Cirrhosis can involve “precarious” changes in hemostatic pathways that tip the scales toward either bleeding or hypercoagulation, experts wrote in an American Gastroenterological Association Clinical Practice Update.

Based on current evidence, clinicians should not routinely correct thrombocytopenia and coagulopathy in patients with cirrhosis prior to low-risk procedures, such as therapeutic paracentesis, thoracentesis, and routine upper endoscopy for variceal ligation, Jacqueline G. O’Leary, MD, of Dallas VA Medical Center and her three coreviewers wrote in Gastroenterology.

To optimize clot formation prior to high-risk procedures, and in patients with active bleeding, a platelet count above 50,000 per mcL is still recommended. However, it may be more meaningful to couple that platelet target with a fibrinogen level above 120 mg/dL rather than rely on the international normalized ratio (INR), the experts wrote. Not only does INR vary significantly depending on which thromboplastin is used in the test, but “correcting” INR with a fresh frozen plasma infusion does not affect thrombin production and worsens portal hypertension. Using cryoprecipitate to replenish fibrinogen has less impact on portal hypertension. “Global tests of clot formation, such as rotational thromboelastometry (ROTEM), thromboelastography (TEG), sonorheometry, and thrombin generation may eventually have a role in the evaluation of clotting in patients with cirrhosis but currently lack validated target levels,” the experts wrote.

They advised clinicians to limit the use of blood products (such as fresh frozen plasma and pooled platelet transfusions) because of cost and the risk of exacerbated portal hypertension, infection, and immunologic complications. For severe anemia and uremia, red blood cell transfusion (250 mL) can be considered. Platelet-rich plasma from one donor is less immunologically risky than a pooled platelet transfusion. Thrombopoietin agonists are “a good alternative” to platelet transfusion but require about 10 days for response. Alternative prothrombotic therapies include oral thrombopoietin receptor agonists (avatrombopag and lusutrombopag) to boost platelet count before an invasive procedure, antifibrinolytic therapy (aminocaproic acid and tranexamic acid) for persistent bleeding from mucosal oozing or puncture wounds. Desmopressin should only be considered for patients with comorbid renal failure.

For anticoagulation, the practice update recommends considering systemic heparin infusion for cirrhotic patients with symptomatic deep venous thrombosis (DVT) or portal vein thrombosis (PVT). However, the anti–factor Xa assay will not reliably monitor response if patients have low liver-derived antithrombin III (heparin cofactor). “With newly diagnosed PVT, the decision to intervene with directed therapy rests on the extent of the thrombosis, presence or absence of attributable symptoms, and the risk of bleeding and falls,” the experts stated.

Six-month follow-up imaging is recommended to assess anticoagulation efficacy. More frequent imaging can be considered for PVT patients considered at high risk for therapeutic anticoagulation. If clots do not fully resolve after 6 months of treatment, options including extending therapy with the same agent, switching to a different anticoagulant class, or receiving transjugular intrahepatic portosystemic shunt (TIPS). “The role for TIPS in PVT is evolving and may address complications like portal hypertensive bleeding, medically refractory clot, and the need for repeated banding after variceal bleeding,” the experts noted.

Prophylaxis of DVT is recommended for all hospitalized patients with cirrhosis. Vitamin K antagonists and direct-acting oral anticoagulants (dabigatran, apixaban, rivaroxaban, and edoxaban) are alternatives to heparin for anticoagulation of cirrhotic patients with either PVT and DVT, the experts wrote. However, DOACs are not recommended for most Child-Pugh B patients or for any Child-Pugh C patients.

No funding sources or conflicts of interest were reported.

SOURCE: O’Leary JG et al. Gastroenterology. 2019. doi: 10.1053/j.gastro.2019.03.070.

Cirrhosis can involve “precarious” changes in hemostatic pathways that tip the scales toward either bleeding or hypercoagulation, experts wrote in an American Gastroenterological Association Clinical Practice Update.

Based on current evidence, clinicians should not routinely correct thrombocytopenia and coagulopathy in patients with cirrhosis prior to low-risk procedures, such as therapeutic paracentesis, thoracentesis, and routine upper endoscopy for variceal ligation, Jacqueline G. O’Leary, MD, of Dallas VA Medical Center and her three coreviewers wrote in Gastroenterology.

To optimize clot formation prior to high-risk procedures, and in patients with active bleeding, a platelet count above 50,000 per mcL is still recommended. However, it may be more meaningful to couple that platelet target with a fibrinogen level above 120 mg/dL rather than rely on the international normalized ratio (INR), the experts wrote. Not only does INR vary significantly depending on which thromboplastin is used in the test, but “correcting” INR with a fresh frozen plasma infusion does not affect thrombin production and worsens portal hypertension. Using cryoprecipitate to replenish fibrinogen has less impact on portal hypertension. “Global tests of clot formation, such as rotational thromboelastometry (ROTEM), thromboelastography (TEG), sonorheometry, and thrombin generation may eventually have a role in the evaluation of clotting in patients with cirrhosis but currently lack validated target levels,” the experts wrote.

They advised clinicians to limit the use of blood products (such as fresh frozen plasma and pooled platelet transfusions) because of cost and the risk of exacerbated portal hypertension, infection, and immunologic complications. For severe anemia and uremia, red blood cell transfusion (250 mL) can be considered. Platelet-rich plasma from one donor is less immunologically risky than a pooled platelet transfusion. Thrombopoietin agonists are “a good alternative” to platelet transfusion but require about 10 days for response. Alternative prothrombotic therapies include oral thrombopoietin receptor agonists (avatrombopag and lusutrombopag) to boost platelet count before an invasive procedure, antifibrinolytic therapy (aminocaproic acid and tranexamic acid) for persistent bleeding from mucosal oozing or puncture wounds. Desmopressin should only be considered for patients with comorbid renal failure.

For anticoagulation, the practice update recommends considering systemic heparin infusion for cirrhotic patients with symptomatic deep venous thrombosis (DVT) or portal vein thrombosis (PVT). However, the anti–factor Xa assay will not reliably monitor response if patients have low liver-derived antithrombin III (heparin cofactor). “With newly diagnosed PVT, the decision to intervene with directed therapy rests on the extent of the thrombosis, presence or absence of attributable symptoms, and the risk of bleeding and falls,” the experts stated.

Six-month follow-up imaging is recommended to assess anticoagulation efficacy. More frequent imaging can be considered for PVT patients considered at high risk for therapeutic anticoagulation. If clots do not fully resolve after 6 months of treatment, options including extending therapy with the same agent, switching to a different anticoagulant class, or receiving transjugular intrahepatic portosystemic shunt (TIPS). “The role for TIPS in PVT is evolving and may address complications like portal hypertensive bleeding, medically refractory clot, and the need for repeated banding after variceal bleeding,” the experts noted.

Prophylaxis of DVT is recommended for all hospitalized patients with cirrhosis. Vitamin K antagonists and direct-acting oral anticoagulants (dabigatran, apixaban, rivaroxaban, and edoxaban) are alternatives to heparin for anticoagulation of cirrhotic patients with either PVT and DVT, the experts wrote. However, DOACs are not recommended for most Child-Pugh B patients or for any Child-Pugh C patients.

No funding sources or conflicts of interest were reported.

SOURCE: O’Leary JG et al. Gastroenterology. 2019. doi: 10.1053/j.gastro.2019.03.070.

Cirrhosis can involve “precarious” changes in hemostatic pathways that tip the scales toward either bleeding or hypercoagulation, experts wrote in an American Gastroenterological Association Clinical Practice Update.

Based on current evidence, clinicians should not routinely correct thrombocytopenia and coagulopathy in patients with cirrhosis prior to low-risk procedures, such as therapeutic paracentesis, thoracentesis, and routine upper endoscopy for variceal ligation, Jacqueline G. O’Leary, MD, of Dallas VA Medical Center and her three coreviewers wrote in Gastroenterology.

To optimize clot formation prior to high-risk procedures, and in patients with active bleeding, a platelet count above 50,000 per mcL is still recommended. However, it may be more meaningful to couple that platelet target with a fibrinogen level above 120 mg/dL rather than rely on the international normalized ratio (INR), the experts wrote. Not only does INR vary significantly depending on which thromboplastin is used in the test, but “correcting” INR with a fresh frozen plasma infusion does not affect thrombin production and worsens portal hypertension. Using cryoprecipitate to replenish fibrinogen has less impact on portal hypertension. “Global tests of clot formation, such as rotational thromboelastometry (ROTEM), thromboelastography (TEG), sonorheometry, and thrombin generation may eventually have a role in the evaluation of clotting in patients with cirrhosis but currently lack validated target levels,” the experts wrote.

They advised clinicians to limit the use of blood products (such as fresh frozen plasma and pooled platelet transfusions) because of cost and the risk of exacerbated portal hypertension, infection, and immunologic complications. For severe anemia and uremia, red blood cell transfusion (250 mL) can be considered. Platelet-rich plasma from one donor is less immunologically risky than a pooled platelet transfusion. Thrombopoietin agonists are “a good alternative” to platelet transfusion but require about 10 days for response. Alternative prothrombotic therapies include oral thrombopoietin receptor agonists (avatrombopag and lusutrombopag) to boost platelet count before an invasive procedure, antifibrinolytic therapy (aminocaproic acid and tranexamic acid) for persistent bleeding from mucosal oozing or puncture wounds. Desmopressin should only be considered for patients with comorbid renal failure.

For anticoagulation, the practice update recommends considering systemic heparin infusion for cirrhotic patients with symptomatic deep venous thrombosis (DVT) or portal vein thrombosis (PVT). However, the anti–factor Xa assay will not reliably monitor response if patients have low liver-derived antithrombin III (heparin cofactor). “With newly diagnosed PVT, the decision to intervene with directed therapy rests on the extent of the thrombosis, presence or absence of attributable symptoms, and the risk of bleeding and falls,” the experts stated.

Six-month follow-up imaging is recommended to assess anticoagulation efficacy. More frequent imaging can be considered for PVT patients considered at high risk for therapeutic anticoagulation. If clots do not fully resolve after 6 months of treatment, options including extending therapy with the same agent, switching to a different anticoagulant class, or receiving transjugular intrahepatic portosystemic shunt (TIPS). “The role for TIPS in PVT is evolving and may address complications like portal hypertensive bleeding, medically refractory clot, and the need for repeated banding after variceal bleeding,” the experts noted.

Prophylaxis of DVT is recommended for all hospitalized patients with cirrhosis. Vitamin K antagonists and direct-acting oral anticoagulants (dabigatran, apixaban, rivaroxaban, and edoxaban) are alternatives to heparin for anticoagulation of cirrhotic patients with either PVT and DVT, the experts wrote. However, DOACs are not recommended for most Child-Pugh B patients or for any Child-Pugh C patients.

No funding sources or conflicts of interest were reported.

SOURCE: O’Leary JG et al. Gastroenterology. 2019. doi: 10.1053/j.gastro.2019.03.070.

Chronic obstructive pulmonary disease (COPD) is a systemic inflammatory disease characterized by irreversible obstructive ventilatory defects.^1-4 It is a major cause of morbidity and mortality, affecting 5% of the population in the United States and ranking as the third leading cause of death in 2008.^5,6 The goals in COPD management are to provide symptom relief, improve the quality of life, preserve lung function, and reduce the frequency of exacerbations and mortality. In this 3-part review, we discuss the management of stable COPD in the context of 3 common clinical scenarios: initiating and optimizing therapy, managing acute exacerbations, and managing advanced disease.

Case Presentation

A 65-year-old man with COPD underwent pulmonary function testing (PFT), which demonstrated an obstructive ventilatory defect: forced expiratory volume in 1 second/forced vital capacity ratio (FEV₁/FVC), 0.45; FEV₁, 2 L (65% of predicted); and diffusing capacity of the lung for carbon monoxide, 15 mL/min/mm Hg (65% of predicted). He has dyspnea with strenuous exercise but is comfortable at rest and with minimal exercise. He has had 1 exacerbation in the past year, and this was treated on an outpatient basis with steroids and antibiotics. His medication regimen includes inhaled tiotropium once daily and inhaled albuterol as needed that he uses roughly twice a week.

What determines the appropriate therapy for a given COPD patient?

COPD management is guided by disease severity that is measured using a multimodal staging system developed by the Global Initiative for Chronic Obstructive Lung Disease (GOLD). The initial classification adopted by the GOLD 2011 report encompassed 4 categories based on symptoms, number of exacerbations, and degree of airflow limitation on PFT. However, in 2017 the GOLD ABCD classification was modified to consider only symptoms and risk of exacerbation in classifying patients, regardless of performance on spirometry and FEV₁ (Figure 1).^7,8 This approach was intended to make therapy more individualized based on the patient clinical profile. The Table provides a summary of the recommended treatments according to classification based on the GOLD 2017 report.

The patient in our clinical scenario can be classified as GOLD category B.

What is the approach to building a pharmacologic regimen for the patient with COPD?

The backbone of the pharmacologic regimen for COPD includes short- and long-acting bronchodilators. They are usually given in an inhaled form to maximize local effects on the lungs and minimize systemic side effects. There are 2 main classes of bronchodilators, beta-agonists and muscarinic antagonists, and each targets specific receptors on the surface of airway smooth muscle cells. Beta- agonists work by stimulating beta-2 receptors, resulting in bronchodilation, while muscarinic antagonists work by blocking the bronchoconstrictor action of M3 muscarinic receptors. Inhaled corticosteroids can be added to long-acting bronchodilator therapy but cannot be used as stand-alone therapy. Theophylline is an oral bronchodilator that is used infrequently due to its narrow therapeutic index, toxicity, and multiple drug interactions.

Figure 2 presents an approach to building a treatment plan for the patient with stable COPD.

Who should be on short-acting bronchodilators? What is the best agent? Should it be scheduled or used as needed?

All patients with COPD should be an on inhaled short-acting bronchodilator as needed for relief of symptoms.⁷ Both short-acting beta-agonists (albuterol and levalbuterol) and short-acting muscarinic antagonists (ipratropium) have been shown in clinical trials and meta-analyses to improve symptoms and lung function in patients with stable COPD^9,10 and seem to have comparative efficacy when compared head-to-head in trials.¹¹ However, the airway bronchodilator effect achieved by both classes seems to be additive when used in combination and is also associated with fewer exacerbations compared to albuterol alone.¹² On the other hand, adding albuterol to ipratropium increased the bronchodilator response but did not reduce the exacerbation rate.^11-13 Inhaled short-acting beta-agonists when used as needed rather than scheduled are associated with less medication use without any significant difference in symptoms or lung function.¹⁴

The side effects related to using recommended doses of a short-acting bronchodilator are minimal. In retrospective studies, short-acting beta-agonists increased the risk of severe cardiac arrhythmias.¹⁵ Levalbuterol, the active enantiomer of albuterol (R-albuterol) developed for the theoretical benefits of reduced tachycardia, increased tolerability, and better or equal efficacy compared to racemic albuterol, failed to show a clinically significant difference in inducing tachycardia.¹⁶ Beta-agonist overuse is associated with tremor and in severe cases hypokalemia, which happens mainly when patients try to achieve maximal bronchodilation; the clinically used doses of beta agonists are associated with fewer side effects but achieve less than maximal bronchodilation.¹⁷ Ipratropium can produce systemic anticholinergic side effects, urinary retention being the most clinically significant, especially when combined with long-acting anticholinergic agents.¹⁸

In light of the above discussion, a combination of a short-acting beta-agonist and a muscarinic antagonist is recommended in all patients with COPD, unless the patient is on a long-acting muscarinic antagonist (LAMA).^7,18 In the latter case, a short-acting beta agonist used as a rescue inhaler is the best option. In our patient, albuterol was the choice for his short-acting bronchodilator, as he was using the LAMA tiotropium.

Are short-acting bronchodilators enough? What do we use for maintenance therapy?

All patients with COPD who are category B or higher according to the modified GOLD staging system should be on a long-acting bronchodilator:^7,19 either a long-acting beta-agonist (LABA) or a LAMA. Long-acting bronchodilators work on the same receptors as their short-acting counterparts but have structural differences. Salmeterol is the prototype long-acting selective beta-2 agonist. It is structurally similar to albuterol but has an elongated side chain that allows it to bind firmly to the area of beta receptors and stimulate them repetitively, resulting in an extended-duration of action.²⁰ Tiotropium on the other hand is a quaternary ammonium of ipratropium that is a nonselective muscarinic antagonist.²¹ Compared to ipratropium, tiotropium dissociates more quickly from M2 receptors, which is responsible for the undesired anticholinergic effects, while at the same time it binds M1 and M3 receptors for a prolonged time, resulting in an extended duration of action.²¹ Revefenacin is a new lung-selective LAMA that is under development and has shown promise among those with moderate to very severe COPD. Results are only limited to phase 3 trials, and clinical studies are still underway.²²

The currently available LABAs include salmeterol, formoterol, arformoterol, olodaterol, and indacaterol. The last 2 have the advantage of once-daily dosing rather than twice daily.^23,24 LABAs have been shown to improve lung function, exacerbation rate, and quality of life in multiple clinical trials.^23,25 Vilanterol is another LABA that has a long duration of action and can be used once daily,²⁶ but is only available in a combination with umeclidinium, a LAMA. Several LAMAs are approved for use in COPD, including the prototype tiotropium, in addition to aclidinium, umeclidinium, and glycopyrronium. These have been shown in clinical trials to improve lung function, symptoms, and exacerbation rate.^27-30

Patients can be started on either a LAMA or LABA depending on the individual patient's needs and the agent's adverse effects.⁷ Both have comparable adverse effects and efficacy, as detailed below. Concerning adverse effects, there is conflicting data concerning an association of cardiovascular events with both classes of long-acting bronchodilators. While clinical trials failed to show an increased risk,^25,31,32 several retrospective studies showed an increased risk of emergency room visits and hospitalizations due to tachyarrhythmias, heart failure, myocardial infarction, and stroke upon initiation of long-acting bronchodilators.^33,34 There was no difference in risk for adverse cardiovascular events between LABA and LAMA in 1 Canadian study, and slightly more with LABA in a study using an American database.^33,34 Wang et al reported that the risk of cardiovascular adverse effects, defined as hospitalizations and emergency room visits from heart failure, arrythmia, stroke, or ischemia, was 1.5 times the baseline risk in the first 30 days of starting a LABA or LAMA.³⁵ The risk was subsequently the same as baseline or even lower after that period. Urinary retention is another possible complication of LAMA supported by evidence from meta-analyses and retrospective studies, but not clinical trials; the possibility of urinary retention should be discussed with patients upon initiation.^36,37 Concerns about increased mortality with the soft mist formulation of tiotropium were put to rest by the Tiotropium Safety and Performance in Respimat (TIOSPIR) trial, which showed no increased mortality compared to Handihaler.³⁸

As far as efficacy and benefits, tiotropium and salmeterol were compared head-to-head in a clinical trial, and tiotropium increased the time before developing first exacerbation and decreased the overall rate of exacerbations.³⁹ No difference in hospitalization rate or mortality was noted in 1 meta-analysis, although tiotropium was more effective in reducing exacerbations.⁴⁰ The choice of agent should be made based on patient comorbidities and side effects. For example, an elderly patient with severe benign prostatic hyperplasia and urinary retention should try a LABA, while a LAMA would be a better first agent for a patient with severe tachycardia induced by albuterol.

What is the role of inhaled corticosteroids in COPD?

Inhaled corticosteroids (ICS) are believed to work in COPD by reducing airway inflammation.⁴¹ ICS should not be used alone for COPD management and are always combined with a LABA.⁷ Several ICS formulations are approved for use in COPD, including budesonide and fluticasone. ICS has been shown to decrease symptoms and exacerbations, with modest effect on lung function and no change in mortality.⁴² Side effects include oral candidiasis, dysphonia, and skin bruising.⁴³ There is also an increased risk of pneumonia.⁴⁴ ICS are best reserved for patients with a component of asthma or asthma–COPD overlap syndrome (ACOS).⁴⁵ ACOS is characterized by persistent airflow limitation with several features usually associated with asthma and several features usually associated with COPD.⁴⁶

What if the patient is still symptomatic on a LABA or LAMA?

For patients whose symptoms are not controlled on one class of LABA, recommendations are to add a bronchodilator from the other class.⁷ There are also multiple combined LAMA-LABA inhalers that are approved in the United States and can possibly improve adherence to therapy. These include tiotropium-olodaterol, umeclidinium-vilanterol, glycopyrronium-indacaterol, and glycopyrrolate-formoterol. In a large systematic review and meta-analysis comparing LABA-LAMA combination to either agent alone, there was a modest improvement in post-bronchodilator FEV₁ and quality of life, with no change in hospital admissions, mortality, or adverse effects.⁴⁷ Interestingly, adding tiotropium to LABA reduced exacerbations, although adding LABA to tiotropium did not.⁴⁷

Current guidelines recommend that patients in GOLD categories C and D who are not well controlled should receive a combination of LABA-ICS.⁷ However, a new randomized trial showed better reduction of exacerbations and decreased occurrence of pneumonia in patients receiving LAMA-LABA compared to LABA-ICS.⁴⁸ In light of this new evidence, it is prudent to use a LAMA-LABA combination before adding ICS.

Triple therapy with LAMA, LABA, and ICS is a common approach for patients with severe uncontrolled disease and has been shown to decrease exacerbations and improve quality of life.^7,49 Adding tiotropium to LABA-ICS decreased exacerbations and improved quality of life and airflow in the landmark UPLIFT trial.²⁷ In another clinical trial, triple therapy with LAMA, LABA, and ICS compared to tiotropium alone decreased severe exacerbations, pre-bronchodilator FEV₁, and morning symptoms.⁵⁰ A combination of triple therapy with fluticasone furoate, umeclidinium, and vilanterol was recently noted to result in a lower rate of moderate or severe COPD exacerbations, preserve lung function, and maintain health-related quality of life, as compared with fluticasone furoate/vilanterol or umeclidinium/vilanterol combination therapy among those with symptomatic COPD with a history of exacerbations.⁵¹

Is there a role for theophylline? Other agents?

Theophylline

Theophylline is an oral adenosine diphosphate antagonist with indirect adrenergic activity, which is responsible for the bronchodilator therapeutic effect in patients with obstructive lung disease. It is also thought to work by an additional mechanism that decreases inflammation in the airways.⁵² Theophylline has a serious adverse-effect profile that includes ventricular arrhythmias, seizures, vomiting, and tremor.⁵³ It is metabolized in the liver and has multiple drug interactions and a narrow therapeutic index. It has been shown to improve lung function, gas exchange and symptoms in meta-analysis and clinical trials.^54,55

In light of the nature of the adverse effects and the wide array of safer and more effective pharmacologic agents available, theophylline should be avoided early on in the treatment of COPD. Its use can be justified as an add-on therapy in patients with refractory disease on triple therapy for symptomatic relief.⁵³ If used, the therapeutic range of theophylline for COPD is 8 to 12 mcg/mL peak level measured 3 to 7 hours after morning dose, and this level is usually achieved using a daily dose of 10 mg per kilogram of body weight for nonobese patients.⁵⁶

Systemic Steroids

Oral steroids are used in COPD exacerbations but should never be used chronically in COPD patients, regardless of disease severity, as they increase morbidity and mortality without improving symptoms or lung function.^57,58 The dose of systemic steroids should be tapered and finally discontinued.

Mucolytics

Classes of mucolytics include thiol derivatives, inhaled dornase alfa, hypertonic saline, and iodine preparations. Thiol derivatives such as N-acetylcysteine are the most widely studied.⁵⁹ There is no consistent evidence of beneficial role of mucolytics in COPD patients.^7,59 The PANTHEON trial showed decreased exacerbations with N-acetylcysteine (1.16 exacerbations per patient-year compared to 1.49 exacerbations per patient-year in the placebo group; risk ratio, 0.78; 95% CI, 0.67-0.90; P = 0.001) but had methodologic issues including high drop-out rate, exclusion of patients on oxygen, and a large of proportion of nonsmokers.⁶⁰

Long-Term Antibiotics

There is no role for long-term antibiotics in the management of COPD.⁷ Macrolides are an exception but are used for their anti-inflammatory effects rather than their antibiotic effects. They should be reserved for patients with frequent exacerbations on optimal therapy and will be discussed later in the review.⁶¹

What nonpharmacologic treatments are recommended for COPD patients?

Smoking cessation, oxygen therapy for severe hypoxemia (resting O₂ saturation ≤ 88% or PaO₂ ≤ 55 mm Hg), vaccination for influenza and pneumococcus, and appropriate nutrition should be provided in all COPD patients. Pulmonary rehabilitation is indicated for patients in GOLD categories B, C, and D.⁷ It improves symptoms, quality of life, exercise tolerance, and health care utilization. Beneficial effects last for about 2 years.^62,63

What other diagnoses should be considered in patients who continue to be symptomatic on optimal therapy?

Other diseases that share the same risk factors as COPD and can contribute to dyspnea, including coronary heart disease, heart failure, thromboembolic disease, and pulmonary hypertension, should be considered. In addition, all patients with refractory disease should have a careful assessment of their inhaler technique, continued smoking, need for oxygen therapy, and associated deconditioning.

Chronic obstructive pulmonary disease (COPD) is a systemic inflammatory disease characterized by irreversible obstructive ventilatory defects.^1-4 It is a major cause of morbidity and mortality, affecting 5% of the population in the United States and ranking as the third leading cause of death in 2008.^5,6 The goals in COPD management are to provide symptom relief, improve the quality of life, preserve lung function, and reduce the frequency of exacerbations and mortality. In this 3-part review, we discuss the management of stable COPD in the context of 3 common clinical scenarios: initiating and optimizing therapy, managing acute exacerbations, and managing advanced disease.

Case Presentation

A 65-year-old man with COPD underwent pulmonary function testing (PFT), which demonstrated an obstructive ventilatory defect: forced expiratory volume in 1 second/forced vital capacity ratio (FEV₁/FVC), 0.45; FEV₁, 2 L (65% of predicted); and diffusing capacity of the lung for carbon monoxide, 15 mL/min/mm Hg (65% of predicted). He has dyspnea with strenuous exercise but is comfortable at rest and with minimal exercise. He has had 1 exacerbation in the past year, and this was treated on an outpatient basis with steroids and antibiotics. His medication regimen includes inhaled tiotropium once daily and inhaled albuterol as needed that he uses roughly twice a week.

What determines the appropriate therapy for a given COPD patient?

