the prevalences of chronic diseases such as type 1 diabetes,¹ gastroesophageal reflux disease,² asthma,³ inflammatory bowel disease,⁴ and, notably, obesity.⁵ I propose the hypothesis that much of this increase may be due to loss of diversity in the bacteria that make our guts their home.⁶ While multiple causes contribute, much of the blame may be attributed to the use—and overuse—of antibiotics.

FAT AND GETTING FATTER

Today, nearly 40% of US adults are obese, and nearly three-fourths are either obese or overweight.⁷ More alarming, the prevalence of obesity is also high and getting higher in children and adolescents,⁸ having increased from 10.0% in 1988–1994 to 17.8% in 2013–2016.

And not just in the United States. Trends in weight have been going up around the world, with a lag of about 30 years between developing countries and industrialized countries.5

OUR BACTERIA, OURSELVES

I believe that the bacteria we carry are not random, but rather have coevolved along with us, passed down from generation to generation in a state of dynamic equilibrium between microbes and host. Evidence supporting this comes from a study by Ochman et al,⁹ who analyzed the DNA from fecal samples from different hominid species (including Homo sapiens) and found that the phylogenic relationships among the bacteria mirrored those among the apes.

Interacting with each other and with us in complex ways, our bacteria are a diverse community to which we can apply the term microbiome. They are acquired in a standard, choreographed process,¹⁰ and their composition comes to resemble that of adults by the age of 3.¹¹

Before modern times, microbes were transferred from mother to child during vaginal birth, from the mother’s breast during nursing, through skin-to-skin contact, and from the mother’s mouth by kissing. Now, widespread cesarean delivery, bottle-feeding, extensive bathing (especially with antibacterial soaps), and especially the use of antibiotics have changed the human ecology and altered transmission and maintenance of ancestral microbes, which affects the composition of the microbiota. The microbes, both good and bad, that are usually acquired early in life are especially important, since they affect a developmentally critical stage.¹²

Loss of microbial diversity in the mother appears to be cumulative over succeeding generations.¹³ For example, in a study in Japanese families, Urita et al¹⁴ found a decline in the prevalence of Helicobacter pylori colonization from 68.7% in the first generation to 43.4% in the second generation and 12.5% in the third. Clemente et al¹⁵ studied the intestinal microbiota in a previously uncontacted group of Yanomami people in the Amazon jungle and found they had the highest diversity of bacteria ever reported in a human group. By comparison, the research team calculated that we in the United States have already lost 50% of our microbial diversity, and 2 other groups, the Guahibo (another Amerindian group) and rural Malawians, were in between. More recent studies are confirming these observations.^16,17

More than 73 billion antibiotic doses are prescribed worldwide yearly,¹⁸ or about 10 doses for every man, woman, and child on Earth, and the numbers are rising. In the United States 262 million courses were prescribed in 2011, or 842 per 1,000 population.¹⁹ Children receive a mean of 2.7 courses by age 2, and 10.9 by age 10. More than 50% of women receive antibiotics during pregnancy or perinatally. This is in addition to an unknown level of exposure from agricultural use of antibiotics.

Repeated antibiotic exposure is common in early life, varies widely by country, and is often not medically justified.²⁰ In the United States, antibiotic use varies by region, with the heaviest use in the South.^19,21 It also varies widely among prescribers.²² Jones et al²³ examined antibiotic prescribing for acute respiratory infections in US veterans and found that the top 10% of physicians gave an antibiotic more than 90% of the time. Physicians in Sweden prescribe about 60% fewer antibiotics than we do in the United States.^21,24

Observational data indicate that people who receive antibiotics have a higher risk of chronic diseases later in life, eg:

• Type 2 diabetes (odds ratio 1.21, 95% confidence interval 1.19–1.23 with 2 to 4 courses, and odds ratio 1.53 (1.50–1.55) with 5 or more courses, up to 15 years after²⁵
• Obesity: US states with the highest prevalence of antibiotic use also have the highest prevalence of obesity²⁶
• Kidney stones: prior antibiotic exposure in a large UK study was associated with increased kidney stone risk, for exposures up to 5 years earlier.²⁷

The meat industry has exploited the weight effect for decades, adding subtherapeutic doses of antibiotics to animals’ feed to make them gain weight.²8

FINDINGS FROM STUDIES IN MICE

Laboratory studies of the relationship between antibiotic exposure and disease phenotypes in mice have yielded interesting findings.

Mice exposed to antibiotics had more body fat at 10 weeks (32.0%) than control mice (22.9%).²⁹

Low-dose penicillin, started at birth, induces long-lasting effects on the expression of genes involved in immunity and enhances the effect of a high-fat diet in terms of weight gain.³⁰ If the antibiotic exposure is limited to early life, the effect on the microbiota is transient, but the mice still gain weight. If the microbiota from the mice who received penicillin is transferred to germ-free mice, the recipients also become fat, indicating that the bacteria, not the antibiotics per se, cause the weight gain.

In other experiments,³¹ a series of short, therapeutic doses of antibiotics early in life modeled after those given to children to treat their acute infections caused long-term changes in the composition of the microbiome and in metabolism.

A single course of a macrolide antibiotic also had long-term effects on the microbial population and on the host’s ileal gene expression, T-cell populations, and secretory immunoglobulin A expression.³² These effects were seen only in mice that had a microbiome to begin with, not in germ-free mice, indicating that the antibiotics had their effect through the changes in the microbiome, not directly. But when germ-free mice received a fecal transplant of an impaired microbiome, it was sufficient to affect immunity.

In nonobese diabetic mice, treatment with antibiotics early in life altered the gut microbiome and its metabolic capacities, intestinal gene expression, and T-cell populations, accelerating the onset of type 1 diabetes.³³

In a study in Danish children,³⁴ the likelihood of inflammatory bowel disease increased with early-life antibiotic exposure: the more courses the child received, the greater the likelihood of disease. This observation led researchers to wonder if an antibiotic-altered microbiome affects the outcome of inflammatory bowel disease in the next generation.³⁵ Germ-free female mice who received microbiota from mice who had received antibiotics passed the altered microbiome to their pups. Mice lacking the gene for interleukin 10 are genetically susceptible to colitis, and when this experiment was done in mice lacking this gene, the offspring developed markedly more colitis. This indicated the mothers could pass down their altered microbiome to the next generation and that it would affect their risk of disease.

WHAT CAN WE DO?

All physicians must adhere to the principles of antibiotic stewardship,³⁶ not only to prevent the development of resistant strains of pathogens and the overgrowth of potentially dangerous species such as Clostridium difficile, but also, possibly, to prevent the loss of diversity in the human microbiome and thus discourage the development of chronic diseases.

In the future, as we discover more about the microbiome and the optimal mix of bacteria to carry, this information may find practical application in medicine. A pediatrician, for example, may want to analyze a child’s microbiome and, if it is abnormal, administer specific organisms to reshape it.

Recent years have seen dramatic increases in the prevalences of chronic diseases such as type 1 diabetes,¹ gastroesophageal reflux disease,² asthma,³ inflammatory bowel disease,⁴ and, notably, obesity.⁵ I propose the hypothesis that much of this increase may be due to loss of diversity in the bacteria that make our guts their home.⁶ While multiple causes contribute, much of the blame may be attributed to the use—and overuse—of antibiotics.

FAT AND GETTING FATTER

Today, nearly 40% of US adults are obese, and nearly three-fourths are either obese or overweight.⁷ More alarming, the prevalence of obesity is also high and getting higher in children and adolescents,⁸ having increased from 10.0% in 1988–1994 to 17.8% in 2013–2016.