COPD management is guided by disease severity that is measured using a multimodal staging system developed by the Global Initiative for Chronic Obstructive Lung Disease (GOLD). The initial classification adopted by the GOLD 2011 report encompassed 4 categories based on symptoms, number of exacerbations, and degree of airflow limitation on PFT. However, in 2017 the GOLD ABCD classification was modified to consider only symptoms and risk of exacerbation in classifying patients, regardless of performance on spirometry and FEV₁ (Figure 1).^7,8 This approach was intended to make therapy more individualized based on the patient clinical profile. The Table provides a summary of the recommended treatments according to classification based on the GOLD 2017 report.

The patient in our clinical scenario can be classified as GOLD category B.

What is the approach to building a pharmacologic regimen for the patient with COPD?

The backbone of the pharmacologic regimen for COPD includes short- and long-acting bronchodilators. They are usually given in an inhaled form to maximize local effects on the lungs and minimize systemic side effects. There are 2 main classes of bronchodilators, beta-agonists and muscarinic antagonists, and each targets specific receptors on the surface of airway smooth muscle cells. Beta- agonists work by stimulating beta-2 receptors, resulting in bronchodilation, while muscarinic antagonists work by blocking the bronchoconstrictor action of M3 muscarinic receptors. Inhaled corticosteroids can be added to long-acting bronchodilator therapy but cannot be used as stand-alone therapy. Theophylline is an oral bronchodilator that is used infrequently due to its narrow therapeutic index, toxicity, and multiple drug interactions.

Figure 2 presents an approach to building a treatment plan for the patient with stable COPD.

Who should be on short-acting bronchodilators? What is the best agent? Should it be scheduled or used as needed?

All patients with COPD should be an on inhaled short-acting bronchodilator as needed for relief of symptoms.⁷ Both short-acting beta-agonists (albuterol and levalbuterol) and short-acting muscarinic antagonists (ipratropium) have been shown in clinical trials and meta-analyses to improve symptoms and lung function in patients with stable COPD^9,10 and seem to have comparative efficacy when compared head-to-head in trials.¹¹ However, the airway bronchodilator effect achieved by both classes seems to be additive when used in combination and is also associated with fewer exacerbations compared to albuterol alone.¹² On the other hand, adding albuterol to ipratropium increased the bronchodilator response but did not reduce the exacerbation rate.^11-13 Inhaled short-acting beta-agonists when used as needed rather than scheduled are associated with less medication use without any significant difference in symptoms or lung function.¹⁴

The side effects related to using recommended doses of a short-acting bronchodilator are minimal. In retrospective studies, short-acting beta-agonists increased the risk of severe cardiac arrhythmias.¹⁵ Levalbuterol, the active enantiomer of albuterol (R-albuterol) developed for the theoretical benefits of reduced tachycardia, increased tolerability, and better or equal efficacy compared to racemic albuterol, failed to show a clinically significant difference in inducing tachycardia.¹⁶ Beta-agonist overuse is associated with tremor and in severe cases hypokalemia, which happens mainly when patients try to achieve maximal bronchodilation; the clinically used doses of beta agonists are associated with fewer side effects but achieve less than maximal bronchodilation.¹⁷ Ipratropium can produce systemic anticholinergic side effects, urinary retention being the most clinically significant, especially when combined with long-acting anticholinergic agents.¹⁸

In light of the above discussion, a combination of a short-acting beta-agonist and a muscarinic antagonist is recommended in all patients with COPD, unless the patient is on a long-acting muscarinic antagonist (LAMA).^7,18 In the latter case, a short-acting beta agonist used as a rescue inhaler is the best option. In our patient, albuterol was the choice for his short-acting bronchodilator, as he was using the LAMA tiotropium.

Are short-acting bronchodilators enough? What do we use for maintenance therapy?

All patients with COPD who are category B or higher according to the modified GOLD staging system should be on a long-acting bronchodilator:^7,19 either a long-acting beta-agonist (LABA) or a LAMA. Long-acting bronchodilators work on the same receptors as their short-acting counterparts but have structural differences. Salmeterol is the prototype long-acting selective beta-2 agonist. It is structurally similar to albuterol but has an elongated side chain that allows it to bind firmly to the area of beta receptors and stimulate them repetitively, resulting in an extended-duration of action.²⁰ Tiotropium on the other hand is a quaternary ammonium of ipratropium that is a nonselective muscarinic antagonist.²¹ Compared to ipratropium, tiotropium dissociates more quickly from M2 receptors, which is responsible for the undesired anticholinergic effects, while at the same time it binds M1 and M3 receptors for a prolonged time, resulting in an extended duration of action.²¹ Revefenacin is a new lung-selective LAMA that is under development and has shown promise among those with moderate to very severe COPD. Results are only limited to phase 3 trials, and clinical studies are still underway.²²

The currently available LABAs include salmeterol, formoterol, arformoterol, olodaterol, and indacaterol. The last 2 have the advantage of once-daily dosing rather than twice daily.^23,24 LABAs have been shown to improve lung function, exacerbation rate, and quality of life in multiple clinical trials.^23,25 Vilanterol is another LABA that has a long duration of action and can be used once daily,²⁶ but is only available in a combination with umeclidinium, a LAMA. Several LAMAs are approved for use in COPD, including the prototype tiotropium, in addition to aclidinium, umeclidinium, and glycopyrronium. These have been shown in clinical trials to improve lung function, symptoms, and exacerbation rate.^27-30

Patients can be started on either a LAMA or LABA depending on the individual patient's needs and the agent's adverse effects.⁷ Both have comparable adverse effects and efficacy, as detailed below. Concerning adverse effects, there is conflicting data concerning an association of cardiovascular events with both classes of long-acting bronchodilators. While clinical trials failed to show an increased risk,^25,31,32 several retrospective studies showed an increased risk of emergency room visits and hospitalizations due to tachyarrhythmias, heart failure, myocardial infarction, and stroke upon initiation of long-acting bronchodilators.^33,34 There was no difference in risk for adverse cardiovascular events between LABA and LAMA in 1 Canadian study, and slightly more with LABA in a study using an American database.^33,34 Wang et al reported that the risk of cardiovascular adverse effects, defined as hospitalizations and emergency room visits from heart failure, arrythmia, stroke, or ischemia, was 1.5 times the baseline risk in the first 30 days of starting a LABA or LAMA.³⁵ The risk was subsequently the same as baseline or even lower after that period. Urinary retention is another possible complication of LAMA supported by evidence from meta-analyses and retrospective studies, but not clinical trials; the possibility of urinary retention should be discussed with patients upon initiation.^36,37 Concerns about increased mortality with the soft mist formulation of tiotropium were put to rest by the Tiotropium Safety and Performance in Respimat (TIOSPIR) trial, which showed no increased mortality compared to Handihaler.³⁸

As far as efficacy and benefits, tiotropium and salmeterol were compared head-to-head in a clinical trial, and tiotropium increased the time before developing first exacerbation and decreased the overall rate of exacerbations.³⁹ No difference in hospitalization rate or mortality was noted in 1 meta-analysis, although tiotropium was more effective in reducing exacerbations.⁴⁰ The choice of agent should be made based on patient comorbidities and side effects. For example, an elderly patient with severe benign prostatic hyperplasia and urinary retention should try a LABA, while a LAMA would be a better first agent for a patient with severe tachycardia induced by albuterol.

What is the role of inhaled corticosteroids in COPD?

Inhaled corticosteroids (ICS) are believed to work in COPD by reducing airway inflammation.⁴¹ ICS should not be used alone for COPD management and are always combined with a LABA.⁷ Several ICS formulations are approved for use in COPD, including budesonide and fluticasone. ICS has been shown to decrease symptoms and exacerbations, with modest effect on lung function and no change in mortality.⁴² Side effects include oral candidiasis, dysphonia, and skin bruising.⁴³ There is also an increased risk of pneumonia.⁴⁴ ICS are best reserved for patients with a component of asthma or asthma–COPD overlap syndrome (ACOS).⁴⁵ ACOS is characterized by persistent airflow limitation with several features usually associated with asthma and several features usually associated with COPD.⁴⁶

What if the patient is still symptomatic on a LABA or LAMA?

For patients whose symptoms are not controlled on one class of LABA, recommendations are to add a bronchodilator from the other class.⁷ There are also multiple combined LAMA-LABA inhalers that are approved in the United States and can possibly improve adherence to therapy. These include tiotropium-olodaterol, umeclidinium-vilanterol, glycopyrronium-indacaterol, and glycopyrrolate-formoterol. In a large systematic review and meta-analysis comparing LABA-LAMA combination to either agent alone, there was a modest improvement in post-bronchodilator FEV₁ and quality of life, with no change in hospital admissions, mortality, or adverse effects.⁴⁷ Interestingly, adding tiotropium to LABA reduced exacerbations, although adding LABA to tiotropium did not.⁴⁷

Current guidelines recommend that patients in GOLD categories C and D who are not well controlled should receive a combination of LABA-ICS.⁷ However, a new randomized trial showed better reduction of exacerbations and decreased occurrence of pneumonia in patients receiving LAMA-LABA compared to LABA-ICS.⁴⁸ In light of this new evidence, it is prudent to use a LAMA-LABA combination before adding ICS.

Triple therapy with LAMA, LABA, and ICS is a common approach for patients with severe uncontrolled disease and has been shown to decrease exacerbations and improve quality of life.^7,49 Adding tiotropium to LABA-ICS decreased exacerbations and improved quality of life and airflow in the landmark UPLIFT trial.²⁷ In another clinical trial, triple therapy with LAMA, LABA, and ICS compared to tiotropium alone decreased severe exacerbations, pre-bronchodilator FEV₁, and morning symptoms.⁵⁰ A combination of triple therapy with fluticasone furoate, umeclidinium, and vilanterol was recently noted to result in a lower rate of moderate or severe COPD exacerbations, preserve lung function, and maintain health-related quality of life, as compared with fluticasone furoate/vilanterol or umeclidinium/vilanterol combination therapy among those with symptomatic COPD with a history of exacerbations.⁵¹

Is there a role for theophylline? Other agents?

Theophylline

Theophylline is an oral adenosine diphosphate antagonist with indirect adrenergic activity, which is responsible for the bronchodilator therapeutic effect in patients with obstructive lung disease. It is also thought to work by an additional mechanism that decreases inflammation in the airways.⁵² Theophylline has a serious adverse-effect profile that includes ventricular arrhythmias, seizures, vomiting, and tremor.⁵³ It is metabolized in the liver and has multiple drug interactions and a narrow therapeutic index. It has been shown to improve lung function, gas exchange and symptoms in meta-analysis and clinical trials.^54,55

In light of the nature of the adverse effects and the wide array of safer and more effective pharmacologic agents available, theophylline should be avoided early on in the treatment of COPD. Its use can be justified as an add-on therapy in patients with refractory disease on triple therapy for symptomatic relief.⁵³ If used, the therapeutic range of theophylline for COPD is 8 to 12 mcg/mL peak level measured 3 to 7 hours after morning dose, and this level is usually achieved using a daily dose of 10 mg per kilogram of body weight for nonobese patients.⁵⁶

Systemic Steroids

Oral steroids are used in COPD exacerbations but should never be used chronically in COPD patients, regardless of disease severity, as they increase morbidity and mortality without improving symptoms or lung function.^57,58 The dose of systemic steroids should be tapered and finally discontinued.

Mucolytics

Classes of mucolytics include thiol derivatives, inhaled dornase alfa, hypertonic saline, and iodine preparations. Thiol derivatives such as N-acetylcysteine are the most widely studied.⁵⁹ There is no consistent evidence of beneficial role of mucolytics in COPD patients.^7,59 The PANTHEON trial showed decreased exacerbations with N-acetylcysteine (1.16 exacerbations per patient-year compared to 1.49 exacerbations per patient-year in the placebo group; risk ratio, 0.78; 95% CI, 0.67-0.90; P = 0.001) but had methodologic issues including high drop-out rate, exclusion of patients on oxygen, and a large of proportion of nonsmokers.⁶⁰

Long-Term Antibiotics

There is no role for long-term antibiotics in the management of COPD.⁷ Macrolides are an exception but are used for their anti-inflammatory effects rather than their antibiotic effects. They should be reserved for patients with frequent exacerbations on optimal therapy and will be discussed later in the review.⁶¹

What nonpharmacologic treatments are recommended for COPD patients?

Smoking cessation, oxygen therapy for severe hypoxemia (resting O₂ saturation ≤ 88% or PaO₂ ≤ 55 mm Hg), vaccination for influenza and pneumococcus, and appropriate nutrition should be provided in all COPD patients. Pulmonary rehabilitation is indicated for patients in GOLD categories B, C, and D.⁷ It improves symptoms, quality of life, exercise tolerance, and health care utilization. Beneficial effects last for about 2 years.^62,63

What other diagnoses should be considered in patients who continue to be symptomatic on optimal therapy?

Other diseases that share the same risk factors as COPD and can contribute to dyspnea, including coronary heart disease, heart failure, thromboembolic disease, and pulmonary hypertension, should be considered. In addition, all patients with refractory disease should have a careful assessment of their inhaler technique, continued smoking, need for oxygen therapy, and associated deconditioning.

Chronic obstructive pulmonary disease (COPD) is a systemic inflammatory disease characterized by irreversible obstructive ventilatory defects.^1-4 It is a major cause of morbidity and mortality, affecting 5% of the population in the United States and ranking as the third leading cause of death in 2008.^5,6 The goals in COPD management are to provide symptom relief, improve the quality of life, preserve lung function, and reduce the frequency of exacerbations and mortality. In this 3-part review, we discuss the management of stable COPD in the context of 3 common clinical scenarios: initiating and optimizing therapy, managing acute exacerbations, and managing advanced disease.

Case Presentation

A 65-year-old man with COPD underwent pulmonary function testing (PFT), which demonstrated an obstructive ventilatory defect: forced expiratory volume in 1 second/forced vital capacity ratio (FEV₁/FVC), 0.45; FEV₁, 2 L (65% of predicted); and diffusing capacity of the lung for carbon monoxide, 15 mL/min/mm Hg (65% of predicted). He has dyspnea with strenuous exercise but is comfortable at rest and with minimal exercise. He has had 1 exacerbation in the past year, and this was treated on an outpatient basis with steroids and antibiotics. His medication regimen includes inhaled tiotropium once daily and inhaled albuterol as needed that he uses roughly twice a week.

What determines the appropriate therapy for a given COPD patient?

COPD management is guided by disease severity that is measured using a multimodal staging system developed by the Global Initiative for Chronic Obstructive Lung Disease (GOLD). The initial classification adopted by the GOLD 2011 report encompassed 4 categories based on symptoms, number of exacerbations, and degree of airflow limitation on PFT. However, in 2017 the GOLD ABCD classification was modified to consider only symptoms and risk of exacerbation in classifying patients, regardless of performance on spirometry and FEV₁ (Figure 1).^7,8 This approach was intended to make therapy more individualized based on the patient clinical profile. The Table provides a summary of the recommended treatments according to classification based on the GOLD 2017 report.

The patient in our clinical scenario can be classified as GOLD category B.

What is the approach to building a pharmacologic regimen for the patient with COPD?

The backbone of the pharmacologic regimen for COPD includes short- and long-acting bronchodilators. They are usually given in an inhaled form to maximize local effects on the lungs and minimize systemic side effects. There are 2 main classes of bronchodilators, beta-agonists and muscarinic antagonists, and each targets specific receptors on the surface of airway smooth muscle cells. Beta- agonists work by stimulating beta-2 receptors, resulting in bronchodilation, while muscarinic antagonists work by blocking the bronchoconstrictor action of M3 muscarinic receptors. Inhaled corticosteroids can be added to long-acting bronchodilator therapy but cannot be used as stand-alone therapy. Theophylline is an oral bronchodilator that is used infrequently due to its narrow therapeutic index, toxicity, and multiple drug interactions.

Figure 2 presents an approach to building a treatment plan for the patient with stable COPD.

Who should be on short-acting bronchodilators? What is the best agent? Should it be scheduled or used as needed?

All patients with COPD should be an on inhaled short-acting bronchodilator as needed for relief of symptoms.⁷ Both short-acting beta-agonists (albuterol and levalbuterol) and short-acting muscarinic antagonists (ipratropium) have been shown in clinical trials and meta-analyses to improve symptoms and lung function in patients with stable COPD^9,10 and seem to have comparative efficacy when compared head-to-head in trials.¹¹ However, the airway bronchodilator effect achieved by both classes seems to be additive when used in combination and is also associated with fewer exacerbations compared to albuterol alone.¹² On the other hand, adding albuterol to ipratropium increased the bronchodilator response but did not reduce the exacerbation rate.^11-13 Inhaled short-acting beta-agonists when used as needed rather than scheduled are associated with less medication use without any significant difference in symptoms or lung function.¹⁴

The side effects related to using recommended doses of a short-acting bronchodilator are minimal. In retrospective studies, short-acting beta-agonists increased the risk of severe cardiac arrhythmias.¹⁵ Levalbuterol, the active enantiomer of albuterol (R-albuterol) developed for the theoretical benefits of reduced tachycardia, increased tolerability, and better or equal efficacy compared to racemic albuterol, failed to show a clinically significant difference in inducing tachycardia.¹⁶ Beta-agonist overuse is associated with tremor and in severe cases hypokalemia, which happens mainly when patients try to achieve maximal bronchodilation; the clinically used doses of beta agonists are associated with fewer side effects but achieve less than maximal bronchodilation.¹⁷ Ipratropium can produce systemic anticholinergic side effects, urinary retention being the most clinically significant, especially when combined with long-acting anticholinergic agents.¹⁸

In light of the above discussion, a combination of a short-acting beta-agonist and a muscarinic antagonist is recommended in all patients with COPD, unless the patient is on a long-acting muscarinic antagonist (LAMA).^7,18 In the latter case, a short-acting beta agonist used as a rescue inhaler is the best option. In our patient, albuterol was the choice for his short-acting bronchodilator, as he was using the LAMA tiotropium.

Are short-acting bronchodilators enough? What do we use for maintenance therapy?

All patients with COPD who are category B or higher according to the modified GOLD staging system should be on a long-acting bronchodilator:^7,19 either a long-acting beta-agonist (LABA) or a LAMA. Long-acting bronchodilators work on the same receptors as their short-acting counterparts but have structural differences. Salmeterol is the prototype long-acting selective beta-2 agonist. It is structurally similar to albuterol but has an elongated side chain that allows it to bind firmly to the area of beta receptors and stimulate them repetitively, resulting in an extended-duration of action.²⁰ Tiotropium on the other hand is a quaternary ammonium of ipratropium that is a nonselective muscarinic antagonist.²¹ Compared to ipratropium, tiotropium dissociates more quickly from M2 receptors, which is responsible for the undesired anticholinergic effects, while at the same time it binds M1 and M3 receptors for a prolonged time, resulting in an extended duration of action.²¹ Revefenacin is a new lung-selective LAMA that is under development and has shown promise among those with moderate to very severe COPD. Results are only limited to phase 3 trials, and clinical studies are still underway.²²

The currently available LABAs include salmeterol, formoterol, arformoterol, olodaterol, and indacaterol. The last 2 have the advantage of once-daily dosing rather than twice daily.^23,24 LABAs have been shown to improve lung function, exacerbation rate, and quality of life in multiple clinical trials.^23,25 Vilanterol is another LABA that has a long duration of action and can be used once daily,²⁶ but is only available in a combination with umeclidinium, a LAMA. Several LAMAs are approved for use in COPD, including the prototype tiotropium, in addition to aclidinium, umeclidinium, and glycopyrronium. These have been shown in clinical trials to improve lung function, symptoms, and exacerbation rate.^27-30

Patients can be started on either a LAMA or LABA depending on the individual patient's needs and the agent's adverse effects.⁷ Both have comparable adverse effects and efficacy, as detailed below. Concerning adverse effects, there is conflicting data concerning an association of cardiovascular events with both classes of long-acting bronchodilators. While clinical trials failed to show an increased risk,^25,31,32 several retrospective studies showed an increased risk of emergency room visits and hospitalizations due to tachyarrhythmias, heart failure, myocardial infarction, and stroke upon initiation of long-acting bronchodilators.^33,34 There was no difference in risk for adverse cardiovascular events between LABA and LAMA in 1 Canadian study, and slightly more with LABA in a study using an American database.^33,34 Wang et al reported that the risk of cardiovascular adverse effects, defined as hospitalizations and emergency room visits from heart failure, arrythmia, stroke, or ischemia, was 1.5 times the baseline risk in the first 30 days of starting a LABA or LAMA.³⁵ The risk was subsequently the same as baseline or even lower after that period. Urinary retention is another possible complication of LAMA supported by evidence from meta-analyses and retrospective studies, but not clinical trials; the possibility of urinary retention should be discussed with patients upon initiation.^36,37 Concerns about increased mortality with the soft mist formulation of tiotropium were put to rest by the Tiotropium Safety and Performance in Respimat (TIOSPIR) trial, which showed no increased mortality compared to Handihaler.³⁸

As far as efficacy and benefits, tiotropium and salmeterol were compared head-to-head in a clinical trial, and tiotropium increased the time before developing first exacerbation and decreased the overall rate of exacerbations.³⁹ No difference in hospitalization rate or mortality was noted in 1 meta-analysis, although tiotropium was more effective in reducing exacerbations.⁴⁰ The choice of agent should be made based on patient comorbidities and side effects. For example, an elderly patient with severe benign prostatic hyperplasia and urinary retention should try a LABA, while a LAMA would be a better first agent for a patient with severe tachycardia induced by albuterol.

What is the role of inhaled corticosteroids in COPD?

Inhaled corticosteroids (ICS) are believed to work in COPD by reducing airway inflammation.⁴¹ ICS should not be used alone for COPD management and are always combined with a LABA.⁷ Several ICS formulations are approved for use in COPD, including budesonide and fluticasone. ICS has been shown to decrease symptoms and exacerbations, with modest effect on lung function and no change in mortality.⁴² Side effects include oral candidiasis, dysphonia, and skin bruising.⁴³ There is also an increased risk of pneumonia.⁴⁴ ICS are best reserved for patients with a component of asthma or asthma–COPD overlap syndrome (ACOS).⁴⁵ ACOS is characterized by persistent airflow limitation with several features usually associated with asthma and several features usually associated with COPD.⁴⁶

What if the patient is still symptomatic on a LABA or LAMA?

For patients whose symptoms are not controlled on one class of LABA, recommendations are to add a bronchodilator from the other class.⁷ There are also multiple combined LAMA-LABA inhalers that are approved in the United States and can possibly improve adherence to therapy. These include tiotropium-olodaterol, umeclidinium-vilanterol, glycopyrronium-indacaterol, and glycopyrrolate-formoterol. In a large systematic review and meta-analysis comparing LABA-LAMA combination to either agent alone, there was a modest improvement in post-bronchodilator FEV₁ and quality of life, with no change in hospital admissions, mortality, or adverse effects.⁴⁷ Interestingly, adding tiotropium to LABA reduced exacerbations, although adding LABA to tiotropium did not.⁴⁷

Current guidelines recommend that patients in GOLD categories C and D who are not well controlled should receive a combination of LABA-ICS.⁷ However, a new randomized trial showed better reduction of exacerbations and decreased occurrence of pneumonia in patients receiving LAMA-LABA compared to LABA-ICS.⁴⁸ In light of this new evidence, it is prudent to use a LAMA-LABA combination before adding ICS.

Triple therapy with LAMA, LABA, and ICS is a common approach for patients with severe uncontrolled disease and has been shown to decrease exacerbations and improve quality of life.^7,49 Adding tiotropium to LABA-ICS decreased exacerbations and improved quality of life and airflow in the landmark UPLIFT trial.²⁷ In another clinical trial, triple therapy with LAMA, LABA, and ICS compared to tiotropium alone decreased severe exacerbations, pre-bronchodilator FEV₁, and morning symptoms.⁵⁰ A combination of triple therapy with fluticasone furoate, umeclidinium, and vilanterol was recently noted to result in a lower rate of moderate or severe COPD exacerbations, preserve lung function, and maintain health-related quality of life, as compared with fluticasone furoate/vilanterol or umeclidinium/vilanterol combination therapy among those with symptomatic COPD with a history of exacerbations.⁵¹

Is there a role for theophylline? Other agents?

Theophylline

Theophylline is an oral adenosine diphosphate antagonist with indirect adrenergic activity, which is responsible for the bronchodilator therapeutic effect in patients with obstructive lung disease. It is also thought to work by an additional mechanism that decreases inflammation in the airways.⁵² Theophylline has a serious adverse-effect profile that includes ventricular arrhythmias, seizures, vomiting, and tremor.⁵³ It is metabolized in the liver and has multiple drug interactions and a narrow therapeutic index. It has been shown to improve lung function, gas exchange and symptoms in meta-analysis and clinical trials.^54,55

In light of the nature of the adverse effects and the wide array of safer and more effective pharmacologic agents available, theophylline should be avoided early on in the treatment of COPD. Its use can be justified as an add-on therapy in patients with refractory disease on triple therapy for symptomatic relief.⁵³ If used, the therapeutic range of theophylline for COPD is 8 to 12 mcg/mL peak level measured 3 to 7 hours after morning dose, and this level is usually achieved using a daily dose of 10 mg per kilogram of body weight for nonobese patients.⁵⁶

Systemic Steroids

Oral steroids are used in COPD exacerbations but should never be used chronically in COPD patients, regardless of disease severity, as they increase morbidity and mortality without improving symptoms or lung function.^57,58 The dose of systemic steroids should be tapered and finally discontinued.

Mucolytics

Classes of mucolytics include thiol derivatives, inhaled dornase alfa, hypertonic saline, and iodine preparations. Thiol derivatives such as N-acetylcysteine are the most widely studied.⁵⁹ There is no consistent evidence of beneficial role of mucolytics in COPD patients.^7,59 The PANTHEON trial showed decreased exacerbations with N-acetylcysteine (1.16 exacerbations per patient-year compared to 1.49 exacerbations per patient-year in the placebo group; risk ratio, 0.78; 95% CI, 0.67-0.90; P = 0.001) but had methodologic issues including high drop-out rate, exclusion of patients on oxygen, and a large of proportion of nonsmokers.⁶⁰

Long-Term Antibiotics

There is no role for long-term antibiotics in the management of COPD.⁷ Macrolides are an exception but are used for their anti-inflammatory effects rather than their antibiotic effects. They should be reserved for patients with frequent exacerbations on optimal therapy and will be discussed later in the review.⁶¹

What nonpharmacologic treatments are recommended for COPD patients?