And not just in the United States. Trends in weight have been going up around the world, with a lag of about 30 years between developing countries and industrialized countries.5

OUR BACTERIA, OURSELVES

I believe that the bacteria we carry are not random, but rather have coevolved along with us, passed down from generation to generation in a state of dynamic equilibrium between microbes and host. Evidence supporting this comes from a study by Ochman et al,⁹ who analyzed the DNA from fecal samples from different hominid species (including Homo sapiens) and found that the phylogenic relationships among the bacteria mirrored those among the apes.

Interacting with each other and with us in complex ways, our bacteria are a diverse community to which we can apply the term microbiome. They are acquired in a standard, choreographed process,¹⁰ and their composition comes to resemble that of adults by the age of 3.¹¹

Before modern times, microbes were transferred from mother to child during vaginal birth, from the mother’s breast during nursing, through skin-to-skin contact, and from the mother’s mouth by kissing. Now, widespread cesarean delivery, bottle-feeding, extensive bathing (especially with antibacterial soaps), and especially the use of antibiotics have changed the human ecology and altered transmission and maintenance of ancestral microbes, which affects the composition of the microbiota. The microbes, both good and bad, that are usually acquired early in life are especially important, since they affect a developmentally critical stage.¹²

Loss of microbial diversity in the mother appears to be cumulative over succeeding generations.¹³ For example, in a study in Japanese families, Urita et al¹⁴ found a decline in the prevalence of Helicobacter pylori colonization from 68.7% in the first generation to 43.4% in the second generation and 12.5% in the third. Clemente et al¹⁵ studied the intestinal microbiota in a previously uncontacted group of Yanomami people in the Amazon jungle and found they had the highest diversity of bacteria ever reported in a human group. By comparison, the research team calculated that we in the United States have already lost 50% of our microbial diversity, and 2 other groups, the Guahibo (another Amerindian group) and rural Malawians, were in between. More recent studies are confirming these observations.^16,17

More than 73 billion antibiotic doses are prescribed worldwide yearly,¹⁸ or about 10 doses for every man, woman, and child on Earth, and the numbers are rising. In the United States 262 million courses were prescribed in 2011, or 842 per 1,000 population.¹⁹ Children receive a mean of 2.7 courses by age 2, and 10.9 by age 10. More than 50% of women receive antibiotics during pregnancy or perinatally. This is in addition to an unknown level of exposure from agricultural use of antibiotics.

Repeated antibiotic exposure is common in early life, varies widely by country, and is often not medically justified.²⁰ In the United States, antibiotic use varies by region, with the heaviest use in the South.^19,21 It also varies widely among prescribers.²² Jones et al²³ examined antibiotic prescribing for acute respiratory infections in US veterans and found that the top 10% of physicians gave an antibiotic more than 90% of the time. Physicians in Sweden prescribe about 60% fewer antibiotics than we do in the United States.^21,24

Observational data indicate that people who receive antibiotics have a higher risk of chronic diseases later in life, eg:

• Type 2 diabetes (odds ratio 1.21, 95% confidence interval 1.19–1.23 with 2 to 4 courses, and odds ratio 1.53 (1.50–1.55) with 5 or more courses, up to 15 years after²⁵
• Obesity: US states with the highest prevalence of antibiotic use also have the highest prevalence of obesity²⁶
• Kidney stones: prior antibiotic exposure in a large UK study was associated with increased kidney stone risk, for exposures up to 5 years earlier.²⁷

The meat industry has exploited the weight effect for decades, adding subtherapeutic doses of antibiotics to animals’ feed to make them gain weight.²8

FINDINGS FROM STUDIES IN MICE

Laboratory studies of the relationship between antibiotic exposure and disease phenotypes in mice have yielded interesting findings.