Smoking cessation, oxygen therapy for severe hypoxemia (resting O₂ saturation ≤ 88% or PaO₂ ≤ 55 mm Hg), vaccination for influenza and pneumococcus, and appropriate nutrition should be provided in all COPD patients. Pulmonary rehabilitation is indicated for patients in GOLD categories B, C, and D.⁷ It improves symptoms, quality of life, exercise tolerance, and health care utilization. Beneficial effects last for about 2 years.^62,63

What other diagnoses should be considered in patients who continue to be symptomatic on optimal therapy?

Other diseases that share the same risk factors as COPD and can contribute to dyspnea, including coronary heart disease, heart failure, thromboembolic disease, and pulmonary hypertension, should be considered. In addition, all patients with refractory disease should have a careful assessment of their inhaler technique, continued smoking, need for oxygen therapy, and associated deconditioning.

Case Presentation

A 70-year-old man with severe chronic obstructive pulmonary disease (COPD) on oxygen therapy and obstructive sleep apnea treated with nocturnal continuous positive airway pressure was seen in the pulmonary clinic for evaluation of his dyspnea. He was symptomatic with minimal activity and had chronic cough with some sputum production. He had been hospitalized 3 times over the past 12 months and had been to the emergency department (ED) the same number of times for dyspnea. Pertinent medications included as-needed albuterol inhaler, inhaled steroids, and tiotropium 18 mcg inhaled daily. He demonstrated good inhaler technique. On examination, his vital signs were pulse 99 beats/min, oxygen saturation 94% on 2 L/min of oxygen by nasal cannula, blood pressure 126/72 mm Hg, respiratory rate 15 breaths/min, and body mass index 35 kg/m². He appeared chronically ill but in no acute distress. No wheezing or rales were heard. He had no lower extremity edema. The remainder of the exam was within normal limits. His last pulmonary function test demonstrated moderate obstruction with significant bronchodilator response to 2 puffs of albuterol. The side effects of chronic steroid therapy were impressed upon the patient and 500 mg of roflumilast was started daily. Over the course of the next 3 months, he had no further exacerbations. Roflumilast was continued. He has not required any further hospitalizations, ED visits, or oral steroid use since the last clinic visit.

What is the significance of acute exacerbations of COPD?

Acute exacerbation of COPD (AECOPD) is a frequently observed complication for many patients with COPD.^1,2 AECOPD is associated with accelerated disease progression, augmented decline in health status and quality of life, and increased mortality.³ Exacerbations account for most of the costs associated with COPD. Estimates suggest that the aggregate costs associated with the treatment of AECOPD are between $3.2 and $3.8 billion, and that annual health care costs are 10-fold greater for patients with COPD associated with acute exacerbations than for patients with COPD but without exacerbations.⁴ Hence, any intervention that could potentially minimize or prevent this complication will have far-reaching benefits to patients with COPD as well as provide significant cost saving.

How is AECOPD defined?

COPD exacerbation is defined as a baseline change of the patient’s dyspnea, cough, and/or sputum that is acute in onset, and may warrant a change in regular medication in a patient with underlying COPD.⁵ Exacerbation in clinical trials has been defined on the basis of whether an increase in the level of care beyond regular care is required primarily in the hospital or ED.⁶ Frequent exacerbations are defined as 3 symptom-defined exacerbations per year or 2 per year if defined by the need for therapy with corticosteroids, antibiotics, or both.⁷

What is the underlying pathophysiology?

AECOPD is associated with enhanced upper and lower airway and systemic inflammation. The bronchial mucosa of stable COPD patients have increased numbers of CD8+ lymphocytes and macrophages. In mild AECOPD, eosinophils are increased in the bronchial mucosa and modest elevation of neutrophils, T lymphocytes (CD3), and TNF-α positive cells has also been reported.² With more severe AECOPD, airway neutrophils are increased. Oxidative stress is a key factor in the development of airway inflammation in COPD.¹ Patients with severe exacerbations have augmented large airway interleukin-8 (IL-8) levels and increased oxidative stress as demonstrated by markers such as hydrogen peroxide and 8-isoprostane.⁶

How do acute exacerbations affect the course of the disease?

In general, as the severity of the underlying COPD increases, exacerbations become both more severe and more frequent. Patients with frequent exacerbations have a worse quality of life than patients with a history of less frequent exacerbations.⁸ Frequent exacerbations have also been linked to a decline in lung function, with studies suggesting that there might be a decline of 7 mL in forced expiratory volume in 1 second (FEV₁) per lower respiratory tract infection per year,^9,10 and approximately 8 mL per year in patients with frequent exacerbations as compared to those with sporadic exacerbations.¹¹

What are the triggers for COPD exacerbation?

Respiratory infections are estimated to trigger approximately two-thirds of exacerbations.² Viral and bacterial infections cause most exacerbations. The effect of the infective triggers is to increase inflammation, cause bronchoconstriction, edema, and mucus production, with a resultant increase in dynamic hyperinflation.¹² Thus, any intervention that reduces inflammation in COPD reduces the number and severity of exacerbations, whereas bronchodilators have an impact on exacerbation by their effects on reducing dynamic hyperinflation. The triggers for the one-third of exacerbations not triggered by infection are postulated to be related to other medical conditions, including pulmonary embolism, aspiration, heart failure, and myocardial ischemia.⁶

In recognition of the importance of preventing COPD exacerbations, the American College of Chest Physicians and Canadian Thoracic Society⁵ have published an evidence-informed clinical guideline specifically examining the prevention of AECOPD, with the goal of assisting clinicians in providing optimal management for COPD patients. The following pharmacologic agents have been recognized as being effective at reducing the frequency of acute exacerbations without any impact on the severity of COPD itself.

Roflumilast

Phosphodiesterase 4 (PDE4) inhibition appears to have inflammatory-modulating properties in the airways, although the exact mechanism of action is unclear. Some have proposed that it reduces inflammation by inhibiting the breakdown of intracellular cyclic adenosine monophosphate.¹³ In 2 large clinical trials,^14,15 daily use of a PDE4 inhibitor (roflumilast) showed a significant (15%–18%) reduction in yearly AECOPD incidence (approximate number needed to treat: 4). This benefit was seen in patients with GOLD stage 3–4 disease (FEV₁ < 50% predicted) with the chronic bronchitic phenotype and who had experienced at least 1 exacerbation in the previous year.

Importantly, these clinical trials specifically prohibited the use of inhaled corticosteroids (ICS) and long-acting muscarinic antagonists (LAMAs). Thus, it remains unclear if PDE4 inhibition should be used as an add-on to ICS/LAMA therapy in patients who continue to have frequent AECOPD or whether PDE4 inhibition could be used instead of these standard therapies in patients with well-controlled daily symptoms without ICS or LAMA therapy but who experience frequent exacerbations.

Of note, earlier trials with roflumilast included patients with ICS and LAMA use.^14,16 These trials were focused on FEV₁ improvement and found no benefit. It was only in post ad hoc analyses that a reduction in AECOPD in patients with frequent exacerbations was found among those taking roflumilast, regardless of ICS or LAMA use.¹⁷ While roflumilast has documented benefit in improving lung function and reducing the rate of exacerbations, it has not been reported to decrease hospitalizations.⁴ This indicates that although the drug reduces the total number of exacerbations, it may not be as useful in preventing episodes of severe exacerbations of COPD.

Although PDE4 inhibitors are easy to administer (a once-daily pill), they are associated with significant gastrointestinal side effects (diarrhea, nausea, reduced appetite), weight loss, headache, and sleep disturbance.¹⁸ Adverse effects tend to occur early during treatment, are reversible, and lessen over time with treatment.⁶ Studies reported an average unexplained weight loss of 2 kg, and monitoring weight during treatment is advised. In addition, it is important to avoid roflumilast in underweight patients. Roflumilast should also be used with caution in depressed patients.⁵

N-acetylcysteine

N-acetylcysteine (NAC) reduces the viscosity of respiratory secretions as a result of the cleavage of the disulfide bonds and has been studied as a mucolytic agent to aid in the elimination of respiratory secretions.¹⁹ Oral NAC is quickly absorbed and is rapidly present in an active form in lung tissue and respiratory secretions after ingestion. NAC is well-tolerated except for occasional patients with GI adverse effects. The role of NAC in preventing AECOPD has been studied for more than 3 decades,^20-22 although the largest clinical trial to date was reported in 2014.²³ Taken together, the combined data demonstrate a significant reduction in the rate of COPD exacerbations associated with the use of NAC when compared with placebo (odds ratio [OR], 0.61; 95% confidence interval [CI], 0.37-0.99). Clinical guidelines suggest that in patients with moderate to severe COPD (FEV₁/forced vital capacity ratio < 0.7, and FEV₁ < 80% predicted) receiving maintenance bronchodilator therapy combined with ICS and history of 2 more exacerbations in the previous 2 years, treatment with oral NAC can be administered to prevent AECOPD.

Macrolides

Continuous prophylactic use of antibiotics in older studies had no effect on the frequency of AECOPD.^24,25 But it is known that macrolide antibiotics have several antimicrobial, anti-inflammatory and immunomodulating effects and have been used for many years in the management of other chronic airway disease, including diffuse pan-bronchiolitis and cystic fibrosis.⁵ One recent study showed that the use of once-daily generic azithromycin 5 days per week appeared to have an impact on AECOPD incidence.²⁶ In this study, the rate of AECOPD was reduced from 1.83 to 1.48 exacerbations per patient-year (relative risk, 0.83; 95% CI, 0.72–0.95; P = 0.01). Azithromycin also prevented severe AECOPD. Greater benefit was obtained with milder forms of the disease and in the elderly. Azithromycin did not appear to provide any benefit in those who continued to smoke (hazard ratio, 0.99).²⁷ Other studies have shown that azithromycin was associated with an increased incidence of bacterial resistance and impaired hearing.²⁸ Overall data from the available clinical trials are robust and demonstrate that regular macrolide therapy definitely reduces the risk of AECOPD. Due to potential adverse effects, however, macrolide therapy is an option rather than a strong recommendation.⁵ The prescribing clinician also needs to consider potential of prolongation of the QT interval.²⁶

Immunostimulants

Immunostimulants have also been reported to reduce frequency of AECOPD.^29,30 Bacterial lysates, reconstituted mixtures of bacterial antigens present in the lower airways of COPD patients, act as immunostimulants through the induction of cellular maturation, stimulating lymphocyte chemotaxis and increasing opsonization when administered to individuals with COPD.⁶ Studies have demonstrated a reduction in the severe complications of exacerbations and hospital admissions in COPD patients with OM-85, a detoxified oral immunoactive bacterial extract.^29,30 However, most of these trials were conducted prior to the routine use of long-acting bronchodilators and ICS in COPD. A study that evaluated the efficacy of ismigen, a bacterial lysate, in reducing AECOPD³¹ found no difference in the exacerbation rate between ismigen and placebo or the time to first exacerbation. Additional studies are needed to examine the long-term effects of this therapy in patients receiving currently recommended COPD maintenance therapy.⁶

β-Blockers

Observational studies of β-blocker use in preventing AECOPD have yielded encouraging results, with one study showing a reduction in AECOPD risk (incidence risk ratio, 0.73; 95% CI, 0.60–0.90) in patients receiving β-blockers versus those not on β-blockers.³² Based on these findings, a clinical trial investigating the impact of metoprolol on risk of AECOPD is ongoing.³³

Proton Pump Inhibitors

Gastroesophageal reflux disease is an independent risk factor for exacerbations.³⁴ Two small, single-center studies,^35,36 have shown that use of lansoprazole decreases the risk and frequency of AECOPD. However, data from the Predicting Outcome using Systemic Markers in Severe Exacerbations of COPD (PROMISE-COPD) study,⁶ which was a multicenter prospective observational study, suggested that patients with stable COPD receiving a proton pump inhibitor were at high risk of frequent and severe exacerbations.³⁷ Thus, at this stage, their definitive role needs to be defined, possibly with a randomized, placebo-controlled study.

Case Presentation

A 70-year-old man with severe chronic obstructive pulmonary disease (COPD) on oxygen therapy and obstructive sleep apnea treated with nocturnal continuous positive airway pressure was seen in the pulmonary clinic for evaluation of his dyspnea. He was symptomatic with minimal activity and had chronic cough with some sputum production. He had been hospitalized 3 times over the past 12 months and had been to the emergency department (ED) the same number of times for dyspnea. Pertinent medications included as-needed albuterol inhaler, inhaled steroids, and tiotropium 18 mcg inhaled daily. He demonstrated good inhaler technique. On examination, his vital signs were pulse 99 beats/min, oxygen saturation 94% on 2 L/min of oxygen by nasal cannula, blood pressure 126/72 mm Hg, respiratory rate 15 breaths/min, and body mass index 35 kg/m². He appeared chronically ill but in no acute distress. No wheezing or rales were heard. He had no lower extremity edema. The remainder of the exam was within normal limits. His last pulmonary function test demonstrated moderate obstruction with significant bronchodilator response to 2 puffs of albuterol. The side effects of chronic steroid therapy were impressed upon the patient and 500 mg of roflumilast was started daily. Over the course of the next 3 months, he had no further exacerbations. Roflumilast was continued. He has not required any further hospitalizations, ED visits, or oral steroid use since the last clinic visit.

What is the significance of acute exacerbations of COPD?

Acute exacerbation of COPD (AECOPD) is a frequently observed complication for many patients with COPD.^1,2 AECOPD is associated with accelerated disease progression, augmented decline in health status and quality of life, and increased mortality.³ Exacerbations account for most of the costs associated with COPD. Estimates suggest that the aggregate costs associated with the treatment of AECOPD are between $3.2 and $3.8 billion, and that annual health care costs are 10-fold greater for patients with COPD associated with acute exacerbations than for patients with COPD but without exacerbations.⁴ Hence, any intervention that could potentially minimize or prevent this complication will have far-reaching benefits to patients with COPD as well as provide significant cost saving.

How is AECOPD defined?

COPD exacerbation is defined as a baseline change of the patient’s dyspnea, cough, and/or sputum that is acute in onset, and may warrant a change in regular medication in a patient with underlying COPD.⁵ Exacerbation in clinical trials has been defined on the basis of whether an increase in the level of care beyond regular care is required primarily in the hospital or ED.⁶ Frequent exacerbations are defined as 3 symptom-defined exacerbations per year or 2 per year if defined by the need for therapy with corticosteroids, antibiotics, or both.⁷

What is the underlying pathophysiology?

AECOPD is associated with enhanced upper and lower airway and systemic inflammation. The bronchial mucosa of stable COPD patients have increased numbers of CD8+ lymphocytes and macrophages. In mild AECOPD, eosinophils are increased in the bronchial mucosa and modest elevation of neutrophils, T lymphocytes (CD3), and TNF-α positive cells has also been reported.² With more severe AECOPD, airway neutrophils are increased. Oxidative stress is a key factor in the development of airway inflammation in COPD.¹ Patients with severe exacerbations have augmented large airway interleukin-8 (IL-8) levels and increased oxidative stress as demonstrated by markers such as hydrogen peroxide and 8-isoprostane.⁶

How do acute exacerbations affect the course of the disease?

In general, as the severity of the underlying COPD increases, exacerbations become both more severe and more frequent. Patients with frequent exacerbations have a worse quality of life than patients with a history of less frequent exacerbations.⁸ Frequent exacerbations have also been linked to a decline in lung function, with studies suggesting that there might be a decline of 7 mL in forced expiratory volume in 1 second (FEV₁) per lower respiratory tract infection per year,^9,10 and approximately 8 mL per year in patients with frequent exacerbations as compared to those with sporadic exacerbations.¹¹

What are the triggers for COPD exacerbation?

Respiratory infections are estimated to trigger approximately two-thirds of exacerbations.² Viral and bacterial infections cause most exacerbations. The effect of the infective triggers is to increase inflammation, cause bronchoconstriction, edema, and mucus production, with a resultant increase in dynamic hyperinflation.¹² Thus, any intervention that reduces inflammation in COPD reduces the number and severity of exacerbations, whereas bronchodilators have an impact on exacerbation by their effects on reducing dynamic hyperinflation. The triggers for the one-third of exacerbations not triggered by infection are postulated to be related to other medical conditions, including pulmonary embolism, aspiration, heart failure, and myocardial ischemia.⁶

In recognition of the importance of preventing COPD exacerbations, the American College of Chest Physicians and Canadian Thoracic Society⁵ have published an evidence-informed clinical guideline specifically examining the prevention of AECOPD, with the goal of assisting clinicians in providing optimal management for COPD patients. The following pharmacologic agents have been recognized as being effective at reducing the frequency of acute exacerbations without any impact on the severity of COPD itself.

Roflumilast

Phosphodiesterase 4 (PDE4) inhibition appears to have inflammatory-modulating properties in the airways, although the exact mechanism of action is unclear. Some have proposed that it reduces inflammation by inhibiting the breakdown of intracellular cyclic adenosine monophosphate.¹³ In 2 large clinical trials,^14,15 daily use of a PDE4 inhibitor (roflumilast) showed a significant (15%–18%) reduction in yearly AECOPD incidence (approximate number needed to treat: 4). This benefit was seen in patients with GOLD stage 3–4 disease (FEV₁ < 50% predicted) with the chronic bronchitic phenotype and who had experienced at least 1 exacerbation in the previous year.

Importantly, these clinical trials specifically prohibited the use of inhaled corticosteroids (ICS) and long-acting muscarinic antagonists (LAMAs). Thus, it remains unclear if PDE4 inhibition should be used as an add-on to ICS/LAMA therapy in patients who continue to have frequent AECOPD or whether PDE4 inhibition could be used instead of these standard therapies in patients with well-controlled daily symptoms without ICS or LAMA therapy but who experience frequent exacerbations.

Of note, earlier trials with roflumilast included patients with ICS and LAMA use.^14,16 These trials were focused on FEV₁ improvement and found no benefit. It was only in post ad hoc analyses that a reduction in AECOPD in patients with frequent exacerbations was found among those taking roflumilast, regardless of ICS or LAMA use.¹⁷ While roflumilast has documented benefit in improving lung function and reducing the rate of exacerbations, it has not been reported to decrease hospitalizations.⁴ This indicates that although the drug reduces the total number of exacerbations, it may not be as useful in preventing episodes of severe exacerbations of COPD.

Although PDE4 inhibitors are easy to administer (a once-daily pill), they are associated with significant gastrointestinal side effects (diarrhea, nausea, reduced appetite), weight loss, headache, and sleep disturbance.¹⁸ Adverse effects tend to occur early during treatment, are reversible, and lessen over time with treatment.⁶ Studies reported an average unexplained weight loss of 2 kg, and monitoring weight during treatment is advised. In addition, it is important to avoid roflumilast in underweight patients. Roflumilast should also be used with caution in depressed patients.⁵

N-acetylcysteine

N-acetylcysteine (NAC) reduces the viscosity of respiratory secretions as a result of the cleavage of the disulfide bonds and has been studied as a mucolytic agent to aid in the elimination of respiratory secretions.¹⁹ Oral NAC is quickly absorbed and is rapidly present in an active form in lung tissue and respiratory secretions after ingestion. NAC is well-tolerated except for occasional patients with GI adverse effects. The role of NAC in preventing AECOPD has been studied for more than 3 decades,^20-22 although the largest clinical trial to date was reported in 2014.²³ Taken together, the combined data demonstrate a significant reduction in the rate of COPD exacerbations associated with the use of NAC when compared with placebo (odds ratio [OR], 0.61; 95% confidence interval [CI], 0.37-0.99). Clinical guidelines suggest that in patients with moderate to severe COPD (FEV₁/forced vital capacity ratio < 0.7, and FEV₁ < 80% predicted) receiving maintenance bronchodilator therapy combined with ICS and history of 2 more exacerbations in the previous 2 years, treatment with oral NAC can be administered to prevent AECOPD.

Macrolides

Continuous prophylactic use of antibiotics in older studies had no effect on the frequency of AECOPD.^24,25 But it is known that macrolide antibiotics have several antimicrobial, anti-inflammatory and immunomodulating effects and have been used for many years in the management of other chronic airway disease, including diffuse pan-bronchiolitis and cystic fibrosis.⁵ One recent study showed that the use of once-daily generic azithromycin 5 days per week appeared to have an impact on AECOPD incidence.²⁶ In this study, the rate of AECOPD was reduced from 1.83 to 1.48 exacerbations per patient-year (relative risk, 0.83; 95% CI, 0.72–0.95; P = 0.01). Azithromycin also prevented severe AECOPD. Greater benefit was obtained with milder forms of the disease and in the elderly. Azithromycin did not appear to provide any benefit in those who continued to smoke (hazard ratio, 0.99).²⁷ Other studies have shown that azithromycin was associated with an increased incidence of bacterial resistance and impaired hearing.²⁸ Overall data from the available clinical trials are robust and demonstrate that regular macrolide therapy definitely reduces the risk of AECOPD. Due to potential adverse effects, however, macrolide therapy is an option rather than a strong recommendation.⁵ The prescribing clinician also needs to consider potential of prolongation of the QT interval.²⁶

Immunostimulants

Immunostimulants have also been reported to reduce frequency of AECOPD.^29,30 Bacterial lysates, reconstituted mixtures of bacterial antigens present in the lower airways of COPD patients, act as immunostimulants through the induction of cellular maturation, stimulating lymphocyte chemotaxis and increasing opsonization when administered to individuals with COPD.⁶ Studies have demonstrated a reduction in the severe complications of exacerbations and hospital admissions in COPD patients with OM-85, a detoxified oral immunoactive bacterial extract.^29,30 However, most of these trials were conducted prior to the routine use of long-acting bronchodilators and ICS in COPD. A study that evaluated the efficacy of ismigen, a bacterial lysate, in reducing AECOPD³¹ found no difference in the exacerbation rate between ismigen and placebo or the time to first exacerbation. Additional studies are needed to examine the long-term effects of this therapy in patients receiving currently recommended COPD maintenance therapy.⁶

β-Blockers

Observational studies of β-blocker use in preventing AECOPD have yielded encouraging results, with one study showing a reduction in AECOPD risk (incidence risk ratio, 0.73; 95% CI, 0.60–0.90) in patients receiving β-blockers versus those not on β-blockers.³² Based on these findings, a clinical trial investigating the impact of metoprolol on risk of AECOPD is ongoing.³³

Proton Pump Inhibitors

Gastroesophageal reflux disease is an independent risk factor for exacerbations.³⁴ Two small, single-center studies,^35,36 have shown that use of lansoprazole decreases the risk and frequency of AECOPD. However, data from the Predicting Outcome using Systemic Markers in Severe Exacerbations of COPD (PROMISE-COPD) study,⁶ which was a multicenter prospective observational study, suggested that patients with stable COPD receiving a proton pump inhibitor were at high risk of frequent and severe exacerbations.³⁷ Thus, at this stage, their definitive role needs to be defined, possibly with a randomized, placebo-controlled study.

Case Presentation

A 70-year-old man with severe chronic obstructive pulmonary disease (COPD) on oxygen therapy and obstructive sleep apnea treated with nocturnal continuous positive airway pressure was seen in the pulmonary clinic for evaluation of his dyspnea. He was symptomatic with minimal activity and had chronic cough with some sputum production. He had been hospitalized 3 times over the past 12 months and had been to the emergency department (ED) the same number of times for dyspnea. Pertinent medications included as-needed albuterol inhaler, inhaled steroids, and tiotropium 18 mcg inhaled daily. He demonstrated good inhaler technique. On examination, his vital signs were pulse 99 beats/min, oxygen saturation 94% on 2 L/min of oxygen by nasal cannula, blood pressure 126/72 mm Hg, respiratory rate 15 breaths/min, and body mass index 35 kg/m². He appeared chronically ill but in no acute distress. No wheezing or rales were heard. He had no lower extremity edema. The remainder of the exam was within normal limits. His last pulmonary function test demonstrated moderate obstruction with significant bronchodilator response to 2 puffs of albuterol. The side effects of chronic steroid therapy were impressed upon the patient and 500 mg of roflumilast was started daily. Over the course of the next 3 months, he had no further exacerbations. Roflumilast was continued. He has not required any further hospitalizations, ED visits, or oral steroid use since the last clinic visit.

What is the significance of acute exacerbations of COPD?

Acute exacerbation of COPD (AECOPD) is a frequently observed complication for many patients with COPD.^1,2 AECOPD is associated with accelerated disease progression, augmented decline in health status and quality of life, and increased mortality.³ Exacerbations account for most of the costs associated with COPD. Estimates suggest that the aggregate costs associated with the treatment of AECOPD are between $3.2 and $3.8 billion, and that annual health care costs are 10-fold greater for patients with COPD associated with acute exacerbations than for patients with COPD but without exacerbations.⁴ Hence, any intervention that could potentially minimize or prevent this complication will have far-reaching benefits to patients with COPD as well as provide significant cost saving.

How is AECOPD defined?

COPD exacerbation is defined as a baseline change of the patient’s dyspnea, cough, and/or sputum that is acute in onset, and may warrant a change in regular medication in a patient with underlying COPD.⁵ Exacerbation in clinical trials has been defined on the basis of whether an increase in the level of care beyond regular care is required primarily in the hospital or ED.⁶ Frequent exacerbations are defined as 3 symptom-defined exacerbations per year or 2 per year if defined by the need for therapy with corticosteroids, antibiotics, or both.⁷

What is the underlying pathophysiology?

AECOPD is associated with enhanced upper and lower airway and systemic inflammation. The bronchial mucosa of stable COPD patients have increased numbers of CD8+ lymphocytes and macrophages. In mild AECOPD, eosinophils are increased in the bronchial mucosa and modest elevation of neutrophils, T lymphocytes (CD3), and TNF-α positive cells has also been reported.² With more severe AECOPD, airway neutrophils are increased. Oxidative stress is a key factor in the development of airway inflammation in COPD.¹ Patients with severe exacerbations have augmented large airway interleukin-8 (IL-8) levels and increased oxidative stress as demonstrated by markers such as hydrogen peroxide and 8-isoprostane.⁶

How do acute exacerbations affect the course of the disease?

In general, as the severity of the underlying COPD increases, exacerbations become both more severe and more frequent. Patients with frequent exacerbations have a worse quality of life than patients with a history of less frequent exacerbations.⁸ Frequent exacerbations have also been linked to a decline in lung function, with studies suggesting that there might be a decline of 7 mL in forced expiratory volume in 1 second (FEV₁) per lower respiratory tract infection per year,^9,10 and approximately 8 mL per year in patients with frequent exacerbations as compared to those with sporadic exacerbations.¹¹

What are the triggers for COPD exacerbation?