Mice exposed to antibiotics had more body fat at 10 weeks (32.0%) than control mice (22.9%).²⁹

Low-dose penicillin, started at birth, induces long-lasting effects on the expression of genes involved in immunity and enhances the effect of a high-fat diet in terms of weight gain.³⁰ If the antibiotic exposure is limited to early life, the effect on the microbiota is transient, but the mice still gain weight. If the microbiota from the mice who received penicillin is transferred to germ-free mice, the recipients also become fat, indicating that the bacteria, not the antibiotics per se, cause the weight gain.

In other experiments,³¹ a series of short, therapeutic doses of antibiotics early in life modeled after those given to children to treat their acute infections caused long-term changes in the composition of the microbiome and in metabolism.

A single course of a macrolide antibiotic also had long-term effects on the microbial population and on the host’s ileal gene expression, T-cell populations, and secretory immunoglobulin A expression.³² These effects were seen only in mice that had a microbiome to begin with, not in germ-free mice, indicating that the antibiotics had their effect through the changes in the microbiome, not directly. But when germ-free mice received a fecal transplant of an impaired microbiome, it was sufficient to affect immunity.

In nonobese diabetic mice, treatment with antibiotics early in life altered the gut microbiome and its metabolic capacities, intestinal gene expression, and T-cell populations, accelerating the onset of type 1 diabetes.³³

In a study in Danish children,³⁴ the likelihood of inflammatory bowel disease increased with early-life antibiotic exposure: the more courses the child received, the greater the likelihood of disease. This observation led researchers to wonder if an antibiotic-altered microbiome affects the outcome of inflammatory bowel disease in the next generation.³⁵ Germ-free female mice who received microbiota from mice who had received antibiotics passed the altered microbiome to their pups. Mice lacking the gene for interleukin 10 are genetically susceptible to colitis, and when this experiment was done in mice lacking this gene, the offspring developed markedly more colitis. This indicated the mothers could pass down their altered microbiome to the next generation and that it would affect their risk of disease.

WHAT CAN WE DO?

All physicians must adhere to the principles of antibiotic stewardship,³⁶ not only to prevent the development of resistant strains of pathogens and the overgrowth of potentially dangerous species such as Clostridium difficile, but also, possibly, to prevent the loss of diversity in the human microbiome and thus discourage the development of chronic diseases.

In the future, as we discover more about the microbiome and the optimal mix of bacteria to carry, this information may find practical application in medicine. A pediatrician, for example, may want to analyze a child’s microbiome and, if it is abnormal, administer specific organisms to reshape it.

Recent years have seen dramatic increases in the prevalences of chronic diseases such as type 1 diabetes,¹ gastroesophageal reflux disease,² asthma,³ inflammatory bowel disease,⁴ and, notably, obesity.⁵ I propose the hypothesis that much of this increase may be due to loss of diversity in the bacteria that make our guts their home.⁶ While multiple causes contribute, much of the blame may be attributed to the use—and overuse—of antibiotics.

FAT AND GETTING FATTER

Today, nearly 40% of US adults are obese, and nearly three-fourths are either obese or overweight.⁷ More alarming, the prevalence of obesity is also high and getting higher in children and adolescents,⁸ having increased from 10.0% in 1988–1994 to 17.8% in 2013–2016.

And not just in the United States. Trends in weight have been going up around the world, with a lag of about 30 years between developing countries and industrialized countries.5

OUR BACTERIA, OURSELVES

I believe that the bacteria we carry are not random, but rather have coevolved along with us, passed down from generation to generation in a state of dynamic equilibrium between microbes and host. Evidence supporting this comes from a study by Ochman et al,⁹ who analyzed the DNA from fecal samples from different hominid species (including Homo sapiens) and found that the phylogenic relationships among the bacteria mirrored those among the apes.