Respiratory infections are estimated to trigger approximately two-thirds of exacerbations.² Viral and bacterial infections cause most exacerbations. The effect of the infective triggers is to increase inflammation, cause bronchoconstriction, edema, and mucus production, with a resultant increase in dynamic hyperinflation.¹² Thus, any intervention that reduces inflammation in COPD reduces the number and severity of exacerbations, whereas bronchodilators have an impact on exacerbation by their effects on reducing dynamic hyperinflation. The triggers for the one-third of exacerbations not triggered by infection are postulated to be related to other medical conditions, including pulmonary embolism, aspiration, heart failure, and myocardial ischemia.⁶

In recognition of the importance of preventing COPD exacerbations, the American College of Chest Physicians and Canadian Thoracic Society⁵ have published an evidence-informed clinical guideline specifically examining the prevention of AECOPD, with the goal of assisting clinicians in providing optimal management for COPD patients. The following pharmacologic agents have been recognized as being effective at reducing the frequency of acute exacerbations without any impact on the severity of COPD itself.

Roflumilast

Phosphodiesterase 4 (PDE4) inhibition appears to have inflammatory-modulating properties in the airways, although the exact mechanism of action is unclear. Some have proposed that it reduces inflammation by inhibiting the breakdown of intracellular cyclic adenosine monophosphate.¹³ In 2 large clinical trials,^14,15 daily use of a PDE4 inhibitor (roflumilast) showed a significant (15%–18%) reduction in yearly AECOPD incidence (approximate number needed to treat: 4). This benefit was seen in patients with GOLD stage 3–4 disease (FEV₁ < 50% predicted) with the chronic bronchitic phenotype and who had experienced at least 1 exacerbation in the previous year.

Importantly, these clinical trials specifically prohibited the use of inhaled corticosteroids (ICS) and long-acting muscarinic antagonists (LAMAs). Thus, it remains unclear if PDE4 inhibition should be used as an add-on to ICS/LAMA therapy in patients who continue to have frequent AECOPD or whether PDE4 inhibition could be used instead of these standard therapies in patients with well-controlled daily symptoms without ICS or LAMA therapy but who experience frequent exacerbations.

Of note, earlier trials with roflumilast included patients with ICS and LAMA use.^14,16 These trials were focused on FEV₁ improvement and found no benefit. It was only in post ad hoc analyses that a reduction in AECOPD in patients with frequent exacerbations was found among those taking roflumilast, regardless of ICS or LAMA use.¹⁷ While roflumilast has documented benefit in improving lung function and reducing the rate of exacerbations, it has not been reported to decrease hospitalizations.⁴ This indicates that although the drug reduces the total number of exacerbations, it may not be as useful in preventing episodes of severe exacerbations of COPD.

Although PDE4 inhibitors are easy to administer (a once-daily pill), they are associated with significant gastrointestinal side effects (diarrhea, nausea, reduced appetite), weight loss, headache, and sleep disturbance.¹⁸ Adverse effects tend to occur early during treatment, are reversible, and lessen over time with treatment.⁶ Studies reported an average unexplained weight loss of 2 kg, and monitoring weight during treatment is advised. In addition, it is important to avoid roflumilast in underweight patients. Roflumilast should also be used with caution in depressed patients.⁵

N-acetylcysteine

N-acetylcysteine (NAC) reduces the viscosity of respiratory secretions as a result of the cleavage of the disulfide bonds and has been studied as a mucolytic agent to aid in the elimination of respiratory secretions.¹⁹ Oral NAC is quickly absorbed and is rapidly present in an active form in lung tissue and respiratory secretions after ingestion. NAC is well-tolerated except for occasional patients with GI adverse effects. The role of NAC in preventing AECOPD has been studied for more than 3 decades,^20-22 although the largest clinical trial to date was reported in 2014.²³ Taken together, the combined data demonstrate a significant reduction in the rate of COPD exacerbations associated with the use of NAC when compared with placebo (odds ratio [OR], 0.61; 95% confidence interval [CI], 0.37-0.99). Clinical guidelines suggest that in patients with moderate to severe COPD (FEV₁/forced vital capacity ratio < 0.7, and FEV₁ < 80% predicted) receiving maintenance bronchodilator therapy combined with ICS and history of 2 more exacerbations in the previous 2 years, treatment with oral NAC can be administered to prevent AECOPD.

Macrolides

Continuous prophylactic use of antibiotics in older studies had no effect on the frequency of AECOPD.^24,25 But it is known that macrolide antibiotics have several antimicrobial, anti-inflammatory and immunomodulating effects and have been used for many years in the management of other chronic airway disease, including diffuse pan-bronchiolitis and cystic fibrosis.⁵ One recent study showed that the use of once-daily generic azithromycin 5 days per week appeared to have an impact on AECOPD incidence.²⁶ In this study, the rate of AECOPD was reduced from 1.83 to 1.48 exacerbations per patient-year (relative risk, 0.83; 95% CI, 0.72–0.95; P = 0.01). Azithromycin also prevented severe AECOPD. Greater benefit was obtained with milder forms of the disease and in the elderly. Azithromycin did not appear to provide any benefit in those who continued to smoke (hazard ratio, 0.99).²⁷ Other studies have shown that azithromycin was associated with an increased incidence of bacterial resistance and impaired hearing.²⁸ Overall data from the available clinical trials are robust and demonstrate that regular macrolide therapy definitely reduces the risk of AECOPD. Due to potential adverse effects, however, macrolide therapy is an option rather than a strong recommendation.⁵ The prescribing clinician also needs to consider potential of prolongation of the QT interval.²⁶

Immunostimulants

Immunostimulants have also been reported to reduce frequency of AECOPD.^29,30 Bacterial lysates, reconstituted mixtures of bacterial antigens present in the lower airways of COPD patients, act as immunostimulants through the induction of cellular maturation, stimulating lymphocyte chemotaxis and increasing opsonization when administered to individuals with COPD.⁶ Studies have demonstrated a reduction in the severe complications of exacerbations and hospital admissions in COPD patients with OM-85, a detoxified oral immunoactive bacterial extract.^29,30 However, most of these trials were conducted prior to the routine use of long-acting bronchodilators and ICS in COPD. A study that evaluated the efficacy of ismigen, a bacterial lysate, in reducing AECOPD³¹ found no difference in the exacerbation rate between ismigen and placebo or the time to first exacerbation. Additional studies are needed to examine the long-term effects of this therapy in patients receiving currently recommended COPD maintenance therapy.⁶

β-Blockers

Observational studies of β-blocker use in preventing AECOPD have yielded encouraging results, with one study showing a reduction in AECOPD risk (incidence risk ratio, 0.73; 95% CI, 0.60–0.90) in patients receiving β-blockers versus those not on β-blockers.³² Based on these findings, a clinical trial investigating the impact of metoprolol on risk of AECOPD is ongoing.³³

Proton Pump Inhibitors

Gastroesophageal reflux disease is an independent risk factor for exacerbations.³⁴ Two small, single-center studies,^35,36 have shown that use of lansoprazole decreases the risk and frequency of AECOPD. However, data from the Predicting Outcome using Systemic Markers in Severe Exacerbations of COPD (PROMISE-COPD) study,⁶ which was a multicenter prospective observational study, suggested that patients with stable COPD receiving a proton pump inhibitor were at high risk of frequent and severe exacerbations.³⁷ Thus, at this stage, their definitive role needs to be defined, possibly with a randomized, placebo-controlled study.

Case Presentation

A 65-year-old man with severe chronic obstructive disease (COPD; forced expiratory volume in 1 second/forced vital capacity ratio [FEV₁/FVC], 27; FEV₁ 25% of predicted; residual volume 170% of predicted for his age and height) was seen in the pulmonary clinic. His medications include a long-acting beta agonist (LABA)/long-acting muscarinic antagonist (LAMA) combination that he uses twice daily as advised. He uses his rescue albuterol inhaler roughly once a week. The patient complains of severe disabling shortness of breath with exertion and severe limitation of his quality of life because of his inability to lead a normal active life. He is on 2 L/min of oxygen at all times. He has received pulmonary rehabilitation in hopes of improving his quality of life but can only climb a flight of stairs before he must stop to rest. He asks about options but does not want to consider lung transplantation today. His most recent chest computed tomography (CT) scan demonstrates upper lobe predominant emphysematous changes with no masses or nodules.

What are the patient's options at this time?

Lung volume reduction surgery (LVRS) attempts to reduce space-occupying severely diseased, hyperexpanded lung, thus allowing the relatively normal adjoining lung parenchyma to expand into the vacated space and function effectively.¹ Hence, such therapies are suitable for patients with emphysematous lungs and not those with bronchitic-predominant COPD. LVRS offers a greater chance of improvement in exercise capacity, lung function, quality of life, and dyspnea in the correctly chosen patient population, as compared with pharmacologic management alone.² However, the procedure is associated with risks, including higher short-term morbidity and mortality.² Patients with predominantly upper-lobe emphysema and a low maximal workload after rehabilitation were noted to have lower mortality, a greater probability of improvement in exercise capacity, and a greater probability of improvement in symptoms if they underwent surgery compared to medical therapy alone.² On the contrary, patients with predominantly non–upper-lobe emphysema and a high maximal workload after rehabilitation had higher mortality if they underwent surgery compared to receiving medical therapy alone.² Thus, a subgroup of patients with homogeneous emphysema symmetrically affecting the upper and lower lobes are considered to be unlikely to benefit from this surgery.^2,3

Valves and other methods of lung volume reduction such as coils, sealants, intrapulmonary vents, and thermal vapor in the bronchi or subsegmental airways have emerged as new techniques for nonsurgical lung volume reduction.^4-9 Endobronchial-valve therapy is associated with improvement in lung function and with clinical benefits that are greatest in the presence of heterogeneous lung involvement. This works by the same principle as LVRS, by reduction of the most severely diseased lung units, expansion of the more viable, less emphysematous lung results in substantial improvements in lung mechanics.^10,11 The most important complications of this procedure include pneumonia, pneumothorax, hemoptysis, and increased frequency of COPD exacerbation in the following 30 days. The fact that a high-heterogeneity subgroup had greater improvements in both the FEV₁ and distance on the 6-minute walk test than did patients with lower heterogeneity supports the use of quantitative high-resolution computed tomography (HRCT) in selecting patients for endobronchial-valve therapy.¹² The HRCT scans also help in identifying those with complete fissures, a marker of lack of collateral ventilation (CV+) between different lobes. Presence of CV+ state predicts failure of endobronchial valve and all forms of endoscopic LVRS.¹³ Bronchoscopic thermal vapor ablation (BTVA) therapy can potentially work on a subsegmental level and be successful for treatment of emphysema with lack of intact fissures on CT scans. Other methods that have the potential to be effective in those with collateral ventilation would be endoscopic coil therapy and polymeric lung volume reduction.^11,14 Unfortunately, there are no randomized controlled trial data demonstrating clinically meaningful improvement following coil therapy or polymeric lung volume reduction in this CV+ patient population. Vapor therapy is perhaps the only technique that has been found to be effective in upper lobe predominant emphysema even with CV+ status.¹³

Our patient has evidence of air trapping and emphysema based on a high residual volume. A CT scan of the chest can determine the nature of the emphysema (heterogeneous versus homogenous) and based on these findings, further determination of the best strategy for lung volume reduction can be made.

Is there a role for long-term oxygen therapy?

Long-term oxygen therapy (LTOT) used for more than 15 hours a day is thought to reduce mortality among patients with COPD and severe resting hypoxemia.^15-18 More recent studies have failed to show similar beneficial effects of LTOT. A recent study examined the effects of LTOT in randomized fashion and determined that supplemental oxygen for patients with stable COPD and resting or exercise-induced moderate desaturation did not affect the time to death or first hospitalization, time to first COPD exacerbation, time to first hospitalization for a COPD exacerbation, the rate of all hospitalizations, the rate of all COPD exacerbations, or changes in measures of quality of life, depression, anxiety, or functional status.¹⁹

Our patient is currently on long-term oxygen therapy and in spite of some uncertainty as to its benefit, it is prudent to order oxygen therapy until further clarification is available.

What is the role of pulmonary rehabilitation?

Pulmonary rehabilitation is an established treatment for patients with chronic lung disease.²⁰ Benefits include improvement in exercise tolerance, symptoms, and quality of life, with a reduction in the use of health care resources.²¹ A Spanish population-based cohort study that looked at the influence of regular physical activity on COPD showed that patients who reported low, moderate, or high physical activity had a lower risk of COPD admissions and all-cause mortality than patients with very low physical activity after adjusting for all confounders.²²

As previously mentioned, patients in GOLD categories B, C, and D should be offered pulmonary rehabilitation as part of their treatment.²³ The ideal patient is one who is not too sick to undergo rehabilitation and is motivated to improve his or her quality of life.

What is the current scope of lung transplantation in the management of severe COPD?

There is an indisputable role for lung transplantation in end-stage COPD. However, lung transplantation does not benefit all COPD patients. There is a subset of patients for whom the treatment provides a survival benefit. It has been reported that 79% of patients with an FEV₁ < 16% predicted will survive at least 1 additional year after transplant, but only 11% of patients with an FEV₁ > 25% will do so.²⁴ The pre-transplant BODE (body mass index, airflow obstruction/FEV₁, dyspnea, and exercise capacity) index score is used to identify patients who will benefit from lung transplantation.^25,26 International guidelines for the selection of lung transplant candidates identify the following patient characteristics:²⁷

• The disease is progressive, despite maximal treatment including medication, pulmonary rehabilitation, and oxygen therapy;
• The patient is not a candidate for endoscopic or surgical LVRS;
• BODE index is 5 to 6;
• The PCO₂ is greater than 50 mm Hg (6.6 kPa) and/or PO₂ is less than 60 mm Hg (8 kPa);
• FEV₁ is 25% predicted.

The perioperative mortality of lung transplantation surgery has been reduced to less than 10%. Risk of complications from surgery in the perioperative period, such as bronchial dehiscence, infectious complications, and acute rejection, have also been reduced but do occur. Chronic allograft dysfunction and the risk of lung cancer in cases of single lung transplant should be discussed with the patient before surgery.²⁸

How can we incorporate palliative care into the management plan for patients with COPD?

Among patients with end-stage COPD on home oxygen therapy who have required mechanical ventilation for an exacerbation, only 55% are alive at 1 year.²⁹ COPD patients at high risk of death within the next year of life as well as patients with refractory symptoms and unmet needs are candidates for early palliative care. Palliative care and palliative care specialists can aid in reducing symptom burden and improving quality of life among these patients and their family members, and palliative care is recommended by multiple international societies for patients with advanced COPD.^30,31 In spite of these recommendations, the utilization of palliative care resources has been dismally low.^32,33 Improving physician-patient communication regarding palliative services and patients’ unmet care needs will help ensure that COPD patients receive adequate palliative care services at the appropriate time.

Conclusion

COPD is a leading cause of morbidity and mortality in the United States and represents a significant economic burden for both individuals and society. The goals in COPD management are to provide symptom relief, improve the quality of life, preserve lung function, and reduce the frequency of exacerbations and mortality. COPD management is guided by disease severity that is measured using the GOLD multimodal staging system and requires a multidisciplinary approach. Several classes of medication are available for treatment, and a step-wise approach should be applied in building an effective pharmacologic regimen. In addition to pharmacologic therapies, nonpharmacologic therapies, including smoking cessation, vaccinations, proper nutrition, and maintaining physical activity, are an important part of long-term management. Those who continue to be symptomatic despite appropriate maximal therapy may be candidates for lung volume reduction. Palliative care services for COPD patients, which can aid in reducing symptom burden and improving quality of life, should not be overlooked.

Case Presentation

A 65-year-old man with severe chronic obstructive disease (COPD; forced expiratory volume in 1 second/forced vital capacity ratio [FEV₁/FVC], 27; FEV₁ 25% of predicted; residual volume 170% of predicted for his age and height) was seen in the pulmonary clinic. His medications include a long-acting beta agonist (LABA)/long-acting muscarinic antagonist (LAMA) combination that he uses twice daily as advised. He uses his rescue albuterol inhaler roughly once a week. The patient complains of severe disabling shortness of breath with exertion and severe limitation of his quality of life because of his inability to lead a normal active life. He is on 2 L/min of oxygen at all times. He has received pulmonary rehabilitation in hopes of improving his quality of life but can only climb a flight of stairs before he must stop to rest. He asks about options but does not want to consider lung transplantation today. His most recent chest computed tomography (CT) scan demonstrates upper lobe predominant emphysematous changes with no masses or nodules.

What are the patient's options at this time?

Lung volume reduction surgery (LVRS) attempts to reduce space-occupying severely diseased, hyperexpanded lung, thus allowing the relatively normal adjoining lung parenchyma to expand into the vacated space and function effectively.¹ Hence, such therapies are suitable for patients with emphysematous lungs and not those with bronchitic-predominant COPD. LVRS offers a greater chance of improvement in exercise capacity, lung function, quality of life, and dyspnea in the correctly chosen patient population, as compared with pharmacologic management alone.² However, the procedure is associated with risks, including higher short-term morbidity and mortality.² Patients with predominantly upper-lobe emphysema and a low maximal workload after rehabilitation were noted to have lower mortality, a greater probability of improvement in exercise capacity, and a greater probability of improvement in symptoms if they underwent surgery compared to medical therapy alone.² On the contrary, patients with predominantly non–upper-lobe emphysema and a high maximal workload after rehabilitation had higher mortality if they underwent surgery compared to receiving medical therapy alone.² Thus, a subgroup of patients with homogeneous emphysema symmetrically affecting the upper and lower lobes are considered to be unlikely to benefit from this surgery.^2,3

Valves and other methods of lung volume reduction such as coils, sealants, intrapulmonary vents, and thermal vapor in the bronchi or subsegmental airways have emerged as new techniques for nonsurgical lung volume reduction.^4-9 Endobronchial-valve therapy is associated with improvement in lung function and with clinical benefits that are greatest in the presence of heterogeneous lung involvement. This works by the same principle as LVRS, by reduction of the most severely diseased lung units, expansion of the more viable, less emphysematous lung results in substantial improvements in lung mechanics.^10,11 The most important complications of this procedure include pneumonia, pneumothorax, hemoptysis, and increased frequency of COPD exacerbation in the following 30 days. The fact that a high-heterogeneity subgroup had greater improvements in both the FEV₁ and distance on the 6-minute walk test than did patients with lower heterogeneity supports the use of quantitative high-resolution computed tomography (HRCT) in selecting patients for endobronchial-valve therapy.¹² The HRCT scans also help in identifying those with complete fissures, a marker of lack of collateral ventilation (CV+) between different lobes. Presence of CV+ state predicts failure of endobronchial valve and all forms of endoscopic LVRS.¹³ Bronchoscopic thermal vapor ablation (BTVA) therapy can potentially work on a subsegmental level and be successful for treatment of emphysema with lack of intact fissures on CT scans. Other methods that have the potential to be effective in those with collateral ventilation would be endoscopic coil therapy and polymeric lung volume reduction.^11,14 Unfortunately, there are no randomized controlled trial data demonstrating clinically meaningful improvement following coil therapy or polymeric lung volume reduction in this CV+ patient population. Vapor therapy is perhaps the only technique that has been found to be effective in upper lobe predominant emphysema even with CV+ status.¹³

Our patient has evidence of air trapping and emphysema based on a high residual volume. A CT scan of the chest can determine the nature of the emphysema (heterogeneous versus homogenous) and based on these findings, further determination of the best strategy for lung volume reduction can be made.

Is there a role for long-term oxygen therapy?

Long-term oxygen therapy (LTOT) used for more than 15 hours a day is thought to reduce mortality among patients with COPD and severe resting hypoxemia.^15-18 More recent studies have failed to show similar beneficial effects of LTOT. A recent study examined the effects of LTOT in randomized fashion and determined that supplemental oxygen for patients with stable COPD and resting or exercise-induced moderate desaturation did not affect the time to death or first hospitalization, time to first COPD exacerbation, time to first hospitalization for a COPD exacerbation, the rate of all hospitalizations, the rate of all COPD exacerbations, or changes in measures of quality of life, depression, anxiety, or functional status.¹⁹

Our patient is currently on long-term oxygen therapy and in spite of some uncertainty as to its benefit, it is prudent to order oxygen therapy until further clarification is available.

What is the role of pulmonary rehabilitation?

Pulmonary rehabilitation is an established treatment for patients with chronic lung disease.²⁰ Benefits include improvement in exercise tolerance, symptoms, and quality of life, with a reduction in the use of health care resources.²¹ A Spanish population-based cohort study that looked at the influence of regular physical activity on COPD showed that patients who reported low, moderate, or high physical activity had a lower risk of COPD admissions and all-cause mortality than patients with very low physical activity after adjusting for all confounders.²²

As previously mentioned, patients in GOLD categories B, C, and D should be offered pulmonary rehabilitation as part of their treatment.²³ The ideal patient is one who is not too sick to undergo rehabilitation and is motivated to improve his or her quality of life.

What is the current scope of lung transplantation in the management of severe COPD?

There is an indisputable role for lung transplantation in end-stage COPD. However, lung transplantation does not benefit all COPD patients. There is a subset of patients for whom the treatment provides a survival benefit. It has been reported that 79% of patients with an FEV₁ < 16% predicted will survive at least 1 additional year after transplant, but only 11% of patients with an FEV₁ > 25% will do so.²⁴ The pre-transplant BODE (body mass index, airflow obstruction/FEV₁, dyspnea, and exercise capacity) index score is used to identify patients who will benefit from lung transplantation.^25,26 International guidelines for the selection of lung transplant candidates identify the following patient characteristics:²⁷

• The disease is progressive, despite maximal treatment including medication, pulmonary rehabilitation, and oxygen therapy;
• The patient is not a candidate for endoscopic or surgical LVRS;
• BODE index is 5 to 6;
• The PCO₂ is greater than 50 mm Hg (6.6 kPa) and/or PO₂ is less than 60 mm Hg (8 kPa);
• FEV₁ is 25% predicted.

The perioperative mortality of lung transplantation surgery has been reduced to less than 10%. Risk of complications from surgery in the perioperative period, such as bronchial dehiscence, infectious complications, and acute rejection, have also been reduced but do occur. Chronic allograft dysfunction and the risk of lung cancer in cases of single lung transplant should be discussed with the patient before surgery.²⁸

How can we incorporate palliative care into the management plan for patients with COPD?

Among patients with end-stage COPD on home oxygen therapy who have required mechanical ventilation for an exacerbation, only 55% are alive at 1 year.²⁹ COPD patients at high risk of death within the next year of life as well as patients with refractory symptoms and unmet needs are candidates for early palliative care. Palliative care and palliative care specialists can aid in reducing symptom burden and improving quality of life among these patients and their family members, and palliative care is recommended by multiple international societies for patients with advanced COPD.^30,31 In spite of these recommendations, the utilization of palliative care resources has been dismally low.^32,33 Improving physician-patient communication regarding palliative services and patients’ unmet care needs will help ensure that COPD patients receive adequate palliative care services at the appropriate time.

Conclusion

COPD is a leading cause of morbidity and mortality in the United States and represents a significant economic burden for both individuals and society. The goals in COPD management are to provide symptom relief, improve the quality of life, preserve lung function, and reduce the frequency of exacerbations and mortality. COPD management is guided by disease severity that is measured using the GOLD multimodal staging system and requires a multidisciplinary approach. Several classes of medication are available for treatment, and a step-wise approach should be applied in building an effective pharmacologic regimen. In addition to pharmacologic therapies, nonpharmacologic therapies, including smoking cessation, vaccinations, proper nutrition, and maintaining physical activity, are an important part of long-term management. Those who continue to be symptomatic despite appropriate maximal therapy may be candidates for lung volume reduction. Palliative care services for COPD patients, which can aid in reducing symptom burden and improving quality of life, should not be overlooked.

Case Presentation

A 65-year-old man with severe chronic obstructive disease (COPD; forced expiratory volume in 1 second/forced vital capacity ratio [FEV₁/FVC], 27; FEV₁ 25% of predicted; residual volume 170% of predicted for his age and height) was seen in the pulmonary clinic. His medications include a long-acting beta agonist (LABA)/long-acting muscarinic antagonist (LAMA) combination that he uses twice daily as advised. He uses his rescue albuterol inhaler roughly once a week. The patient complains of severe disabling shortness of breath with exertion and severe limitation of his quality of life because of his inability to lead a normal active life. He is on 2 L/min of oxygen at all times. He has received pulmonary rehabilitation in hopes of improving his quality of life but can only climb a flight of stairs before he must stop to rest. He asks about options but does not want to consider lung transplantation today. His most recent chest computed tomography (CT) scan demonstrates upper lobe predominant emphysematous changes with no masses or nodules.

What are the patient's options at this time?

Lung volume reduction surgery (LVRS) attempts to reduce space-occupying severely diseased, hyperexpanded lung, thus allowing the relatively normal adjoining lung parenchyma to expand into the vacated space and function effectively.¹ Hence, such therapies are suitable for patients with emphysematous lungs and not those with bronchitic-predominant COPD. LVRS offers a greater chance of improvement in exercise capacity, lung function, quality of life, and dyspnea in the correctly chosen patient population, as compared with pharmacologic management alone.² However, the procedure is associated with risks, including higher short-term morbidity and mortality.² Patients with predominantly upper-lobe emphysema and a low maximal workload after rehabilitation were noted to have lower mortality, a greater probability of improvement in exercise capacity, and a greater probability of improvement in symptoms if they underwent surgery compared to medical therapy alone.² On the contrary, patients with predominantly non–upper-lobe emphysema and a high maximal workload after rehabilitation had higher mortality if they underwent surgery compared to receiving medical therapy alone.² Thus, a subgroup of patients with homogeneous emphysema symmetrically affecting the upper and lower lobes are considered to be unlikely to benefit from this surgery.^2,3

Valves and other methods of lung volume reduction such as coils, sealants, intrapulmonary vents, and thermal vapor in the bronchi or subsegmental airways have emerged as new techniques for nonsurgical lung volume reduction.^4-9 Endobronchial-valve therapy is associated with improvement in lung function and with clinical benefits that are greatest in the presence of heterogeneous lung involvement. This works by the same principle as LVRS, by reduction of the most severely diseased lung units, expansion of the more viable, less emphysematous lung results in substantial improvements in lung mechanics.^10,11 The most important complications of this procedure include pneumonia, pneumothorax, hemoptysis, and increased frequency of COPD exacerbation in the following 30 days. The fact that a high-heterogeneity subgroup had greater improvements in both the FEV₁ and distance on the 6-minute walk test than did patients with lower heterogeneity supports the use of quantitative high-resolution computed tomography (HRCT) in selecting patients for endobronchial-valve therapy.¹² The HRCT scans also help in identifying those with complete fissures, a marker of lack of collateral ventilation (CV+) between different lobes. Presence of CV+ state predicts failure of endobronchial valve and all forms of endoscopic LVRS.¹³ Bronchoscopic thermal vapor ablation (BTVA) therapy can potentially work on a subsegmental level and be successful for treatment of emphysema with lack of intact fissures on CT scans. Other methods that have the potential to be effective in those with collateral ventilation would be endoscopic coil therapy and polymeric lung volume reduction.^11,14 Unfortunately, there are no randomized controlled trial data demonstrating clinically meaningful improvement following coil therapy or polymeric lung volume reduction in this CV+ patient population. Vapor therapy is perhaps the only technique that has been found to be effective in upper lobe predominant emphysema even with CV+ status.¹³

Our patient has evidence of air trapping and emphysema based on a high residual volume. A CT scan of the chest can determine the nature of the emphysema (heterogeneous versus homogenous) and based on these findings, further determination of the best strategy for lung volume reduction can be made.