Interacting with each other and with us in complex ways, our bacteria are a diverse community to which we can apply the term microbiome. They are acquired in a standard, choreographed process,¹⁰ and their composition comes to resemble that of adults by the age of 3.¹¹

Before modern times, microbes were transferred from mother to child during vaginal birth, from the mother’s breast during nursing, through skin-to-skin contact, and from the mother’s mouth by kissing. Now, widespread cesarean delivery, bottle-feeding, extensive bathing (especially with antibacterial soaps), and especially the use of antibiotics have changed the human ecology and altered transmission and maintenance of ancestral microbes, which affects the composition of the microbiota. The microbes, both good and bad, that are usually acquired early in life are especially important, since they affect a developmentally critical stage.¹²

Loss of microbial diversity in the mother appears to be cumulative over succeeding generations.¹³ For example, in a study in Japanese families, Urita et al¹⁴ found a decline in the prevalence of Helicobacter pylori colonization from 68.7% in the first generation to 43.4% in the second generation and 12.5% in the third. Clemente et al¹⁵ studied the intestinal microbiota in a previously uncontacted group of Yanomami people in the Amazon jungle and found they had the highest diversity of bacteria ever reported in a human group. By comparison, the research team calculated that we in the United States have already lost 50% of our microbial diversity, and 2 other groups, the Guahibo (another Amerindian group) and rural Malawians, were in between. More recent studies are confirming these observations.^16,17

More than 73 billion antibiotic doses are prescribed worldwide yearly,¹⁸ or about 10 doses for every man, woman, and child on Earth, and the numbers are rising. In the United States 262 million courses were prescribed in 2011, or 842 per 1,000 population.¹⁹ Children receive a mean of 2.7 courses by age 2, and 10.9 by age 10. More than 50% of women receive antibiotics during pregnancy or perinatally. This is in addition to an unknown level of exposure from agricultural use of antibiotics.

Repeated antibiotic exposure is common in early life, varies widely by country, and is often not medically justified.²⁰ In the United States, antibiotic use varies by region, with the heaviest use in the South.^19,21 It also varies widely among prescribers.²² Jones et al²³ examined antibiotic prescribing for acute respiratory infections in US veterans and found that the top 10% of physicians gave an antibiotic more than 90% of the time. Physicians in Sweden prescribe about 60% fewer antibiotics than we do in the United States.^21,24

Observational data indicate that people who receive antibiotics have a higher risk of chronic diseases later in life, eg:

• Type 2 diabetes (odds ratio 1.21, 95% confidence interval 1.19–1.23 with 2 to 4 courses, and odds ratio 1.53 (1.50–1.55) with 5 or more courses, up to 15 years after²⁵
• Obesity: US states with the highest prevalence of antibiotic use also have the highest prevalence of obesity²⁶
• Kidney stones: prior antibiotic exposure in a large UK study was associated with increased kidney stone risk, for exposures up to 5 years earlier.²⁷

The meat industry has exploited the weight effect for decades, adding subtherapeutic doses of antibiotics to animals’ feed to make them gain weight.²8

FINDINGS FROM STUDIES IN MICE

Laboratory studies of the relationship between antibiotic exposure and disease phenotypes in mice have yielded interesting findings.

Mice exposed to antibiotics had more body fat at 10 weeks (32.0%) than control mice (22.9%).²⁹

Low-dose penicillin, started at birth, induces long-lasting effects on the expression of genes involved in immunity and enhances the effect of a high-fat diet in terms of weight gain.³⁰ If the antibiotic exposure is limited to early life, the effect on the microbiota is transient, but the mice still gain weight. If the microbiota from the mice who received penicillin is transferred to germ-free mice, the recipients also become fat, indicating that the bacteria, not the antibiotics per se, cause the weight gain.

In other experiments,³¹ a series of short, therapeutic doses of antibiotics early in life modeled after those given to children to treat their acute infections caused long-term changes in the composition of the microbiome and in metabolism.

A single course of a macrolide antibiotic also had long-term effects on the microbial population and on the host’s ileal gene expression, T-cell populations, and secretory immunoglobulin A expression.³² These effects were seen only in mice that had a microbiome to begin with, not in germ-free mice, indicating that the antibiotics had their effect through the changes in the microbiome, not directly. But when germ-free mice received a fecal transplant of an impaired microbiome, it was sufficient to affect immunity.