Is there a role for long-term oxygen therapy?

Long-term oxygen therapy (LTOT) used for more than 15 hours a day is thought to reduce mortality among patients with COPD and severe resting hypoxemia.^15-18 More recent studies have failed to show similar beneficial effects of LTOT. A recent study examined the effects of LTOT in randomized fashion and determined that supplemental oxygen for patients with stable COPD and resting or exercise-induced moderate desaturation did not affect the time to death or first hospitalization, time to first COPD exacerbation, time to first hospitalization for a COPD exacerbation, the rate of all hospitalizations, the rate of all COPD exacerbations, or changes in measures of quality of life, depression, anxiety, or functional status.¹⁹

Our patient is currently on long-term oxygen therapy and in spite of some uncertainty as to its benefit, it is prudent to order oxygen therapy until further clarification is available.

What is the role of pulmonary rehabilitation?

Pulmonary rehabilitation is an established treatment for patients with chronic lung disease.²⁰ Benefits include improvement in exercise tolerance, symptoms, and quality of life, with a reduction in the use of health care resources.²¹ A Spanish population-based cohort study that looked at the influence of regular physical activity on COPD showed that patients who reported low, moderate, or high physical activity had a lower risk of COPD admissions and all-cause mortality than patients with very low physical activity after adjusting for all confounders.²²

As previously mentioned, patients in GOLD categories B, C, and D should be offered pulmonary rehabilitation as part of their treatment.²³ The ideal patient is one who is not too sick to undergo rehabilitation and is motivated to improve his or her quality of life.

What is the current scope of lung transplantation in the management of severe COPD?

There is an indisputable role for lung transplantation in end-stage COPD. However, lung transplantation does not benefit all COPD patients. There is a subset of patients for whom the treatment provides a survival benefit. It has been reported that 79% of patients with an FEV₁ < 16% predicted will survive at least 1 additional year after transplant, but only 11% of patients with an FEV₁ > 25% will do so.²⁴ The pre-transplant BODE (body mass index, airflow obstruction/FEV₁, dyspnea, and exercise capacity) index score is used to identify patients who will benefit from lung transplantation.^25,26 International guidelines for the selection of lung transplant candidates identify the following patient characteristics:²⁷

• The disease is progressive, despite maximal treatment including medication, pulmonary rehabilitation, and oxygen therapy;
• The patient is not a candidate for endoscopic or surgical LVRS;
• BODE index is 5 to 6;
• The PCO₂ is greater than 50 mm Hg (6.6 kPa) and/or PO₂ is less than 60 mm Hg (8 kPa);
• FEV₁ is 25% predicted.

The perioperative mortality of lung transplantation surgery has been reduced to less than 10%. Risk of complications from surgery in the perioperative period, such as bronchial dehiscence, infectious complications, and acute rejection, have also been reduced but do occur. Chronic allograft dysfunction and the risk of lung cancer in cases of single lung transplant should be discussed with the patient before surgery.²⁸

How can we incorporate palliative care into the management plan for patients with COPD?

Among patients with end-stage COPD on home oxygen therapy who have required mechanical ventilation for an exacerbation, only 55% are alive at 1 year.²⁹ COPD patients at high risk of death within the next year of life as well as patients with refractory symptoms and unmet needs are candidates for early palliative care. Palliative care and palliative care specialists can aid in reducing symptom burden and improving quality of life among these patients and their family members, and palliative care is recommended by multiple international societies for patients with advanced COPD.^30,31 In spite of these recommendations, the utilization of palliative care resources has been dismally low.^32,33 Improving physician-patient communication regarding palliative services and patients’ unmet care needs will help ensure that COPD patients receive adequate palliative care services at the appropriate time.

Conclusion

COPD is a leading cause of morbidity and mortality in the United States and represents a significant economic burden for both individuals and society. The goals in COPD management are to provide symptom relief, improve the quality of life, preserve lung function, and reduce the frequency of exacerbations and mortality. COPD management is guided by disease severity that is measured using the GOLD multimodal staging system and requires a multidisciplinary approach. Several classes of medication are available for treatment, and a step-wise approach should be applied in building an effective pharmacologic regimen. In addition to pharmacologic therapies, nonpharmacologic therapies, including smoking cessation, vaccinations, proper nutrition, and maintaining physical activity, are an important part of long-term management. Those who continue to be symptomatic despite appropriate maximal therapy may be candidates for lung volume reduction. Palliative care services for COPD patients, which can aid in reducing symptom burden and improving quality of life, should not be overlooked.

Here are 5 articles from the July issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Cloud of inconsistency hangs over cannabis data

To take the posttest, go to: https://bit.ly/2NfjaDS
Expires February 6, 2020

2. Roux-en-Y achieves diabetes remission in majority of patients

To take the posttest, go to: https://bit.ly/2x9hLnE
Expires February 6, 2020

3. Socioeconomic status, race found to impact CPAP compliance

To take the posttest, go to: https://bit.ly/2RBpLa9
Expires February 8, 2020

4. Exercise type matters for fall prevention among elderly

To take the posttest, go to: https://bit.ly/2X26OUh
Expires February 12, 2020

5. Adult HIV patients should receive standard vaccinations, with caveats

To take the posttest, go to: https://bit.ly/2X1S7LV
Expires February 12, 2020

Here are 5 articles from the July issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Cloud of inconsistency hangs over cannabis data

To take the posttest, go to: https://bit.ly/2NfjaDS
Expires February 6, 2020

2. Roux-en-Y achieves diabetes remission in majority of patients

To take the posttest, go to: https://bit.ly/2x9hLnE
Expires February 6, 2020

3. Socioeconomic status, race found to impact CPAP compliance

To take the posttest, go to: https://bit.ly/2RBpLa9
Expires February 8, 2020

4. Exercise type matters for fall prevention among elderly

To take the posttest, go to: https://bit.ly/2X26OUh
Expires February 12, 2020

5. Adult HIV patients should receive standard vaccinations, with caveats

To take the posttest, go to: https://bit.ly/2X1S7LV
Expires February 12, 2020

Here are 5 articles from the July issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Cloud of inconsistency hangs over cannabis data

To take the posttest, go to: https://bit.ly/2NfjaDS
Expires February 6, 2020

2. Roux-en-Y achieves diabetes remission in majority of patients

To take the posttest, go to: https://bit.ly/2x9hLnE
Expires February 6, 2020

3. Socioeconomic status, race found to impact CPAP compliance

To take the posttest, go to: https://bit.ly/2RBpLa9
Expires February 8, 2020

4. Exercise type matters for fall prevention among elderly

To take the posttest, go to: https://bit.ly/2X26OUh
Expires February 12, 2020

5. Adult HIV patients should receive standard vaccinations, with caveats

To take the posttest, go to: https://bit.ly/2X1S7LV
Expires February 12, 2020

Establishing a diagnosis of hypersomnia—recurrent episodes of excessive daytime sleepiness (EDS) or prolonged nighttime sleep—requires a stepwise assessment. We describe a complex case of an older adult who presented with multiple potential causes of hypersomnolence.

CASE REPORT

Persistent daytime sleepiness

Mr. W, age 63, is a veteran with a medical history significant for severe obstructive sleep apnea (OSA), insomnia, restless leg syndrome, hypertension, and major depressive disorder. He reported long-standing EDS that was causing functional and social impairment. Mr. W’s EDS persisted despite the use of continuous positive airway pressure (CPAP) therapy. A download of his CPAP compliance summary revealed both optimal CPAP adherence (>7-hour usage for 95%) and control of OSA (Apnea Hypopnea Index <5). His Epworth Sleepiness Scale (ESS) score remained at 20 out of 24. Another clinician had previously prescribed modafinil to treat Mr. W’s EDS, which was presumed to be related to sleep apnea. At the time of assessment, Mr. W was taking modafinil, 200 mg every morning, without significant relief of his daytime somnolence. Laboratory results revealed normal liver function tests, electrolytes, and hormonal levels, and a urine toxicology was negative. Mr. W said he constantly rubbed his legs to ease his bilateral leg movement. He reported both sensory and motor components, and relief with movement and absence of sensations in the morning.¹ Gabapentin was initiated and titrated to a therapeutic dose to stabilize these symptoms.

Further contemplation led the treating clinician to investigate sleep deprivation or insomnia as potential causes of Mr. W’s daytime somnolence. Mr. W also reported occasional insomnia symptoms. To probe for the culprit of daytime sleepiness, actigraphy wrist monitoring was performed and showed no persistent insomnia or circadian rhythm disturbances.² Medication reconciliation revealed Mr. W was taking 2 medications (fluoxetine and modafinil) that made him alert, but because he took these in the morning, it was unlikely that they were affecting his sleep. Upon review of his sleep habits, Mr. W’s naps were rare and unrefreshing during the day and he was not drinking excessive amounts of caffeinated beverages.

The diagnostic uncertainty led the treating clinician to order a polysomnography sleep study (PSG) with Multiple Sleep Latency Test (MSLT), which revealed a mean sleep latency of 4.1 minutes with no rapid eye movement (REM) periods during his PSG nor next-day napping.³ The PSG showed sleep fragmentation with a sleep efficiency of 90%. The results indicated residual sleepiness secondary to OSA.

Next, the clinician prescribed dextroamphetamine, 25 mg/d, which lowered Mr. W’s ESS score by 2 points (18 out of 24). The clinician presumed that if the stimulant worked, the diagnosis would more likely fit the criteria for residual sleepiness from OSA, rather than idiopathic hypersomnia (IH). Due to a lack of efficacy and adverse effects, the patient was tapered off this medication.

Mr. W reported that he experienced sleepiness during his service in the military at age 23. He also said he did not feel refreshed if he napped during the day.

To address the hypersomnia, he was prescribed off-label sodium oxybate. Sodium oxybate was efficacious and well tolerated; it was slowly titrated up to 9 g/d. After taking sodium oxybate for 2 months, Mr. W’s ESS score diminished to 6. Currently, he reports no functional impairment. A repeat actigraphy showed minimal sleep fragmentation and a strong normal circadian rhythm.

Continue to: Identifying hypersomnia

Identifying hypersomnia

Idiopathic hypersomnia should be considered when a patient’s excessive sleep or EDS are not better explained by another sleep disorder, other medical or psychiatric disorders, or the use of illicit drugs or medications.⁴ Idiopathic hypersomnia is characterized by EDS that occurs in the absence of cataplexy and is accompanied by no more than 1 sleep-onset REM (SOREM) period on an MSLT and the preceding PSG combined. The differential diagnosis includes narcolepsy, sleep apnea, and other conditions; most importantly, insufficient sleep syndrome must be carefully considered and excluded.

In IH, evidence of hypersomnia must be demonstrated by an MSLT showing a mean sleep latency of <8 minutes or by PSG or wrist actigraphy showing a total 24-hour sleep time of >660 minutes.⁴ A prolonged and severe form of sleep inertia, consisting of prolonged difficulty waking up with repeated returns to sleep, irritability, automatic behavior, and confusion, often occurs in IH but is not pathognomonic.⁴

Naps are long—often 60 minutes—and described as unrefreshing by 46% to 78% of patients.⁴ Sleep efficiency on polysomnography is usually high (mean 90% to 94%). Self-reported total sleep time is longer than in controls and is >10 hours in at least 30% of patients.⁴ Unfortunately, symptoms and certain objective findings of IH are not unique to the disorder and are considered ubiquitous.

For Mr. W, a diagnosis of narcolepsy was unlikely due to his MSLT results. Patients with narcolepsy have cataplexy (REM dissociation) and/or at least 2 SOREM periods on MLST, or at least 1 SOREM period on MLST in conjunction with a SOREM on the preceding PSG,⁴ which Mr. W did not exhibit. Patients with narcolepsy typically take refreshing naps lasting 15 to 30 minutes. Although not unique to narcolepsy, common findings include hypnagogic hallucinations and sleep paralysis. Patients with narcolepsy typically do not have sleep inertia but, when seemingly awake, have lapses in vigilance sometimes in combination with automatic behavior, such as writing gibberish or interrupting a conversation with a completely different topic. Another characteristic PSG finding is moderate to severe sleep fragmentation, which may be due to associated periodic limb movements or instability in sleep/wake transitions.⁵ Mr. W had no history of traumatic brain injury that would suggest hypersomnolence secondary to a brain injury.

Among medical conditions, OSA is the predominant cause of EDS, but this, too, was unlikely for Mr. W because the CPAP therapy reports indicated excellent chronic use and effect. His apnea/hypopnea index was low, and the lowest oxygen saturation recorded on his pre-MSLT PSG using CPAP was 93%. Subjectively, Mr. W reported no choking, gasping, or snoring while receiving CPAP therapy.

Continue to: Restless leg syndrome...

Restless leg syndrome was excluded because after receiving gabapentin, both Mr. W and his wife reported improvement in his leg movements.

Although patients with mood disorders such as depression have normal MSLT results, Mr. W reported no excessive time lying in bed awake, which patients with depression often describe as fatigue and sleepiness. In addition, Mr. W’s score on the Clinically Useful Depression Outcome Scale indicated he was not depressed.

Mr. W’s clinician prescribed off-label sodium oxybate to address his EDS. Its potential benefit in this case may be related to its activity on gamma-aminobutyric acid (GABA_B) receptors and its effects in prolonging slow-wave sleep, which has restorative properties. This treatment’s effectiveness in this patient was surprising and without precedent. Because the causes of IH often are not precisely defined, we do not recommend administering a trial of this medication without stepwise exclusion of other causes of sleepiness as demonstrated in Pagel’s algorithm “Diagnosis and Management of Conditions That Cause Excessive Daytime Sleepiness,”⁶ available at www.aafp.org/afp/2009/0301/p391.html.

Establishing a diagnosis of hypersomnia—recurrent episodes of excessive daytime sleepiness (EDS) or prolonged nighttime sleep—requires a stepwise assessment. We describe a complex case of an older adult who presented with multiple potential causes of hypersomnolence.

CASE REPORT

Persistent daytime sleepiness

Mr. W, age 63, is a veteran with a medical history significant for severe obstructive sleep apnea (OSA), insomnia, restless leg syndrome, hypertension, and major depressive disorder. He reported long-standing EDS that was causing functional and social impairment. Mr. W’s EDS persisted despite the use of continuous positive airway pressure (CPAP) therapy. A download of his CPAP compliance summary revealed both optimal CPAP adherence (>7-hour usage for 95%) and control of OSA (Apnea Hypopnea Index <5). His Epworth Sleepiness Scale (ESS) score remained at 20 out of 24. Another clinician had previously prescribed modafinil to treat Mr. W’s EDS, which was presumed to be related to sleep apnea. At the time of assessment, Mr. W was taking modafinil, 200 mg every morning, without significant relief of his daytime somnolence. Laboratory results revealed normal liver function tests, electrolytes, and hormonal levels, and a urine toxicology was negative. Mr. W said he constantly rubbed his legs to ease his bilateral leg movement. He reported both sensory and motor components, and relief with movement and absence of sensations in the morning.¹ Gabapentin was initiated and titrated to a therapeutic dose to stabilize these symptoms.

Further contemplation led the treating clinician to investigate sleep deprivation or insomnia as potential causes of Mr. W’s daytime somnolence. Mr. W also reported occasional insomnia symptoms. To probe for the culprit of daytime sleepiness, actigraphy wrist monitoring was performed and showed no persistent insomnia or circadian rhythm disturbances.² Medication reconciliation revealed Mr. W was taking 2 medications (fluoxetine and modafinil) that made him alert, but because he took these in the morning, it was unlikely that they were affecting his sleep. Upon review of his sleep habits, Mr. W’s naps were rare and unrefreshing during the day and he was not drinking excessive amounts of caffeinated beverages.

The diagnostic uncertainty led the treating clinician to order a polysomnography sleep study (PSG) with Multiple Sleep Latency Test (MSLT), which revealed a mean sleep latency of 4.1 minutes with no rapid eye movement (REM) periods during his PSG nor next-day napping.³ The PSG showed sleep fragmentation with a sleep efficiency of 90%. The results indicated residual sleepiness secondary to OSA.

Next, the clinician prescribed dextroamphetamine, 25 mg/d, which lowered Mr. W’s ESS score by 2 points (18 out of 24). The clinician presumed that if the stimulant worked, the diagnosis would more likely fit the criteria for residual sleepiness from OSA, rather than idiopathic hypersomnia (IH). Due to a lack of efficacy and adverse effects, the patient was tapered off this medication.

Mr. W reported that he experienced sleepiness during his service in the military at age 23. He also said he did not feel refreshed if he napped during the day.

To address the hypersomnia, he was prescribed off-label sodium oxybate. Sodium oxybate was efficacious and well tolerated; it was slowly titrated up to 9 g/d. After taking sodium oxybate for 2 months, Mr. W’s ESS score diminished to 6. Currently, he reports no functional impairment. A repeat actigraphy showed minimal sleep fragmentation and a strong normal circadian rhythm.

Continue to: Identifying hypersomnia

Identifying hypersomnia

Idiopathic hypersomnia should be considered when a patient’s excessive sleep or EDS are not better explained by another sleep disorder, other medical or psychiatric disorders, or the use of illicit drugs or medications.⁴ Idiopathic hypersomnia is characterized by EDS that occurs in the absence of cataplexy and is accompanied by no more than 1 sleep-onset REM (SOREM) period on an MSLT and the preceding PSG combined. The differential diagnosis includes narcolepsy, sleep apnea, and other conditions; most importantly, insufficient sleep syndrome must be carefully considered and excluded.

In IH, evidence of hypersomnia must be demonstrated by an MSLT showing a mean sleep latency of <8 minutes or by PSG or wrist actigraphy showing a total 24-hour sleep time of >660 minutes.⁴ A prolonged and severe form of sleep inertia, consisting of prolonged difficulty waking up with repeated returns to sleep, irritability, automatic behavior, and confusion, often occurs in IH but is not pathognomonic.⁴

Naps are long—often 60 minutes—and described as unrefreshing by 46% to 78% of patients.⁴ Sleep efficiency on polysomnography is usually high (mean 90% to 94%). Self-reported total sleep time is longer than in controls and is >10 hours in at least 30% of patients.⁴ Unfortunately, symptoms and certain objective findings of IH are not unique to the disorder and are considered ubiquitous.

For Mr. W, a diagnosis of narcolepsy was unlikely due to his MSLT results. Patients with narcolepsy have cataplexy (REM dissociation) and/or at least 2 SOREM periods on MLST, or at least 1 SOREM period on MLST in conjunction with a SOREM on the preceding PSG,⁴ which Mr. W did not exhibit. Patients with narcolepsy typically take refreshing naps lasting 15 to 30 minutes. Although not unique to narcolepsy, common findings include hypnagogic hallucinations and sleep paralysis. Patients with narcolepsy typically do not have sleep inertia but, when seemingly awake, have lapses in vigilance sometimes in combination with automatic behavior, such as writing gibberish or interrupting a conversation with a completely different topic. Another characteristic PSG finding is moderate to severe sleep fragmentation, which may be due to associated periodic limb movements or instability in sleep/wake transitions.⁵ Mr. W had no history of traumatic brain injury that would suggest hypersomnolence secondary to a brain injury.

Among medical conditions, OSA is the predominant cause of EDS, but this, too, was unlikely for Mr. W because the CPAP therapy reports indicated excellent chronic use and effect. His apnea/hypopnea index was low, and the lowest oxygen saturation recorded on his pre-MSLT PSG using CPAP was 93%. Subjectively, Mr. W reported no choking, gasping, or snoring while receiving CPAP therapy.

Continue to: Restless leg syndrome...

Restless leg syndrome was excluded because after receiving gabapentin, both Mr. W and his wife reported improvement in his leg movements.

Although patients with mood disorders such as depression have normal MSLT results, Mr. W reported no excessive time lying in bed awake, which patients with depression often describe as fatigue and sleepiness. In addition, Mr. W’s score on the Clinically Useful Depression Outcome Scale indicated he was not depressed.

Mr. W’s clinician prescribed off-label sodium oxybate to address his EDS. Its potential benefit in this case may be related to its activity on gamma-aminobutyric acid (GABA_B) receptors and its effects in prolonging slow-wave sleep, which has restorative properties. This treatment’s effectiveness in this patient was surprising and without precedent. Because the causes of IH often are not precisely defined, we do not recommend administering a trial of this medication without stepwise exclusion of other causes of sleepiness as demonstrated in Pagel’s algorithm “Diagnosis and Management of Conditions That Cause Excessive Daytime Sleepiness,”⁶ available at www.aafp.org/afp/2009/0301/p391.html.

Establishing a diagnosis of hypersomnia—recurrent episodes of excessive daytime sleepiness (EDS) or prolonged nighttime sleep—requires a stepwise assessment. We describe a complex case of an older adult who presented with multiple potential causes of hypersomnolence.

CASE REPORT

Persistent daytime sleepiness

Mr. W, age 63, is a veteran with a medical history significant for severe obstructive sleep apnea (OSA), insomnia, restless leg syndrome, hypertension, and major depressive disorder. He reported long-standing EDS that was causing functional and social impairment. Mr. W’s EDS persisted despite the use of continuous positive airway pressure (CPAP) therapy. A download of his CPAP compliance summary revealed both optimal CPAP adherence (>7-hour usage for 95%) and control of OSA (Apnea Hypopnea Index <5). His Epworth Sleepiness Scale (ESS) score remained at 20 out of 24. Another clinician had previously prescribed modafinil to treat Mr. W’s EDS, which was presumed to be related to sleep apnea. At the time of assessment, Mr. W was taking modafinil, 200 mg every morning, without significant relief of his daytime somnolence. Laboratory results revealed normal liver function tests, electrolytes, and hormonal levels, and a urine toxicology was negative. Mr. W said he constantly rubbed his legs to ease his bilateral leg movement. He reported both sensory and motor components, and relief with movement and absence of sensations in the morning.¹ Gabapentin was initiated and titrated to a therapeutic dose to stabilize these symptoms.

Further contemplation led the treating clinician to investigate sleep deprivation or insomnia as potential causes of Mr. W’s daytime somnolence. Mr. W also reported occasional insomnia symptoms. To probe for the culprit of daytime sleepiness, actigraphy wrist monitoring was performed and showed no persistent insomnia or circadian rhythm disturbances.² Medication reconciliation revealed Mr. W was taking 2 medications (fluoxetine and modafinil) that made him alert, but because he took these in the morning, it was unlikely that they were affecting his sleep. Upon review of his sleep habits, Mr. W’s naps were rare and unrefreshing during the day and he was not drinking excessive amounts of caffeinated beverages.

The diagnostic uncertainty led the treating clinician to order a polysomnography sleep study (PSG) with Multiple Sleep Latency Test (MSLT), which revealed a mean sleep latency of 4.1 minutes with no rapid eye movement (REM) periods during his PSG nor next-day napping.³ The PSG showed sleep fragmentation with a sleep efficiency of 90%. The results indicated residual sleepiness secondary to OSA.

Next, the clinician prescribed dextroamphetamine, 25 mg/d, which lowered Mr. W’s ESS score by 2 points (18 out of 24). The clinician presumed that if the stimulant worked, the diagnosis would more likely fit the criteria for residual sleepiness from OSA, rather than idiopathic hypersomnia (IH). Due to a lack of efficacy and adverse effects, the patient was tapered off this medication.

Mr. W reported that he experienced sleepiness during his service in the military at age 23. He also said he did not feel refreshed if he napped during the day.

To address the hypersomnia, he was prescribed off-label sodium oxybate. Sodium oxybate was efficacious and well tolerated; it was slowly titrated up to 9 g/d. After taking sodium oxybate for 2 months, Mr. W’s ESS score diminished to 6. Currently, he reports no functional impairment. A repeat actigraphy showed minimal sleep fragmentation and a strong normal circadian rhythm.

Continue to: Identifying hypersomnia

Identifying hypersomnia

Idiopathic hypersomnia should be considered when a patient’s excessive sleep or EDS are not better explained by another sleep disorder, other medical or psychiatric disorders, or the use of illicit drugs or medications.⁴ Idiopathic hypersomnia is characterized by EDS that occurs in the absence of cataplexy and is accompanied by no more than 1 sleep-onset REM (SOREM) period on an MSLT and the preceding PSG combined. The differential diagnosis includes narcolepsy, sleep apnea, and other conditions; most importantly, insufficient sleep syndrome must be carefully considered and excluded.

In IH, evidence of hypersomnia must be demonstrated by an MSLT showing a mean sleep latency of <8 minutes or by PSG or wrist actigraphy showing a total 24-hour sleep time of >660 minutes.⁴ A prolonged and severe form of sleep inertia, consisting of prolonged difficulty waking up with repeated returns to sleep, irritability, automatic behavior, and confusion, often occurs in IH but is not pathognomonic.⁴

Naps are long—often 60 minutes—and described as unrefreshing by 46% to 78% of patients.⁴ Sleep efficiency on polysomnography is usually high (mean 90% to 94%). Self-reported total sleep time is longer than in controls and is >10 hours in at least 30% of patients.⁴ Unfortunately, symptoms and certain objective findings of IH are not unique to the disorder and are considered ubiquitous.