In nonobese diabetic mice, treatment with antibiotics early in life altered the gut microbiome and its metabolic capacities, intestinal gene expression, and T-cell populations, accelerating the onset of type 1 diabetes.³³

In a study in Danish children,³⁴ the likelihood of inflammatory bowel disease increased with early-life antibiotic exposure: the more courses the child received, the greater the likelihood of disease. This observation led researchers to wonder if an antibiotic-altered microbiome affects the outcome of inflammatory bowel disease in the next generation.³⁵ Germ-free female mice who received microbiota from mice who had received antibiotics passed the altered microbiome to their pups. Mice lacking the gene for interleukin 10 are genetically susceptible to colitis, and when this experiment was done in mice lacking this gene, the offspring developed markedly more colitis. This indicated the mothers could pass down their altered microbiome to the next generation and that it would affect their risk of disease.

WHAT CAN WE DO?

All physicians must adhere to the principles of antibiotic stewardship,³⁶ not only to prevent the development of resistant strains of pathogens and the overgrowth of potentially dangerous species such as Clostridium difficile, but also, possibly, to prevent the loss of diversity in the human microbiome and thus discourage the development of chronic diseases.

In the future, as we discover more about the microbiome and the optimal mix of bacteria to carry, this information may find practical application in medicine. A pediatrician, for example, may want to analyze a child’s microbiome and, if it is abnormal, administer specific organisms to reshape it.

With intensive insulin regimens and home blood glucose monitoring, patients with type 1 diabetes are controlling their blood glucose better than in the past. Nevertheless, glucose regulation is still imperfect and tedious, and striving for tight glycemic control poses the risk of hypoglycemia.

Prominent among the challenges are the sheer numbers involved. Some 1.25 million Americans have type 1 diabetes, and another 30 million have type 2, but only about 7,000 to 8,000 pancreases are available for transplant each year.¹ While awaiting a breakthrough—perhaps involving stem cells, perhaps involving organs obtained from animals—an insulin pump may offer better diabetes control for many. Another possibility is a closed-loop system with a continuous glucose monitor that drives a dual-infusion pump, delivering insulin when glucose levels rise too high, and glucagon when they dip too low.

DIABETES WAS KNOWN IN ANCIENT TIMES

About 3,000 years ago, Egyptians described the syndrome of thirst, emaciation, and sweet urine that attracted ants. The term diabetes (Greek for siphon) was first recorded in 1425; mellitus (Latin for sweet with honey) was not added until 1675.

In 1857, Bernard hypothesized that diabetes was caused by overproduction of glucose in the liver. This idea was replaced in 1889, when Mering and Minkowski proposed the dysfunctional pancreas theory that eventually led to the discovery of the beta cell.²

In 1921, Banting and Best isolated insulin, and for the past 100 years subcutaneous insulin replacement has been the mainstay of treatment. But starting about 50 years ago, researchers have been looking for safe and long-lasting ways to replace beta cells and eliminate the need for exogenous insulin replacement.

TRANSPLANTING THE WHOLE PANCREAS

The first whole-pancreas transplant was performed in 1966 by Kelly et al,³ followed by 13 more by 1973.⁴ These first transplant grafts were short-lived, with only 1 graft surviving longer than 1 year. Since then, more than 12,000 pancreases have been transplanted worldwide, as refinements in surgical techniques and immunosuppressive therapies have improved patient and graft survival rates.⁴

Today, most pancreas transplants are in patients who have both type 1 diabetes and end-stage renal disease due to diabetic neph­ropathy, and most receive both a kidney and a pancreas at the same time. Far fewer patients receive a pancreas after previously receiving a kidney, or receive a pancreas alone.

The bile duct of the transplanted pancreas is usually routed into the patient’s small intestine, as nature intended, and less often into the bladder. Although bladder drainage is associated with urinary complications, it has the advantage of allowing measurement of pancreatic amylase levels in the urine to monitor for graft rejection. With simultaneous pancreas and kidney transplant, the serum creatinine concentration can also be monitored for rejection of the kidney graft.

Current immunosuppressive regimens vary but generally consist of anti-T-cell antibodies at the time of surgery, followed by lifelong treatment with the combination of a calcineurin inhibitor (cyclosporine or tacrolimus) and an antimetabolite (mycophenolate mofetil or azathioprine).

Outcomes are good. The rates of patient and graft survival are highest with simultaneous pancreas-kidney transplant, and somewhat lower with pancreas-after-kidney and pancreas-alone transplant.

Benefits of pancreas transplant

Most recipients can stop taking insulin immediately after the procedure, and their hemoglobin A_1c levels normalize and stay low for the life of the graft. Lipid levels also decrease, although this has not been directly correlated with lower risk of vascular disease.⁴

Transplant also reduces or eliminates some complications of diabetes, including retinopathy, nephropathy, cardiomyopathy, and gastropathy.

For example, in patients undergoing simultaneous pancreas-kidney transplant, diabetic nephropathy does not recur in the new kidney. Fioretto et al⁵ reported that nephropathy lesions reversed during the 10 years after pancreas transplant.

Kennedy et al^6,7 found that preexisting diabetic neuropathy improved slightly (although neurologic status did not completely return to normal) over a period of up to 42 months in a group of patients who received a pancreas transplant, whereas it tended to worsen in a control group. Both groups were assessed at baseline and at 12 and 24 months, with a subgroup followed through 42 months, and they underwent testing of motor, sensory, and autonomic function.^6,7

Disadvantages of pancreas transplant

Disadvantages of whole-pancreas transplant include hypoglycemia (usually mild), adverse effects of immunosuppression, potential for surgical complications including an increased rate of death in the first 90 days after the procedure, and cost.

In an analysis comparing the 5-year estimated costs of dialysis, kidney transplant alone from cadavers or live donors, or simultaneous pancreas-kidney transplant for diabetic patients with end-stage renal disease, the least expensive option was kidney transplant from a live donor.⁸ The most expensive option was simultaneous pancreas-kidney transplant, but quality of life was better with this option. The analysis did not consider the potential cost of long-term treatments for complications related to diabetes that could be saved with a pancreas transplant.

Data conflict regarding the risk of death with different types of pancreas transplants. A retrospective cohort study of data from 124 US transplant centers reported in 2003 found higher mortality rates in pancreas-alone transplant recipients than in patients on a transplant waiting list receiving conventional therapy.⁹ In contrast, a 2004 study reported that after the first 90 days, when the risk of death was clearly higher, mortality rates were lower after simultaneous pancreas-kidney transplant and pancreas-after-kidney transplant.¹⁰ After pancreas-alone transplant, however, mortality rates were higher than with exogenous insulin therapy.

Although outcomes have improved, fewer patients with type 1 diabetes are undergoing pancreas transplant in recent years.

Interestingly, more simultaneous pancreas-kidney transplants are being successfully performed in patients with type 2 diabetes, who now account for 8% of all simultaneous pancreas-kidney transplant recipients.¹¹ Outcomes of pancreas transplant appear to be similar regardless of diabetes type.

Bottom line

Pancreas transplant is a viable option for certain cases of complicated diabetes.

TRANSPLANTING ISLET CELLS

Despite its successes, pancreas transplant is major surgery and requires lifetime immunosuppression. Research is ongoing into a less-invasive procedure that, it is hoped, would require less immunosuppression: transplanting islets by themselves.

Islet autotransplant after pancreatectomy

For some patients with chronic pancreatitis, the only option to relieve chronic pain, narcotic dependence, and poor quality of life is to remove the pancreas. In the past, this desperate measure would instantly and inevitably cause diabetes, but not anymore.