For Mr. W, a diagnosis of narcolepsy was unlikely due to his MSLT results. Patients with narcolepsy have cataplexy (REM dissociation) and/or at least 2 SOREM periods on MLST, or at least 1 SOREM period on MLST in conjunction with a SOREM on the preceding PSG,⁴ which Mr. W did not exhibit. Patients with narcolepsy typically take refreshing naps lasting 15 to 30 minutes. Although not unique to narcolepsy, common findings include hypnagogic hallucinations and sleep paralysis. Patients with narcolepsy typically do not have sleep inertia but, when seemingly awake, have lapses in vigilance sometimes in combination with automatic behavior, such as writing gibberish or interrupting a conversation with a completely different topic. Another characteristic PSG finding is moderate to severe sleep fragmentation, which may be due to associated periodic limb movements or instability in sleep/wake transitions.⁵ Mr. W had no history of traumatic brain injury that would suggest hypersomnolence secondary to a brain injury.

Among medical conditions, OSA is the predominant cause of EDS, but this, too, was unlikely for Mr. W because the CPAP therapy reports indicated excellent chronic use and effect. His apnea/hypopnea index was low, and the lowest oxygen saturation recorded on his pre-MSLT PSG using CPAP was 93%. Subjectively, Mr. W reported no choking, gasping, or snoring while receiving CPAP therapy.

Continue to: Restless leg syndrome...

Restless leg syndrome was excluded because after receiving gabapentin, both Mr. W and his wife reported improvement in his leg movements.

Although patients with mood disorders such as depression have normal MSLT results, Mr. W reported no excessive time lying in bed awake, which patients with depression often describe as fatigue and sleepiness. In addition, Mr. W’s score on the Clinically Useful Depression Outcome Scale indicated he was not depressed.

Mr. W’s clinician prescribed off-label sodium oxybate to address his EDS. Its potential benefit in this case may be related to its activity on gamma-aminobutyric acid (GABA_B) receptors and its effects in prolonging slow-wave sleep, which has restorative properties. This treatment’s effectiveness in this patient was surprising and without precedent. Because the causes of IH often are not precisely defined, we do not recommend administering a trial of this medication without stepwise exclusion of other causes of sleepiness as demonstrated in Pagel’s algorithm “Diagnosis and Management of Conditions That Cause Excessive Daytime Sleepiness,”⁶ available at www.aafp.org/afp/2009/0301/p391.html.

Polypharmacy is often defined as the simultaneous prescription of multiple medications (usually ≥5) to a single patient for a single condition or multiple conditions.¹ Patients with psychiatric illnesses may easily be prescribed multiple psychotropic medications regardless of how many other medications they may already take for nonpsychiatric comorbidities. According to 2011-2014 Centers for Disease Control and Prevention data, 11.9% of the US population used ≥5 medications in the past 30 days.² Risks of polypharmacy include higher rates of adverse effects as well as treatment noncompliance.³

There are, however, many patients for whom a combination of psychotropic agents can be beneficial. It is important to carefully assess your patient’s regimen, and to document the rationale for prescribing multiple medications. Here I describe some factors that can help you to determine whether a multi-medication regimen might be warranted for your patient.

Accepted medication pairings. This describes a medication combination that has been recognized as generally safe and may provide more benefits than either single agent alone. Examples of clinically accepted medication combinations include^4,5:

• a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) plus bupropion
• an SSRI or SNRI plus mirtazapine
• ziprasidone as an adjunct to valproate or lithium for treating bipolar disorder
• aripiprazole as an adjunctive treatment for major depressive disorder (MDD).

Comorbid diagnoses. Each of a patient’s psychiatric comorbidities may require a different medication to address specific symptoms.³ Psychiatric comorbidities that might be appropriate for multiple medications include attention-deficit/hyperactivity disorder and bipolar disorder, MDD and generalized anxiety disorder, and a mood disorder and a substance use disorder.

Treatment resistance. The patient has demonstrated poor or no response to prior trials with simpler medication regimens, and/or there is a history of decompensation or hospitalization when medications were pared down.

Severe acute symptoms. The patient has been experiencing acute symptoms that do not respond to one medication class. For example, a patient with bipolar disorder who has acute mania and psychosis may require significant doses of both a mood stabilizer and an antipsychotic.

Amelioration of adverse effects. One medication may be prescribed to address the adverse effects of other medications. For example, propranolol may be added to address akathisia from aripiprazole or tremors from lithium. In these cases, it is important to determine if the medication that’s causing adverse effects continues to provide benefits, in order to justify continuing it as well as adding a new agent.³

Continue to: After reviewing...

After reviewing your patient’s medication regimen, if one of these scenarios does not clearly exist, consider a “deprescribing” approach—reducing or stopping medications—to address unnecessary and potentially detrimental polypharmacy. For more information on deprescribing, see “6 Steps to deprescribing: A practical approach,” (Current Psychiatry, June 2017, p. 36-37).

Polypharmacy is often defined as the simultaneous prescription of multiple medications (usually ≥5) to a single patient for a single condition or multiple conditions.¹ Patients with psychiatric illnesses may easily be prescribed multiple psychotropic medications regardless of how many other medications they may already take for nonpsychiatric comorbidities. According to 2011-2014 Centers for Disease Control and Prevention data, 11.9% of the US population used ≥5 medications in the past 30 days.² Risks of polypharmacy include higher rates of adverse effects as well as treatment noncompliance.³

There are, however, many patients for whom a combination of psychotropic agents can be beneficial. It is important to carefully assess your patient’s regimen, and to document the rationale for prescribing multiple medications. Here I describe some factors that can help you to determine whether a multi-medication regimen might be warranted for your patient.

Accepted medication pairings. This describes a medication combination that has been recognized as generally safe and may provide more benefits than either single agent alone. Examples of clinically accepted medication combinations include^4,5:

• a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) plus bupropion
• an SSRI or SNRI plus mirtazapine
• ziprasidone as an adjunct to valproate or lithium for treating bipolar disorder
• aripiprazole as an adjunctive treatment for major depressive disorder (MDD).

Comorbid diagnoses. Each of a patient’s psychiatric comorbidities may require a different medication to address specific symptoms.³ Psychiatric comorbidities that might be appropriate for multiple medications include attention-deficit/hyperactivity disorder and bipolar disorder, MDD and generalized anxiety disorder, and a mood disorder and a substance use disorder.

Treatment resistance. The patient has demonstrated poor or no response to prior trials with simpler medication regimens, and/or there is a history of decompensation or hospitalization when medications were pared down.

Severe acute symptoms. The patient has been experiencing acute symptoms that do not respond to one medication class. For example, a patient with bipolar disorder who has acute mania and psychosis may require significant doses of both a mood stabilizer and an antipsychotic.

Amelioration of adverse effects. One medication may be prescribed to address the adverse effects of other medications. For example, propranolol may be added to address akathisia from aripiprazole or tremors from lithium. In these cases, it is important to determine if the medication that’s causing adverse effects continues to provide benefits, in order to justify continuing it as well as adding a new agent.³

Continue to: After reviewing...

After reviewing your patient’s medication regimen, if one of these scenarios does not clearly exist, consider a “deprescribing” approach—reducing or stopping medications—to address unnecessary and potentially detrimental polypharmacy. For more information on deprescribing, see “6 Steps to deprescribing: A practical approach,” (Current Psychiatry, June 2017, p. 36-37).

Polypharmacy is often defined as the simultaneous prescription of multiple medications (usually ≥5) to a single patient for a single condition or multiple conditions.¹ Patients with psychiatric illnesses may easily be prescribed multiple psychotropic medications regardless of how many other medications they may already take for nonpsychiatric comorbidities. According to 2011-2014 Centers for Disease Control and Prevention data, 11.9% of the US population used ≥5 medications in the past 30 days.² Risks of polypharmacy include higher rates of adverse effects as well as treatment noncompliance.³

There are, however, many patients for whom a combination of psychotropic agents can be beneficial. It is important to carefully assess your patient’s regimen, and to document the rationale for prescribing multiple medications. Here I describe some factors that can help you to determine whether a multi-medication regimen might be warranted for your patient.

Accepted medication pairings. This describes a medication combination that has been recognized as generally safe and may provide more benefits than either single agent alone. Examples of clinically accepted medication combinations include^4,5:

• a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) plus bupropion
• an SSRI or SNRI plus mirtazapine
• ziprasidone as an adjunct to valproate or lithium for treating bipolar disorder
• aripiprazole as an adjunctive treatment for major depressive disorder (MDD).

Comorbid diagnoses. Each of a patient’s psychiatric comorbidities may require a different medication to address specific symptoms.³ Psychiatric comorbidities that might be appropriate for multiple medications include attention-deficit/hyperactivity disorder and bipolar disorder, MDD and generalized anxiety disorder, and a mood disorder and a substance use disorder.

Treatment resistance. The patient has demonstrated poor or no response to prior trials with simpler medication regimens, and/or there is a history of decompensation or hospitalization when medications were pared down.

Severe acute symptoms. The patient has been experiencing acute symptoms that do not respond to one medication class. For example, a patient with bipolar disorder who has acute mania and psychosis may require significant doses of both a mood stabilizer and an antipsychotic.

Amelioration of adverse effects. One medication may be prescribed to address the adverse effects of other medications. For example, propranolol may be added to address akathisia from aripiprazole or tremors from lithium. In these cases, it is important to determine if the medication that’s causing adverse effects continues to provide benefits, in order to justify continuing it as well as adding a new agent.³

Continue to: After reviewing...

After reviewing your patient’s medication regimen, if one of these scenarios does not clearly exist, consider a “deprescribing” approach—reducing or stopping medications—to address unnecessary and potentially detrimental polypharmacy. For more information on deprescribing, see “6 Steps to deprescribing: A practical approach,” (Current Psychiatry, June 2017, p. 36-37).

CASE Anxious and jealous

Mrs. H, age 28, presents to the emergency department (ED) with pressured speech, emotional lability, loose associations, and echolalia. On physical examination, Mrs. H is noted to have hand tremors. Mrs. H says she has not slept for the past 5 days and is experiencing anxiety and heart palpitations.

She also says that for the past 2 years she has believed that her husband is having an affair with her best friend. However, her current presentation—which she attributes to the alleged affair—began a week before she came to the ED. According to her husband, Mrs. H was “perfectly fine until a week ago” and her symptoms “appeared out of nowhere.” He reports that this has never happened before.

Mrs. H is admitted to the psychiatry unit. The nursing team reports that on the first night, Mrs. H was “running and screaming on the unit, out of control,” and was “tearful, manicky, and dysphoric.”

Mrs. H has no significant medical or psychiatric history. Her family history is significant for hyperthyroidism in her mother and maternal grandmother. Mrs. H says she smokes cigarettes (1 pack/d) but denies alcohol or illicit drug use.

EVALUATION A telling thyroid panel

Mrs. H undergoes laboratory testing, including a complete blood count, comprehensive metabolic panel, and thyroid panel due to her family history of thyroid-related disorders. The thyroid panel shows the presence of the thyroid-stimulating hormone (TSH) receptor antibody; a low TSH level; elevated triiodothyronine (T3) and thyroxine (T4) levels, with T3 > T4; elevated thyroid peroxidase (TPO) antibody; and elevated thyroglobulin antibody (Table 1). A scan shows the thyroid gland to be normal/top-normal size and is read by radiology to be indicative of a resolving thyroiditis vs Graves’ disease. An electrocardiogram indicates a heart rate of 139 beats per minute.

[polldaddy:10352133]

The authors’ observations

Mrs. H fits the presentation of psychosis secondary to Graves’ disease. However, our differential consisted of thyroiditis, brief psychotic disorder, delusional disorder (jealous type), and bipolar mania.

Brief psychotic disorder, bipolar mania, and delusional disorder were better explained by Graves’ disease, and Mrs. H’s jealous delusion resulted in functional impairment, which eliminated delusional disorder. Her family history of hyper­thyroidism, as well as her sex and history of tobacco use, supported the diagnosis of Graves’ disease. Although Mrs. H did not experience goiter, ophthalmopathy, or dermopathy, which are common signs and symptoms of Graves’ disease (Table 2), she did present with irritability, insomnia, tachycardia, and a hand tremor. Her psychiatric symptoms included anxiety, emotional lability and, most importantly, psychosis. Her laboratory results included the presence of the TSH-receptor antibody, a low TSH level, and elevated T3 and T4 levels (T3>T4), confirming the diagnosis of early-onset Graves’ disease.

Continue to: Graves' disease

 

 

Graves’ disease

Graves’ disease is the most common cause of hyperthyroidism, representing approximately 50% to 80% of cases.¹ Graves’ disease occurs most often in women, smokers, and those with a personal or family history of autoimmune disease; although patients of any age may be affected, the peak incidence occurs between age 40 and 60.¹

Graves’ disease results from the production of immunoglobulin G (IgG) antibodies that activate the TSH receptor on the surface of thyroid follicular cells.¹ The presence of the TSH-receptor antibody, in addition to a low TSH and elevated T3 and T4 levels (T3>T4), are common laboratory findings in patients with this disease. A thyroid scan will also show increased radiotracer accumulation.

Patients with Graves’ disease, as well as those with hyperthyroidism, tend to report weight loss, increased appetite, heat intolerance, irritability, insomnia, and palpitations. In addition to the above symptoms, the identifying signs and symptoms of Graves’ disease include a goiter, ophthalmopathy, and dermopathy (Table 2). Rarely, patients with Graves’ disease can present with psychosis, which is often complicated by thyrotoxicosis.²

[polldaddy:10352135]

TREATMENT Antipsychotic and a beta blocker

Based on her signs, symptoms, and laboratory findings, Mrs. H receives risperidone, 1 mg twice daily, for psychosis, and atenolol, 25 mg twice daily, for heart palpitations. Over 4 days, her symptoms decrease; she experiences more linear thought and decreased flight-of-ideas, and becomes unsure about the truth of her husband’s alleged affair. Her impulsive behaviors and severe mood lability cease. Her tachycardia remains controlled with atenolol.

The authors’ observations

Rapid initiation of treatment is important when managing patients with Graves’ disease, because untreated patients have a higher risk of psychiatric illness, cardiac disease, arrhythmia, and sudden cardiac death.¹ Patients with Graves’ disease typically are treated with thionamides, radioactive iodine, and/or surgery. When a patient presents with psychosis as a result of thyrotoxicosis, treatment focuses on improving the thyrotoxicosis through anti-thyroid medications and beta blockers (Table 3³). Psychotropic medications, such as antipsychotics, are not indicated for primary treatment, but are given to patients who have severe psychosis until symptoms have resolved.³ For Mrs. H, the severity of her psychosis necessitated risperidone in addition to atenolol.

OUTCOME Continuous medical management; no ablation

Mrs. H is discharged with immediate out­patient follow-up with an endocrinology team to discuss the best long-term management of her thyroiditis. Mrs. H opts for continuous medical management (as opposed to ablation) and is administered methimazole, 15 mg/d, to treat Graves’ disease.

The authors’ observations

This case provides useful information regarding recognizing psychosis as the initial sign of Graves’ disease. Although Graves’ disease represents 50% to 80% of cases of hyperthyroidism,¹ psychosis as the first clinical presentation of this disease is extremely rare. Several case reports, however, have described this phenomenon,^2,3 and further studies would be helpful to determine its true prevalence.

Continue to: Bottom Line

 

 

Bottom Line

Although extremely rare, psychosis as the initial clinical presentation of Graves’ disease can occur. The early diagnosis of Graves’ disease is critical to prevent cardiovascular implications and death.

Related Resources

• Abraham P, Acharya S. Current and emerging treatment options for Graves’ hyperthyroidism. Ther Clin Risk Manag. 2010;6:29-40.
• Bunevicius R, Prange AJ Jr. Psychiatric manifestations of Graves’ hyperthyroidism: pathophysiology and treatment options. CNS Drugs. 2006;20(11):897-909.
• Ginsberg J. Diagnosis and management of Graves’ disease. CMAJ. 2003;168(5):575-585.

Drug Brand Names

Atenolol • Tenormin
Methimazole • Tapazole
Risperidone • Risperdal

CASE Anxious and jealous

Mrs. H, age 28, presents to the emergency department (ED) with pressured speech, emotional lability, loose associations, and echolalia. On physical examination, Mrs. H is noted to have hand tremors. Mrs. H says she has not slept for the past 5 days and is experiencing anxiety and heart palpitations.

She also says that for the past 2 years she has believed that her husband is having an affair with her best friend. However, her current presentation—which she attributes to the alleged affair—began a week before she came to the ED. According to her husband, Mrs. H was “perfectly fine until a week ago” and her symptoms “appeared out of nowhere.” He reports that this has never happened before.

Mrs. H is admitted to the psychiatry unit. The nursing team reports that on the first night, Mrs. H was “running and screaming on the unit, out of control,” and was “tearful, manicky, and dysphoric.”

Mrs. H has no significant medical or psychiatric history. Her family history is significant for hyperthyroidism in her mother and maternal grandmother. Mrs. H says she smokes cigarettes (1 pack/d) but denies alcohol or illicit drug use.

EVALUATION A telling thyroid panel

Mrs. H undergoes laboratory testing, including a complete blood count, comprehensive metabolic panel, and thyroid panel due to her family history of thyroid-related disorders. The thyroid panel shows the presence of the thyroid-stimulating hormone (TSH) receptor antibody; a low TSH level; elevated triiodothyronine (T3) and thyroxine (T4) levels, with T3 > T4; elevated thyroid peroxidase (TPO) antibody; and elevated thyroglobulin antibody (Table 1). A scan shows the thyroid gland to be normal/top-normal size and is read by radiology to be indicative of a resolving thyroiditis vs Graves’ disease. An electrocardiogram indicates a heart rate of 139 beats per minute.

[polldaddy:10352133]

The authors’ observations

Mrs. H fits the presentation of psychosis secondary to Graves’ disease. However, our differential consisted of thyroiditis, brief psychotic disorder, delusional disorder (jealous type), and bipolar mania.

Brief psychotic disorder, bipolar mania, and delusional disorder were better explained by Graves’ disease, and Mrs. H’s jealous delusion resulted in functional impairment, which eliminated delusional disorder. Her family history of hyper­thyroidism, as well as her sex and history of tobacco use, supported the diagnosis of Graves’ disease. Although Mrs. H did not experience goiter, ophthalmopathy, or dermopathy, which are common signs and symptoms of Graves’ disease (Table 2), she did present with irritability, insomnia, tachycardia, and a hand tremor. Her psychiatric symptoms included anxiety, emotional lability and, most importantly, psychosis. Her laboratory results included the presence of the TSH-receptor antibody, a low TSH level, and elevated T3 and T4 levels (T3>T4), confirming the diagnosis of early-onset Graves’ disease.

Continue to: Graves' disease

 

 

Graves’ disease

Graves’ disease is the most common cause of hyperthyroidism, representing approximately 50% to 80% of cases.¹ Graves’ disease occurs most often in women, smokers, and those with a personal or family history of autoimmune disease; although patients of any age may be affected, the peak incidence occurs between age 40 and 60.¹

Graves’ disease results from the production of immunoglobulin G (IgG) antibodies that activate the TSH receptor on the surface of thyroid follicular cells.¹ The presence of the TSH-receptor antibody, in addition to a low TSH and elevated T3 and T4 levels (T3>T4), are common laboratory findings in patients with this disease. A thyroid scan will also show increased radiotracer accumulation.

Patients with Graves’ disease, as well as those with hyperthyroidism, tend to report weight loss, increased appetite, heat intolerance, irritability, insomnia, and palpitations. In addition to the above symptoms, the identifying signs and symptoms of Graves’ disease include a goiter, ophthalmopathy, and dermopathy (Table 2). Rarely, patients with Graves’ disease can present with psychosis, which is often complicated by thyrotoxicosis.²

[polldaddy:10352135]

TREATMENT Antipsychotic and a beta blocker

Based on her signs, symptoms, and laboratory findings, Mrs. H receives risperidone, 1 mg twice daily, for psychosis, and atenolol, 25 mg twice daily, for heart palpitations. Over 4 days, her symptoms decrease; she experiences more linear thought and decreased flight-of-ideas, and becomes unsure about the truth of her husband’s alleged affair. Her impulsive behaviors and severe mood lability cease. Her tachycardia remains controlled with atenolol.

The authors’ observations

Rapid initiation of treatment is important when managing patients with Graves’ disease, because untreated patients have a higher risk of psychiatric illness, cardiac disease, arrhythmia, and sudden cardiac death.¹ Patients with Graves’ disease typically are treated with thionamides, radioactive iodine, and/or surgery. When a patient presents with psychosis as a result of thyrotoxicosis, treatment focuses on improving the thyrotoxicosis through anti-thyroid medications and beta blockers (Table 3³). Psychotropic medications, such as antipsychotics, are not indicated for primary treatment, but are given to patients who have severe psychosis until symptoms have resolved.³ For Mrs. H, the severity of her psychosis necessitated risperidone in addition to atenolol.

OUTCOME Continuous medical management; no ablation

Mrs. H is discharged with immediate out­patient follow-up with an endocrinology team to discuss the best long-term management of her thyroiditis. Mrs. H opts for continuous medical management (as opposed to ablation) and is administered methimazole, 15 mg/d, to treat Graves’ disease.

The authors’ observations

This case provides useful information regarding recognizing psychosis as the initial sign of Graves’ disease. Although Graves’ disease represents 50% to 80% of cases of hyperthyroidism,¹ psychosis as the first clinical presentation of this disease is extremely rare. Several case reports, however, have described this phenomenon,^2,3 and further studies would be helpful to determine its true prevalence.

Continue to: Bottom Line

 

 

Bottom Line

Although extremely rare, psychosis as the initial clinical presentation of Graves’ disease can occur. The early diagnosis of Graves’ disease is critical to prevent cardiovascular implications and death.

Related Resources

• Abraham P, Acharya S. Current and emerging treatment options for Graves’ hyperthyroidism. Ther Clin Risk Manag. 2010;6:29-40.
• Bunevicius R, Prange AJ Jr. Psychiatric manifestations of Graves’ hyperthyroidism: pathophysiology and treatment options. CNS Drugs. 2006;20(11):897-909.
• Ginsberg J. Diagnosis and management of Graves’ disease. CMAJ. 2003;168(5):575-585.

Drug Brand Names

Atenolol • Tenormin
Methimazole • Tapazole
Risperidone • Risperdal

CASE Anxious and jealous

Mrs. H, age 28, presents to the emergency department (ED) with pressured speech, emotional lability, loose associations, and echolalia. On physical examination, Mrs. H is noted to have hand tremors. Mrs. H says she has not slept for the past 5 days and is experiencing anxiety and heart palpitations.

She also says that for the past 2 years she has believed that her husband is having an affair with her best friend. However, her current presentation—which she attributes to the alleged affair—began a week before she came to the ED. According to her husband, Mrs. H was “perfectly fine until a week ago” and her symptoms “appeared out of nowhere.” He reports that this has never happened before.

Mrs. H is admitted to the psychiatry unit. The nursing team reports that on the first night, Mrs. H was “running and screaming on the unit, out of control,” and was “tearful, manicky, and dysphoric.”

Mrs. H has no significant medical or psychiatric history. Her family history is significant for hyperthyroidism in her mother and maternal grandmother. Mrs. H says she smokes cigarettes (1 pack/d) but denies alcohol or illicit drug use.

EVALUATION A telling thyroid panel

Mrs. H undergoes laboratory testing, including a complete blood count, comprehensive metabolic panel, and thyroid panel due to her family history of thyroid-related disorders. The thyroid panel shows the presence of the thyroid-stimulating hormone (TSH) receptor antibody; a low TSH level; elevated triiodothyronine (T3) and thyroxine (T4) levels, with T3 > T4; elevated thyroid peroxidase (TPO) antibody; and elevated thyroglobulin antibody (Table 1). A scan shows the thyroid gland to be normal/top-normal size and is read by radiology to be indicative of a resolving thyroiditis vs Graves’ disease. An electrocardiogram indicates a heart rate of 139 beats per minute.

[polldaddy:10352133]

The authors’ observations

Mrs. H fits the presentation of psychosis secondary to Graves’ disease. However, our differential consisted of thyroiditis, brief psychotic disorder, delusional disorder (jealous type), and bipolar mania.

Brief psychotic disorder, bipolar mania, and delusional disorder were better explained by Graves’ disease, and Mrs. H’s jealous delusion resulted in functional impairment, which eliminated delusional disorder. Her family history of hyper­thyroidism, as well as her sex and history of tobacco use, supported the diagnosis of Graves’ disease. Although Mrs. H did not experience goiter, ophthalmopathy, or dermopathy, which are common signs and symptoms of Graves’ disease (Table 2), she did present with irritability, insomnia, tachycardia, and a hand tremor. Her psychiatric symptoms included anxiety, emotional lability and, most importantly, psychosis. Her laboratory results included the presence of the TSH-receptor antibody, a low TSH level, and elevated T3 and T4 levels (T3>T4), confirming the diagnosis of early-onset Graves’ disease.

Continue to: Graves' disease

 

 

Graves’ disease

Graves’ disease is the most common cause of hyperthyroidism, representing approximately 50% to 80% of cases.¹ Graves’ disease occurs most often in women, smokers, and those with a personal or family history of autoimmune disease; although patients of any age may be affected, the peak incidence occurs between age 40 and 60.¹

Graves’ disease results from the production of immunoglobulin G (IgG) antibodies that activate the TSH receptor on the surface of thyroid follicular cells.¹ The presence of the TSH-receptor antibody, in addition to a low TSH and elevated T3 and T4 levels (T3>T4), are common laboratory findings in patients with this disease. A thyroid scan will also show increased radiotracer accumulation.

Patients with Graves’ disease, as well as those with hyperthyroidism, tend to report weight loss, increased appetite, heat intolerance, irritability, insomnia, and palpitations. In addition to the above symptoms, the identifying signs and symptoms of Graves’ disease include a goiter, ophthalmopathy, and dermopathy (Table 2). Rarely, patients with Graves’ disease can present with psychosis, which is often complicated by thyrotoxicosis.²

[polldaddy:10352135]

TREATMENT Antipsychotic and a beta blocker

Based on her signs, symptoms, and laboratory findings, Mrs. H receives risperidone, 1 mg twice daily, for psychosis, and atenolol, 25 mg twice daily, for heart palpitations. Over 4 days, her symptoms decrease; she experiences more linear thought and decreased flight-of-ideas, and becomes unsure about the truth of her husband’s alleged affair. Her impulsive behaviors and severe mood lability cease. Her tachycardia remains controlled with atenolol.

The authors’ observations

Rapid initiation of treatment is important when managing patients with Graves’ disease, because untreated patients have a higher risk of psychiatric illness, cardiac disease, arrhythmia, and sudden cardiac death.¹ Patients with Graves’ disease typically are treated with thionamides, radioactive iodine, and/or surgery. When a patient presents with psychosis as a result of thyrotoxicosis, treatment focuses on improving the thyrotoxicosis through anti-thyroid medications and beta blockers (Table 3³). Psychotropic medications, such as antipsychotics, are not indicated for primary treatment, but are given to patients who have severe psychosis until symptoms have resolved.³ For Mrs. H, the severity of her psychosis necessitated risperidone in addition to atenolol.

OUTCOME Continuous medical management; no ablation

Mrs. H is discharged with immediate out­patient follow-up with an endocrinology team to discuss the best long-term management of her thyroiditis. Mrs. H opts for continuous medical management (as opposed to ablation) and is administered methimazole, 15 mg/d, to treat Graves’ disease.

The authors’ observations

This case provides useful information regarding recognizing psychosis as the initial sign of Graves’ disease. Although Graves’ disease represents 50% to 80% of cases of hyperthyroidism,¹ psychosis as the first clinical presentation of this disease is extremely rare. Several case reports, however, have described this phenomenon,^2,3 and further studies would be helpful to determine its true prevalence.

Continue to: Bottom Line

 

 

Bottom Line

Although extremely rare, psychosis as the initial clinical presentation of Graves’ disease can occur. The early diagnosis of Graves’ disease is critical to prevent cardiovascular implications and death.

Related Resources

• Abraham P, Acharya S. Current and emerging treatment options for Graves’ hyperthyroidism. Ther Clin Risk Manag. 2010;6:29-40.
• Bunevicius R, Prange AJ Jr. Psychiatric manifestations of Graves’ hyperthyroidism: pathophysiology and treatment options. CNS Drugs. 2006;20(11):897-909.
• Ginsberg J. Diagnosis and management of Graves’ disease. CMAJ. 2003;168(5):575-585.

Drug Brand Names

Atenolol • Tenormin
Methimazole • Tapazole
Risperidone • Risperdal

Mr. S, age 55, comes to your clinic as a walk-in for management of major depressive disorder, insomnia, and migraines. He also has tobacco use disorder and hypertension. Several days ago, Mr. S had visited the clinic because he was continuing to experience depressive symptoms, so his sertraline was increased from 100 to 200 mg/d. His current medication regimen includes sertraline 200 mg/d, trazodone 100 mg/d, lisinopril 10 mg/d, and sumatriptan, 100 mg as needed for migraine. He says last week he used 4 or 5 doses of sumatriptan because he experienced several migraines. Mr. S also reports occasionally taking 2 tablets of trazodone instead of 1 on nights that he has trouble falling asleep.

Today, Mr. S presents with a low-grade fever, diarrhea, internal restlessness, and a racing heartbeat that started shortly after his last visit. During physical examination, he exhibits slow, continuous lateral eye movements. His vital signs are markedly elevated: blood pressure, 175/85 mm Hg; heart rate, 110 beats per minute; and temperature, 39°C (102.2°F). Based on his presentation, the treatment team decides to send Mr. S to urgent care for closer monitoring.

Serotonin syndrome is a drug-induced syndrome caused by overstimulation of serotonin receptors. The syndrome is characterized by a classic clinical triad consisting of mental status changes, autonomic hyperactivity, and neuromuscular abnormalities. The clinical presentation is highly variable, and the severity ranges from mild to life-threatening.^1-3 The incidence and prevalence of serotonin syndrome has not been well defined.³ Serotonin syndrome may be underreported because mild cases are often overlooked due to nonspecific symptoms. In addition, lack of physician awareness of drug–drug interactions, signs and symptoms, and differential diagnoses may result in underdiagnosis or misdiagnosis.^1-3

What causes it?

Serotonin syndrome is usually a consequence of a drug–drug interaction between 2 or more serotonergic agents.⁴ Serotonin syndrome may result following medication misuse, overdose, initiation of a serotonergic agent, or increase in the dose of a currently prescribed serotonergic agent.^3,4 In addition to medication classes and specific agents, Table 1^2-5 lists the drug mechanisms associated with serotonin syndrome:

• inhibition of serotonin reuptake
• inhibition of serotonin metabolism
• increased serotonin synthesis
• agonism of the serotonin receptor.

The amount of serotonergic activity most likely to cause serotonin syndrome is unclear.⁴

Pathophysiology. Serotonin, also known as 5-hydroxytryptamine (5-HT), is a metabolite of the amino acid tryptophan. This neuro­transmitter is located in both the CNS and the periphery. Regulation of the serotonergic system begins in the presynaptic neurons with decarboxylation and hydroxylation of tryptophan resulting in serotonin synthesis. Once serotonin is produced, it is released into the synaptic cleft, where it binds to serotonin receptors.^1,4,5 After receptor binding, serotonin reuptake occurs in the presynaptic neurons, where it can be metabolized by the monoamine oxidase enzyme. Finally, the metabolites are excreted in the urine. Serotonin syndrome results when this regulatory system is disrupted due to hyperstimulation of the postsynaptic serotonin receptors, mainly via agonism of the 5-HT2A and 5-HT1A receptors.^1,4,5

Continue to: A nonspecific presentation

A nonspecific presentation

Unfortunately, many of the symptoms of serotonin syndrome are nonspecific, and the severity varies among patients.^2,3 The onset of symptoms usually occurs within 6 to 8 hours after ingestion of a serotonergic agent.⁵ It is important to immediately recognize the symptoms (Table 2^2-5) and formulate a differential diagnosis because sudden progression of symptoms is common and may lead to life-threatening circumstances.^1,3

In mild cases of serotonin syndrome, patients may have a low-grade fever or be afebrile. Hyperthermia tends to be present in moderate and severe cases, with temperatures >41°C (105.8°F) during life-threatening cases. Diaphoresis and tachycardia may be present regardless of severity. Additional autonomic irregularities include hypertension, tachypnea, nausea, vomiting, diarrhea, and hyperactive bowel sounds. In terms of neuromuscular abnormalities, hyperreflexia is a primary concern, as well as myoclonus. As the severity progresses to life-threatening, the clonus may convert from inducible to spontaneous and slow, continuous lateral eye movements may be present. Additional neuromuscular symptoms include tremor, akathisia, and muscle rigidity.^1,3-5

Common mental status changes during mild cases include restlessness and anxiety. Abnormal mentation during moderate cases may present as increased hypervigilance and agitation, and this may advance to delirium or coma in severe cases. As the severity intensifies, the risk of developing additional physiological complications also increases. Rhabdomyolysis may occur due to muscle damage and myoglobinuria secondary to hyperreflexia, myoclonus, hypertonicity, and muscle rigidity. Muscle breakdown may then progress to further complications, such as renal failure. In rare instances, serotonin syndrome can result in seizures or death.^1,3-5

Medication history tips off the diagnosis

The first step in diagnosing serotonin syndrome is to conduct a thorough review of the patient’s medication history, specifically taking into account any recent exposure to serotonergic agents.^3,5 It is important to ask about prescription medications as well as over-the-counter products, herbal supplements, and illicit substances.^1,4 When reviewing the medication history, investigate whether there may have been a recent change in therapy with serotonergic agents. Also, determine when the patient’s symptoms began in relation to exposure to serotonergic agents.⁴

After the medication review, conduct a thorough physical and neurologic examination to identify current symptoms and severity.^1,3 No specific laboratory test is available to definitively confirm the diagnosis of serotonin syndrome.^1,4 Monitoring of serum serotonin is not recommended because the levels do not correlate with symptom severity.³ The recommended diagnostic tool is the Hunter Serotonin Toxicity Criteria (Figure^1,3).^3,4 Historically, the Sternbach’s Diagnostic Criteria for serotonin syndrome were used for diagnosis; however, the Hunter Serotonin Toxicity Criteria are more sensitive (96% vs 75%) and more specific (97% vs 84%) than the Sternbach’s Diagnostic Criteria for serotonin syndrome.^1,3-5

Continue to: In addition to using the proper diagnostic tool...

In addition to using the proper diagnostic tool, conduct a differential diagnosis to rule out other drug-induced syndromes, such as anticholinergic toxidrome, neuroleptic malignant syndrome, or malignant hyperthermia.^1,3,5 Autonomic instability, including hypertension, tachycardia, tachypnea, and hyperthermia, may be present in all of the aforementioned drug-induced syndromes.¹ As a result, the clinician must monitor for other symptoms that may differentiate the disease states to establish a clear diagnosis.

Discontinue agents, offer supportive care

There are no official published guidelines for managing serotonin syndrome.⁵ Regardless of the severity of a patient’s presentation, all serotonergic agents should be discontinued immediately. In addition, supportive care should be initiated for symptom management. Intravenous fluid replacement is recommended for hydration and to treat hyperthermia. External cooling may also be warranted to reduce body temperatures. Vital signs should be stabilized with appropriate pharmacotherapy.^1,3-5

Benzodiazepines are considered a mainstay for relief of agitation during serotonin syndrome of any severity. In life-threatening cases—which are characterized by hyperthermia >41°C (105.8°F)—sedation, paralysis, and intubation may be necessary to maintain the airway, breathing, and circulation.^1,3-5 Because treatment of hyperthermia requires elimination of hyperreflexia, paralysis is recommended.¹ Nondepolarizing neuromuscular blocking agents, such as vecuronium, are preferred over depolarizing agents due to their decreased potential for rhabdomyolysis.^1,3

Cyproheptadine, a histamine-1 receptor antagonist and a 5-HT2A receptor antagonist, is recommended for off-label treatment of serotonin syndrome to help decrease the intensity of symptoms. This should be initiated as a single dose of 12 mg followed by 2 mg every 2 hours until symptoms improve.^1,3,5 After stabilization, a maintenance dose of 8 mg every 6 hours is recommended. Doses should not exceed the maximum recommended dose of 0.5 mg/kg/d.^1,3,6 The most common adverse reactions associated with cyproheptadine are sedation and anticholinergic adverse effects.^1,4,6

Antipsychotics, such as olanzapine and chlorpromazine, have been considered treatment alternatives due to their associated 5-HT2A receptor antagonism. However, there is limited data supporting such use.^1,4 Antipsychotics should be used with caution because neuroleptic malignant syndrome may be mistaken for serotonin syndrome. Use of antipyretics is not recommended for treating fever and hyperthermia because the increase in body temperature is secondary to excessive muscle activity rather than dysfunction of the hypothalamic temperature set point.^1,3,5 Physical restraints are also not recommended because their use may provoke further hyperthermia and increase the risk of rhabdomyolysis.^3,5

Continue to: Ultimately, the duration of treatment...

Ultimately, the duration of treatment will be influenced by the pharmacokinetics of the serotonergic agents that induced the serotonin syndrome. Following resolution, retrial of the offending serotonergic agents should be carefully assessed. A retrial should only be considered after an adequate washout period has been observed, and clinicians should consider utilizing lower doses.^2,5

Take steps for prevention

Patients at highest risk of developing serotonin syndrome are those who have multiple comorbidities that result in treatment with multiple serotonergic agents.³ Clinicians and patients alike need to be educated about the signs and symptoms of serotonin syndrome to promote early recognition. Also consider modifying your prescribing practices to minimize the use of multiple serotonergic agents. When switching between serotonergic agents, institute safe washout periods. Encourage patients to adhere to their prescribed medication regimens. Using electronic ordering systems can help detect drug–drug interactions.^1,3 Prophylaxis with cyproheptadine may be considered in high-risk patients; however, no clinical trials have been conducted to evaluate using cyproheptadine to prevent serotonin syndrome.⁷

CASE CONTINUED

Upon further assessment in urgent care, Mr. S is found to have muscle rigidity in addition to ocular clonus and a temperature >38°C (100.4°F). Because Mr. S’s symptoms coincide with a recent increase of sertraline and increased use of both trazodone and sumatriptan, he meets Hunter Serotonin Toxicity Criteria. Therefore, his symptoms are likely related to excessive increase in serotonergic activity. Mr. S is admitted to the hospital for closer monitoring, and his sertraline, trazodone, and sumatriptan are held. He receives IV fluids for several days as well as cyproheptadine, 8 mg every 6 hours after stabilization, until his symptoms resolve. On Day 4, Mr. S no longer experiences diarrhea and internal restlessness. His vital signs return to normal, and as a result of symptom resolution, he is discharged from the hospital. The treatment team discusses changing his medication regimen to avoid multiple serotonergic agents. Mr. S is switched from sertraline to bupropion XL, 150 mg/d. Sumatriptan, 100 mg/d as needed, is continued for acute migraine treatment. Trazodone is discontinued and replaced with melatonin, 3 mg/d. The team also counsels Mr. S on the importance of proper adherence to his medication regimen. He is advised to return to the clinic in 2 weeks for reassessment of safety and efficacy.

Related Resource

• Turner AH, Kim JJ, McCarron RM. Differentiating serotonin syndrome and neuroleptic malignant syndrome. Current Psychiatry. 2019;18(2):30-36.

Drug Brand Names

Almotriptan • Axert
Buprenorphine • Subutex
Bupropion • Wellbutrin, Zyban
Buspirone • BuSpar
Carbamazepine • Carbatrol, Tegretol
Chlorpromazine • Thorazine
Cyproheptadine • Periactin
Eletriptan • Relpax
Frovatriptan • Frova
Granisetron • Kytril
Lisinopril • Prinivil, Zestril
Meperidine • Demerol
Methadone • Dolophine, Methadose
Metoclopramide • Reglan
Mirtazapine • Remeron
Naratriptan • Amerge
Olanzapine • Zyprexa
Ondansetron • Zofran
Rizatriptan • Maxalt
Sertraline • Zoloft
Sumatriptan • Imitrex tablets
Tapentadol • Nucynta
Tramadol • Conzip
Trazodone • Desyrel, Oleptro
Valproic acid • Depakene, Depakote
Vecuronium • Norcuron
Zolmitriptan • Zomig

Mr. S, age 55, comes to your clinic as a walk-in for management of major depressive disorder, insomnia, and migraines. He also has tobacco use disorder and hypertension. Several days ago, Mr. S had visited the clinic because he was continuing to experience depressive symptoms, so his sertraline was increased from 100 to 200 mg/d. His current medication regimen includes sertraline 200 mg/d, trazodone 100 mg/d, lisinopril 10 mg/d, and sumatriptan, 100 mg as needed for migraine. He says last week he used 4 or 5 doses of sumatriptan because he experienced several migraines. Mr. S also reports occasionally taking 2 tablets of trazodone instead of 1 on nights that he has trouble falling asleep.

Today, Mr. S presents with a low-grade fever, diarrhea, internal restlessness, and a racing heartbeat that started shortly after his last visit. During physical examination, he exhibits slow, continuous lateral eye movements. His vital signs are markedly elevated: blood pressure, 175/85 mm Hg; heart rate, 110 beats per minute; and temperature, 39°C (102.2°F). Based on his presentation, the treatment team decides to send Mr. S to urgent care for closer monitoring.

Serotonin syndrome is a drug-induced syndrome caused by overstimulation of serotonin receptors. The syndrome is characterized by a classic clinical triad consisting of mental status changes, autonomic hyperactivity, and neuromuscular abnormalities. The clinical presentation is highly variable, and the severity ranges from mild to life-threatening.^1-3 The incidence and prevalence of serotonin syndrome has not been well defined.³ Serotonin syndrome may be underreported because mild cases are often overlooked due to nonspecific symptoms. In addition, lack of physician awareness of drug–drug interactions, signs and symptoms, and differential diagnoses may result in underdiagnosis or misdiagnosis.^1-3

What causes it?

Serotonin syndrome is usually a consequence of a drug–drug interaction between 2 or more serotonergic agents.⁴ Serotonin syndrome may result following medication misuse, overdose, initiation of a serotonergic agent, or increase in the dose of a currently prescribed serotonergic agent.^3,4 In addition to medication classes and specific agents, Table 1^2-5 lists the drug mechanisms associated with serotonin syndrome:

• inhibition of serotonin reuptake
• inhibition of serotonin metabolism
• increased serotonin synthesis
• agonism of the serotonin receptor.

The amount of serotonergic activity most likely to cause serotonin syndrome is unclear.⁴

Pathophysiology. Serotonin, also known as 5-hydroxytryptamine (5-HT), is a metabolite of the amino acid tryptophan. This neuro­transmitter is located in both the CNS and the periphery. Regulation of the serotonergic system begins in the presynaptic neurons with decarboxylation and hydroxylation of tryptophan resulting in serotonin synthesis. Once serotonin is produced, it is released into the synaptic cleft, where it binds to serotonin receptors.^1,4,5 After receptor binding, serotonin reuptake occurs in the presynaptic neurons, where it can be metabolized by the monoamine oxidase enzyme. Finally, the metabolites are excreted in the urine. Serotonin syndrome results when this regulatory system is disrupted due to hyperstimulation of the postsynaptic serotonin receptors, mainly via agonism of the 5-HT2A and 5-HT1A receptors.^1,4,5

Continue to: A nonspecific presentation

A nonspecific presentation

Unfortunately, many of the symptoms of serotonin syndrome are nonspecific, and the severity varies among patients.^2,3 The onset of symptoms usually occurs within 6 to 8 hours after ingestion of a serotonergic agent.⁵ It is important to immediately recognize the symptoms (Table 2^2-5) and formulate a differential diagnosis because sudden progression of symptoms is common and may lead to life-threatening circumstances.^1,3

In mild cases of serotonin syndrome, patients may have a low-grade fever or be afebrile. Hyperthermia tends to be present in moderate and severe cases, with temperatures >41°C (105.8°F) during life-threatening cases. Diaphoresis and tachycardia may be present regardless of severity. Additional autonomic irregularities include hypertension, tachypnea, nausea, vomiting, diarrhea, and hyperactive bowel sounds. In terms of neuromuscular abnormalities, hyperreflexia is a primary concern, as well as myoclonus. As the severity progresses to life-threatening, the clonus may convert from inducible to spontaneous and slow, continuous lateral eye movements may be present. Additional neuromuscular symptoms include tremor, akathisia, and muscle rigidity.^1,3-5

Common mental status changes during mild cases include restlessness and anxiety. Abnormal mentation during moderate cases may present as increased hypervigilance and agitation, and this may advance to delirium or coma in severe cases. As the severity intensifies, the risk of developing additional physiological complications also increases. Rhabdomyolysis may occur due to muscle damage and myoglobinuria secondary to hyperreflexia, myoclonus, hypertonicity, and muscle rigidity. Muscle breakdown may then progress to further complications, such as renal failure. In rare instances, serotonin syndrome can result in seizures or death.^1,3-5

Medication history tips off the diagnosis

The first step in diagnosing serotonin syndrome is to conduct a thorough review of the patient’s medication history, specifically taking into account any recent exposure to serotonergic agents.^3,5 It is important to ask about prescription medications as well as over-the-counter products, herbal supplements, and illicit substances.^1,4 When reviewing the medication history, investigate whether there may have been a recent change in therapy with serotonergic agents. Also, determine when the patient’s symptoms began in relation to exposure to serotonergic agents.⁴

After the medication review, conduct a thorough physical and neurologic examination to identify current symptoms and severity.^1,3 No specific laboratory test is available to definitively confirm the diagnosis of serotonin syndrome.^1,4 Monitoring of serum serotonin is not recommended because the levels do not correlate with symptom severity.³ The recommended diagnostic tool is the Hunter Serotonin Toxicity Criteria (Figure^1,3).^3,4 Historically, the Sternbach’s Diagnostic Criteria for serotonin syndrome were used for diagnosis; however, the Hunter Serotonin Toxicity Criteria are more sensitive (96% vs 75%) and more specific (97% vs 84%) than the Sternbach’s Diagnostic Criteria for serotonin syndrome.^1,3-5

Continue to: In addition to using the proper diagnostic tool...

In addition to using the proper diagnostic tool, conduct a differential diagnosis to rule out other drug-induced syndromes, such as anticholinergic toxidrome, neuroleptic malignant syndrome, or malignant hyperthermia.^1,3,5 Autonomic instability, including hypertension, tachycardia, tachypnea, and hyperthermia, may be present in all of the aforementioned drug-induced syndromes.¹ As a result, the clinician must monitor for other symptoms that may differentiate the disease states to establish a clear diagnosis.

Discontinue agents, offer supportive care

There are no official published guidelines for managing serotonin syndrome.⁵ Regardless of the severity of a patient’s presentation, all serotonergic agents should be discontinued immediately. In addition, supportive care should be initiated for symptom management. Intravenous fluid replacement is recommended for hydration and to treat hyperthermia. External cooling may also be warranted to reduce body temperatures. Vital signs should be stabilized with appropriate pharmacotherapy.^1,3-5

Benzodiazepines are considered a mainstay for relief of agitation during serotonin syndrome of any severity. In life-threatening cases—which are characterized by hyperthermia >41°C (105.8°F)—sedation, paralysis, and intubation may be necessary to maintain the airway, breathing, and circulation.^1,3-5 Because treatment of hyperthermia requires elimination of hyperreflexia, paralysis is recommended.¹ Nondepolarizing neuromuscular blocking agents, such as vecuronium, are preferred over depolarizing agents due to their decreased potential for rhabdomyolysis.^1,3

Cyproheptadine, a histamine-1 receptor antagonist and a 5-HT2A receptor antagonist, is recommended for off-label treatment of serotonin syndrome to help decrease the intensity of symptoms. This should be initiated as a single dose of 12 mg followed by 2 mg every 2 hours until symptoms improve.^1,3,5 After stabilization, a maintenance dose of 8 mg every 6 hours is recommended. Doses should not exceed the maximum recommended dose of 0.5 mg/kg/d.^1,3,6 The most common adverse reactions associated with cyproheptadine are sedation and anticholinergic adverse effects.^1,4,6

Antipsychotics, such as olanzapine and chlorpromazine, have been considered treatment alternatives due to their associated 5-HT2A receptor antagonism. However, there is limited data supporting such use.^1,4 Antipsychotics should be used with caution because neuroleptic malignant syndrome may be mistaken for serotonin syndrome. Use of antipyretics is not recommended for treating fever and hyperthermia because the increase in body temperature is secondary to excessive muscle activity rather than dysfunction of the hypothalamic temperature set point.^1,3,5 Physical restraints are also not recommended because their use may provoke further hyperthermia and increase the risk of rhabdomyolysis.^3,5

Continue to: Ultimately, the duration of treatment...

Ultimately, the duration of treatment will be influenced by the pharmacokinetics of the serotonergic agents that induced the serotonin syndrome. Following resolution, retrial of the offending serotonergic agents should be carefully assessed. A retrial should only be considered after an adequate washout period has been observed, and clinicians should consider utilizing lower doses.^2,5

Take steps for prevention

Patients at highest risk of developing serotonin syndrome are those who have multiple comorbidities that result in treatment with multiple serotonergic agents.³ Clinicians and patients alike need to be educated about the signs and symptoms of serotonin syndrome to promote early recognition. Also consider modifying your prescribing practices to minimize the use of multiple serotonergic agents. When switching between serotonergic agents, institute safe washout periods. Encourage patients to adhere to their prescribed medication regimens. Using electronic ordering systems can help detect drug–drug interactions.^1,3 Prophylaxis with cyproheptadine may be considered in high-risk patients; however, no clinical trials have been conducted to evaluate using cyproheptadine to prevent serotonin syndrome.⁷

CASE CONTINUED

Upon further assessment in urgent care, Mr. S is found to have muscle rigidity in addition to ocular clonus and a temperature >38°C (100.4°F). Because Mr. S’s symptoms coincide with a recent increase of sertraline and increased use of both trazodone and sumatriptan, he meets Hunter Serotonin Toxicity Criteria. Therefore, his symptoms are likely related to excessive increase in serotonergic activity. Mr. S is admitted to the hospital for closer monitoring, and his sertraline, trazodone, and sumatriptan are held. He receives IV fluids for several days as well as cyproheptadine, 8 mg every 6 hours after stabilization, until his symptoms resolve. On Day 4, Mr. S no longer experiences diarrhea and internal restlessness. His vital signs return to normal, and as a result of symptom resolution, he is discharged from the hospital. The treatment team discusses changing his medication regimen to avoid multiple serotonergic agents. Mr. S is switched from sertraline to bupropion XL, 150 mg/d. Sumatriptan, 100 mg/d as needed, is continued for acute migraine treatment. Trazodone is discontinued and replaced with melatonin, 3 mg/d. The team also counsels Mr. S on the importance of proper adherence to his medication regimen. He is advised to return to the clinic in 2 weeks for reassessment of safety and efficacy.

Related Resource

• Turner AH, Kim JJ, McCarron RM. Differentiating serotonin syndrome and neuroleptic malignant syndrome. Current Psychiatry. 2019;18(2):30-36.

Drug Brand Names

Almotriptan • Axert
Buprenorphine • Subutex
Bupropion • Wellbutrin, Zyban
Buspirone • BuSpar
Carbamazepine • Carbatrol, Tegretol
Chlorpromazine • Thorazine
Cyproheptadine • Periactin
Eletriptan • Relpax
Frovatriptan • Frova
Granisetron • Kytril
Lisinopril • Prinivil, Zestril
Meperidine • Demerol
Methadone • Dolophine, Methadose
Metoclopramide • Reglan
Mirtazapine • Remeron
Naratriptan • Amerge
Olanzapine • Zyprexa
Ondansetron • Zofran
Rizatriptan • Maxalt
Sertraline • Zoloft
Sumatriptan • Imitrex tablets
Tapentadol • Nucynta
Tramadol • Conzip
Trazodone • Desyrel, Oleptro
Valproic acid • Depakene, Depakote
Vecuronium • Norcuron
Zolmitriptan • Zomig

Mr. S, age 55, comes to your clinic as a walk-in for management of major depressive disorder, insomnia, and migraines. He also has tobacco use disorder and hypertension. Several days ago, Mr. S had visited the clinic because he was continuing to experience depressive symptoms, so his sertraline was increased from 100 to 200 mg/d. His current medication regimen includes sertraline 200 mg/d, trazodone 100 mg/d, lisinopril 10 mg/d, and sumatriptan, 100 mg as needed for migraine. He says last week he used 4 or 5 doses of sumatriptan because he experienced several migraines. Mr. S also reports occasionally taking 2 tablets of trazodone instead of 1 on nights that he has trouble falling asleep.

Today, Mr. S presents with a low-grade fever, diarrhea, internal restlessness, and a racing heartbeat that started shortly after his last visit. During physical examination, he exhibits slow, continuous lateral eye movements. His vital signs are markedly elevated: blood pressure, 175/85 mm Hg; heart rate, 110 beats per minute; and temperature, 39°C (102.2°F). Based on his presentation, the treatment team decides to send Mr. S to urgent care for closer monitoring.

Serotonin syndrome is a drug-induced syndrome caused by overstimulation of serotonin receptors. The syndrome is characterized by a classic clinical triad consisting of mental status changes, autonomic hyperactivity, and neuromuscular abnormalities. The clinical presentation is highly variable, and the severity ranges from mild to life-threatening.^1-3 The incidence and prevalence of serotonin syndrome has not been well defined.³ Serotonin syndrome may be underreported because mild cases are often overlooked due to nonspecific symptoms. In addition, lack of physician awareness of drug–drug interactions, signs and symptoms, and differential diagnoses may result in underdiagnosis or misdiagnosis.^1-3

What causes it?

Serotonin syndrome is usually a consequence of a drug–drug interaction between 2 or more serotonergic agents.⁴ Serotonin syndrome may result following medication misuse, overdose, initiation of a serotonergic agent, or increase in the dose of a currently prescribed serotonergic agent.^3,4 In addition to medication classes and specific agents, Table 1^2-5 lists the drug mechanisms associated with serotonin syndrome:

• inhibition of serotonin reuptake
• inhibition of serotonin metabolism
• increased serotonin synthesis
• agonism of the serotonin receptor.

The amount of serotonergic activity most likely to cause serotonin syndrome is unclear.⁴

Pathophysiology. Serotonin, also known as 5-hydroxytryptamine (5-HT), is a metabolite of the amino acid tryptophan. This neuro­transmitter is located in both the CNS and the periphery. Regulation of the serotonergic system begins in the presynaptic neurons with decarboxylation and hydroxylation of tryptophan resulting in serotonin synthesis. Once serotonin is produced, it is released into the synaptic cleft, where it binds to serotonin receptors.^1,4,5 After receptor binding, serotonin reuptake occurs in the presynaptic neurons, where it can be metabolized by the monoamine oxidase enzyme. Finally, the metabolites are excreted in the urine. Serotonin syndrome results when this regulatory system is disrupted due to hyperstimulation of the postsynaptic serotonin receptors, mainly via agonism of the 5-HT2A and 5-HT1A receptors.^1,4,5

Continue to: A nonspecific presentation

A nonspecific presentation

Unfortunately, many of the symptoms of serotonin syndrome are nonspecific, and the severity varies among patients.^2,3 The onset of symptoms usually occurs within 6 to 8 hours after ingestion of a serotonergic agent.⁵ It is important to immediately recognize the symptoms (Table 2^2-5) and formulate a differential diagnosis because sudden progression of symptoms is common and may lead to life-threatening circumstances.^1,3

In mild cases of serotonin syndrome, patients may have a low-grade fever or be afebrile. Hyperthermia tends to be present in moderate and severe cases, with temperatures >41°C (105.8°F) during life-threatening cases. Diaphoresis and tachycardia may be present regardless of severity. Additional autonomic irregularities include hypertension, tachypnea, nausea, vomiting, diarrhea, and hyperactive bowel sounds. In terms of neuromuscular abnormalities, hyperreflexia is a primary concern, as well as myoclonus. As the severity progresses to life-threatening, the clonus may convert from inducible to spontaneous and slow, continuous lateral eye movements may be present. Additional neuromuscular symptoms include tremor, akathisia, and muscle rigidity.^1,3-5

Common mental status changes during mild cases include restlessness and anxiety. Abnormal mentation during moderate cases may present as increased hypervigilance and agitation, and this may advance to delirium or coma in severe cases. As the severity intensifies, the risk of developing additional physiological complications also increases. Rhabdomyolysis may occur due to muscle damage and myoglobinuria secondary to hyperreflexia, myoclonus, hypertonicity, and muscle rigidity. Muscle breakdown may then progress to further complications, such as renal failure. In rare instances, serotonin syndrome can result in seizures or death.^1,3-5

Medication history tips off the diagnosis

The first step in diagnosing serotonin syndrome is to conduct a thorough review of the patient’s medication history, specifically taking into account any recent exposure to serotonergic agents.^3,5 It is important to ask about prescription medications as well as over-the-counter products, herbal supplements, and illicit substances.^1,4 When reviewing the medication history, investigate whether there may have been a recent change in therapy with serotonergic agents. Also, determine when the patient’s symptoms began in relation to exposure to serotonergic agents.⁴

After the medication review, conduct a thorough physical and neurologic examination to identify current symptoms and severity.^1,3 No specific laboratory test is available to definitively confirm the diagnosis of serotonin syndrome.^1,4 Monitoring of serum serotonin is not recommended because the levels do not correlate with symptom severity.³ The recommended diagnostic tool is the Hunter Serotonin Toxicity Criteria (Figure^1,3).^3,4 Historically, the Sternbach’s Diagnostic Criteria for serotonin syndrome were used for diagnosis; however, the Hunter Serotonin Toxicity Criteria are more sensitive (96% vs 75%) and more specific (97% vs 84%) than the Sternbach’s Diagnostic Criteria for serotonin syndrome.^1,3-5

Continue to: In addition to using the proper diagnostic tool...

In addition to using the proper diagnostic tool, conduct a differential diagnosis to rule out other drug-induced syndromes, such as anticholinergic toxidrome, neuroleptic malignant syndrome, or malignant hyperthermia.^1,3,5 Autonomic instability, including hypertension, tachycardia, tachypnea, and hyperthermia, may be present in all of the aforementioned drug-induced syndromes.¹ As a result, the clinician must monitor for other symptoms that may differentiate the disease states to establish a clear diagnosis.

Discontinue agents, offer supportive care

There are no official published guidelines for managing serotonin syndrome.⁵ Regardless of the severity of a patient’s presentation, all serotonergic agents should be discontinued immediately. In addition, supportive care should be initiated for symptom management. Intravenous fluid replacement is recommended for hydration and to treat hyperthermia. External cooling may also be warranted to reduce body temperatures. Vital signs should be stabilized with appropriate pharmacotherapy.^1,3-5

Benzodiazepines are considered a mainstay for relief of agitation during serotonin syndrome of any severity. In life-threatening cases—which are characterized by hyperthermia >41°C (105.8°F)—sedation, paralysis, and intubation may be necessary to maintain the airway, breathing, and circulation.^1,3-5 Because treatment of hyperthermia requires elimination of hyperreflexia, paralysis is recommended.¹ Nondepolarizing neuromuscular blocking agents, such as vecuronium, are preferred over depolarizing agents due to their decreased potential for rhabdomyolysis.^1,3

Cyproheptadine, a histamine-1 receptor antagonist and a 5-HT2A receptor antagonist, is recommended for off-label treatment of serotonin syndrome to help decrease the intensity of symptoms. This should be initiated as a single dose of 12 mg followed by 2 mg every 2 hours until symptoms improve.^1,3,5 After stabilization, a maintenance dose of 8 mg every 6 hours is recommended. Doses should not exceed the maximum recommended dose of 0.5 mg/kg/d.^1,3,6 The most common adverse reactions associated with cyproheptadine are sedation and anticholinergic adverse effects.^1,4,6

Antipsychotics, such as olanzapine and chlorpromazine, have been considered treatment alternatives due to their associated 5-HT2A receptor antagonism. However, there is limited data supporting such use.^1,4 Antipsychotics should be used with caution because neuroleptic malignant syndrome may be mistaken for serotonin syndrome. Use of antipyretics is not recommended for treating fever and hyperthermia because the increase in body temperature is secondary to excessive muscle activity rather than dysfunction of the hypothalamic temperature set point.^1,3,5 Physical restraints are also not recommended because their use may provoke further hyperthermia and increase the risk of rhabdomyolysis.^3,5

Continue to: Ultimately, the duration of treatment...

Ultimately, the duration of treatment will be influenced by the pharmacokinetics of the serotonergic agents that induced the serotonin syndrome. Following resolution, retrial of the offending serotonergic agents should be carefully assessed. A retrial should only be considered after an adequate washout period has been observed, and clinicians should consider utilizing lower doses.^2,5

Take steps for prevention

Patients at highest risk of developing serotonin syndrome are those who have multiple comorbidities that result in treatment with multiple serotonergic agents.³ Clinicians and patients alike need to be educated about the signs and symptoms of serotonin syndrome to promote early recognition. Also consider modifying your prescribing practices to minimize the use of multiple serotonergic agents. When switching between serotonergic agents, institute safe washout periods. Encourage patients to adhere to their prescribed medication regimens. Using electronic ordering systems can help detect drug–drug interactions.^1,3 Prophylaxis with cyproheptadine may be considered in high-risk patients; however, no clinical trials have been conducted to evaluate using cyproheptadine to prevent serotonin syndrome.⁷

CASE CONTINUED

Upon further assessment in urgent care, Mr. S is found to have muscle rigidity in addition to ocular clonus and a temperature >38°C (100.4°F). Because Mr. S’s symptoms coincide with a recent increase of sertraline and increased use of both trazodone and sumatriptan, he meets Hunter Serotonin Toxicity Criteria. Therefore, his symptoms are likely related to excessive increase in serotonergic activity. Mr. S is admitted to the hospital for closer monitoring, and his sertraline, trazodone, and sumatriptan are held. He receives IV fluids for several days as well as cyproheptadine, 8 mg every 6 hours after stabilization, until his symptoms resolve. On Day 4, Mr. S no longer experiences diarrhea and internal restlessness. His vital signs return to normal, and as a result of symptom resolution, he is discharged from the hospital. The treatment team discusses changing his medication regimen to avoid multiple serotonergic agents. Mr. S is switched from sertraline to bupropion XL, 150 mg/d. Sumatriptan, 100 mg/d as needed, is continued for acute migraine treatment. Trazodone is discontinued and replaced with melatonin, 3 mg/d. The team also counsels Mr. S on the importance of proper adherence to his medication regimen. He is advised to return to the clinic in 2 weeks for reassessment of safety and efficacy.

Related Resource

• Turner AH, Kim JJ, McCarron RM. Differentiating serotonin syndrome and neuroleptic malignant syndrome. Current Psychiatry. 2019;18(2):30-36.

Drug Brand Names

Almotriptan • Axert
Buprenorphine • Subutex
Bupropion • Wellbutrin, Zyban
Buspirone • BuSpar
Carbamazepine • Carbatrol, Tegretol
Chlorpromazine • Thorazine
Cyproheptadine • Periactin
Eletriptan • Relpax
Frovatriptan • Frova
Granisetron • Kytril
Lisinopril • Prinivil, Zestril
Meperidine • Demerol
Methadone • Dolophine, Methadose
Metoclopramide • Reglan
Mirtazapine • Remeron
Naratriptan • Amerge
Olanzapine • Zyprexa
Ondansetron • Zofran
Rizatriptan • Maxalt
Sertraline • Zoloft
Sumatriptan • Imitrex tablets
Tapentadol • Nucynta
Tramadol • Conzip
Trazodone • Desyrel, Oleptro
Valproic acid • Depakene, Depakote
Vecuronium • Norcuron
Zolmitriptan • Zomig

Delirium is defined as a disturbance in attention, awareness, and cognition that develops over hours to days as a direct physiological consequence of an underlying medical condition and is not better explained by another neurocognitive disorder.¹ This condition is found in up to 31% of general medical patients and up to 87% of critically ill medical patients. Delirium is commonly seen in patients who have undergone surgery, those who are in palliative care, and patients with cancer.² It is associated with increased morbidity and mortality. Compared with those who do not develop delirium, patients who are hospitalized who develop delirium have a higher risk of longer hospital stays, post-hospitalization nursing facility placement, persistent cognitive dysfunction, and death.³

Thus far, the management and treatment of delirium have been complicated by an incomplete understanding of the pathophysiology of this condition. However, prevailing theories suggest a dysregulation of neurotransmitter synthesis, function, or availability.² Recent literature reflects this theory; researchers have investigated agents that target dopamine or acetylcholine. Below we review some of this recent literature on treating delirium; these studies are summarized in the Table.^4-6

1. Burry L, Mehta S, Perreault MM, et al. Antipsychotics for treatment of delirium in hospitalized non-ICU patients. Cochrane Database Syst Rev. 2018;6:CD005594.

An extensive literature review identified randomized or quasi-randomized trials on the treatment of delirium among non-critically ill hospitalized patients in which antipsychotics were compared with nonantipsychotic medications or placebo, or in which a first-generation antipsychotic (FGA) was compared with a second-generation antipsychotic (SGA).⁴

Study design

• Researchers conducted a literature review of 9 trials that included 727 hospitalized but not critically ill patients (ie, they were not in an ICU) who developed delirium.
• Four trials compared an antipsychotic with a medication from another drug class or with placebo.
• Seven trials compared a FGA with an SGA.

Outcomes

• Although the intended primary outcome was the duration of delirium, none of the included studies reported on duration of delirium. Secondary outcomes were delirium severity and resolution, mortality, hospital length of stay, discharge disposition, health-related quality of life, and adverse effects.
• Among the secondary outcomes, no statistical difference was observed between delirium severity, delirium resolution, or mortality.
• None of the included studies reported on hospital length of stay, discharge disposition, or health-related quality of life.
• Evidence related to adverse effects was determined to be very low quality due to potential bias, inconsistency, and imprecision.

Conclusion

• A review of 9 randomized trials did not find any evidence supporting the use of antipsychotics for treating delirium. However, most of the studies included were of lower quality because they were single-center trials with insufficient sample sizes, heterogeneous study populations, and risk of bias.

Continue to: 2...

 

 

2. Girard TD, Exline MC, Carson SS, et al; MIND-USA Investigators. Haloperidol and ziprasidone for treatment of delirium in critical illness. N Engl J Med. 2018;379(26):2506-2516.

Study design

• Researchers used the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) to assess 1,183 patients with acute respiratory failure or shock in 16 medical centers in the United States.⁵
• Overall, 566 patients developed delirium and were randomized in a double-blind fashion to receive IV haloperidol, ziprasidone, or placebo.
• Haloperidol was started at 2.5 mg (age <70) or 1.25 mg (age ≥70) every 12 hours and titrated to a maximum dose of 20 mg/d as tolerated.
• Ziprasidone was started at 5 mg (age <70) or 2.5 mg (age ≥70) every 12 hours and titrated to a maximum dose of 40 mg/d as tolerated.

Outcomes

• The primary endpoint was days alive without delirium or coma. Secondary endpoints included duration of delirium, time to freedom from mechanical ventilation, time to final successful ICU discharge, time to ICU readmission, time to successful hospital discharge, 30-day survival, and 90-day survival.
• Neither ziprasidone nor haloperidol had an impact on number of days alive without delirium or coma.
• There was also no statistically significant difference in 30-day survival, 90-day survival, time to freedom from mechanical ventilation, ICU discharge, ICU readmission, or hospital discharge.

Conclusion

• This study found no evidence supporting haloperidol or ziprasidone for the treatment of delirium. Because all patients in this study were critically ill, it is unclear if these results would be generalizable to other hospitalized patient populations.

3. Yu A, Wu S, Zhang Z, et al. Cholinesterase inhibitors for the treatment of delirium in non-ICU settings. Cochrane Database Syst Rev. 2018;6:CD012494.

Continue to: Study design

 

 

Study design

• A literature review identified published and unpublished randomized controlled trials in English and Chinese in which cholinesterase inhibitors were compared with placebo or another drug for treating delirium in non-critically ill patients.⁶
• Only one study met the criteria to be included in the review. It included 15 participants treated with rivastigmine or placebo.

Outcomes

• The intended primary outcomes were severity of delirium and duration of delirium. However, the included study did not report on the severity of delirium. It also lacked statistical power to determine a difference in duration of delirium between the rivastigmine and placebo groups.
• Secondary outcomes included use of a rescue medication, persistent cognitive impairment, length of hospitalization, institutionalization, mortality, cost of intervention, early departure from the study, and quality of life.
• There was no clear difference between the rivastigmine group and the placebo group in terms of the use of rescue medications, mortality, or early departure from the study. The included study did not report on persistent cognitive impairment, length of hospitalization, institutionalization, cost of intervention, or quality of life.

Conclusion

• This literature review did not find any evidence to support the use of cholinesterase inhibitors for treating delirium. However, because this review included only a single small study, limited conclusions can be drawn from this research.

In summary, delirium is common, especially among patients who are acutely medically ill, and it is associated with poor physical and cognitive clinical outcomes. Because of these poor outcomes, it is important to identify delirium early and intervene aggressively. Clearly, there is a need for further research into short- and long-term treatments for delirium.

Delirium is defined as a disturbance in attention, awareness, and cognition that develops over hours to days as a direct physiological consequence of an underlying medical condition and is not better explained by another neurocognitive disorder.¹ This condition is found in up to 31% of general medical patients and up to 87% of critically ill medical patients. Delirium is commonly seen in patients who have undergone surgery, those who are in palliative care, and patients with cancer.² It is associated with increased morbidity and mortality. Compared with those who do not develop delirium, patients who are hospitalized who develop delirium have a higher risk of longer hospital stays, post-hospitalization nursing facility placement, persistent cognitive dysfunction, and death.³

Thus far, the management and treatment of delirium have been complicated by an incomplete understanding of the pathophysiology of this condition. However, prevailing theories suggest a dysregulation of neurotransmitter synthesis, function, or availability.² Recent literature reflects this theory; researchers have investigated agents that target dopamine or acetylcholine. Below we review some of this recent literature on treating delirium; these studies are summarized in the Table.^4-6

1. Burry L, Mehta S, Perreault MM, et al. Antipsychotics for treatment of delirium in hospitalized non-ICU patients. Cochrane Database Syst Rev. 2018;6:CD005594.

An extensive literature review identified randomized or quasi-randomized trials on the treatment of delirium among non-critically ill hospitalized patients in which antipsychotics were compared with nonantipsychotic medications or placebo, or in which a first-generation antipsychotic (FGA) was compared with a second-generation antipsychotic (SGA).⁴

Study design

• Researchers conducted a literature review of 9 trials that included 727 hospitalized but not critically ill patients (ie, they were not in an ICU) who developed delirium.
• Four trials compared an antipsychotic with a medication from another drug class or with placebo.
• Seven trials compared a FGA with an SGA.

Outcomes

• Although the intended primary outcome was the duration of delirium, none of the included studies reported on duration of delirium. Secondary outcomes were delirium severity and resolution, mortality, hospital length of stay, discharge disposition, health-related quality of life, and adverse effects.
• Among the secondary outcomes, no statistical difference was observed between delirium severity, delirium resolution, or mortality.
• None of the included studies reported on hospital length of stay, discharge disposition, or health-related quality of life.
• Evidence related to adverse effects was determined to be very low quality due to potential bias, inconsistency, and imprecision.

Conclusion

• A review of 9 randomized trials did not find any evidence supporting the use of antipsychotics for treating delirium. However, most of the studies included were of lower quality because they were single-center trials with insufficient sample sizes, heterogeneous study populations, and risk of bias.

Continue to: 2...

 

 

2. Girard TD, Exline MC, Carson SS, et al; MIND-USA Investigators. Haloperidol and ziprasidone for treatment of delirium in critical illness. N Engl J Med. 2018;379(26):2506-2516.

Study design

• Researchers used the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) to assess 1,183 patients with acute respiratory failure or shock in 16 medical centers in the United States.⁵
• Overall, 566 patients developed delirium and were randomized in a double-blind fashion to receive IV haloperidol, ziprasidone, or placebo.
• Haloperidol was started at 2.5 mg (age <70) or 1.25 mg (age ≥70) every 12 hours and titrated to a maximum dose of 20 mg/d as tolerated.
• Ziprasidone was started at 5 mg (age <70) or 2.5 mg (age ≥70) every 12 hours and titrated to a maximum dose of 40 mg/d as tolerated.

Outcomes

• The primary endpoint was days alive without delirium or coma. Secondary endpoints included duration of delirium, time to freedom from mechanical ventilation, time to final successful ICU discharge, time to ICU readmission, time to successful hospital discharge, 30-day survival, and 90-day survival.
• Neither ziprasidone nor haloperidol had an impact on number of days alive without delirium or coma.
• There was also no statistically significant difference in 30-day survival, 90-day survival, time to freedom from mechanical ventilation, ICU discharge, ICU readmission, or hospital discharge.

Conclusion

• This study found no evidence supporting haloperidol or ziprasidone for the treatment of delirium. Because all patients in this study were critically ill, it is unclear if these results would be generalizable to other hospitalized patient populations.

3. Yu A, Wu S, Zhang Z, et al. Cholinesterase inhibitors for the treatment of delirium in non-ICU settings. Cochrane Database Syst Rev. 2018;6:CD012494.

Continue to: Study design

 

 

Study design

• A literature review identified published and unpublished randomized controlled trials in English and Chinese in which cholinesterase inhibitors were compared with placebo or another drug for treating delirium in non-critically ill patients.⁶
• Only one study met the criteria to be included in the review. It included 15 participants treated with rivastigmine or placebo.

Outcomes

• The intended primary outcomes were severity of delirium and duration of delirium. However, the included study did not report on the severity of delirium. It also lacked statistical power to determine a difference in duration of delirium between the rivastigmine and placebo groups.
• Secondary outcomes included use of a rescue medication, persistent cognitive impairment, length of hospitalization, institutionalization, mortality, cost of intervention, early departure from the study, and quality of life.
• There was no clear difference between the rivastigmine group and the placebo group in terms of the use of rescue medications, mortality, or early departure from the study. The included study did not report on persistent cognitive impairment, length of hospitalization, institutionalization, cost of intervention, or quality of life.

Conclusion

• This literature review did not find any evidence to support the use of cholinesterase inhibitors for treating delirium. However, because this review included only a single small study, limited conclusions can be drawn from this research.

In summary, delirium is common, especially among patients who are acutely medically ill, and it is associated with poor physical and cognitive clinical outcomes. Because of these poor outcomes, it is important to identify delirium early and intervene aggressively. Clearly, there is a need for further research into short- and long-term treatments for delirium.

Delirium is defined as a disturbance in attention, awareness, and cognition that develops over hours to days as a direct physiological consequence of an underlying medical condition and is not better explained by another neurocognitive disorder.¹ This condition is found in up to 31% of general medical patients and up to 87% of critically ill medical patients. Delirium is commonly seen in patients who have undergone surgery, those who are in palliative care, and patients with cancer.² It is associated with increased morbidity and mortality. Compared with those who do not develop delirium, patients who are hospitalized who develop delirium have a higher risk of longer hospital stays, post-hospitalization nursing facility placement, persistent cognitive dysfunction, and death.³

Thus far, the management and treatment of delirium have been complicated by an incomplete understanding of the pathophysiology of this condition. However, prevailing theories suggest a dysregulation of neurotransmitter synthesis, function, or availability.² Recent literature reflects this theory; researchers have investigated agents that target dopamine or acetylcholine. Below we review some of this recent literature on treating delirium; these studies are summarized in the Table.^4-6

1. Burry L, Mehta S, Perreault MM, et al. Antipsychotics for treatment of delirium in hospitalized non-ICU patients. Cochrane Database Syst Rev. 2018;6:CD005594.

An extensive literature review identified randomized or quasi-randomized trials on the treatment of delirium among non-critically ill hospitalized patients in which antipsychotics were compared with nonantipsychotic medications or placebo, or in which a first-generation antipsychotic (FGA) was compared with a second-generation antipsychotic (SGA).⁴

Study design

• Researchers conducted a literature review of 9 trials that included 727 hospitalized but not critically ill patients (ie, they were not in an ICU) who developed delirium.
• Four trials compared an antipsychotic with a medication from another drug class or with placebo.
• Seven trials compared a FGA with an SGA.

Outcomes

• Although the intended primary outcome was the duration of delirium, none of the included studies reported on duration of delirium. Secondary outcomes were delirium severity and resolution, mortality, hospital length of stay, discharge disposition, health-related quality of life, and adverse effects.
• Among the secondary outcomes, no statistical difference was observed between delirium severity, delirium resolution, or mortality.
• None of the included studies reported on hospital length of stay, discharge disposition, or health-related quality of life.
• Evidence related to adverse effects was determined to be very low quality due to potential bias, inconsistency, and imprecision.

Conclusion

• A review of 9 randomized trials did not find any evidence supporting the use of antipsychotics for treating delirium. However, most of the studies included were of lower quality because they were single-center trials with insufficient sample sizes, heterogeneous study populations, and risk of bias.

Continue to: 2...

 

 

2. Girard TD, Exline MC, Carson SS, et al; MIND-USA Investigators. Haloperidol and ziprasidone for treatment of delirium in critical illness. N Engl J Med. 2018;379(26):2506-2516.

Study design

• Researchers used the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) to assess 1,183 patients with acute respiratory failure or shock in 16 medical centers in the United States.⁵
• Overall, 566 patients developed delirium and were randomized in a double-blind fashion to receive IV haloperidol, ziprasidone, or placebo.
• Haloperidol was started at 2.5 mg (age <70) or 1.25 mg (age ≥70) every 12 hours and titrated to a maximum dose of 20 mg/d as tolerated.
• Ziprasidone was started at 5 mg (age <70) or 2.5 mg (age ≥70) every 12 hours and titrated to a maximum dose of 40 mg/d as tolerated.

Outcomes

• The primary endpoint was days alive without delirium or coma. Secondary endpoints included duration of delirium, time to freedom from mechanical ventilation, time to final successful ICU discharge, time to ICU readmission, time to successful hospital discharge, 30-day survival, and 90-day survival.
• Neither ziprasidone nor haloperidol had an impact on number of days alive without delirium or coma.
• There was also no statistically significant difference in 30-day survival, 90-day survival, time to freedom from mechanical ventilation, ICU discharge, ICU readmission, or hospital discharge.

Conclusion

• This study found no evidence supporting haloperidol or ziprasidone for the treatment of delirium. Because all patients in this study were critically ill, it is unclear if these results would be generalizable to other hospitalized patient populations.

3. Yu A, Wu S, Zhang Z, et al. Cholinesterase inhibitors for the treatment of delirium in non-ICU settings. Cochrane Database Syst Rev. 2018;6:CD012494.

Continue to: Study design

 

 

Study design

• A literature review identified published and unpublished randomized controlled trials in English and Chinese in which cholinesterase inhibitors were compared with placebo or another drug for treating delirium in non-critically ill patients.⁶
• Only one study met the criteria to be included in the review. It included 15 participants treated with rivastigmine or placebo.

Outcomes

• The intended primary outcomes were severity of delirium and duration of delirium. However, the included study did not report on the severity of delirium. It also lacked statistical power to determine a difference in duration of delirium between the rivastigmine and placebo groups.
• Secondary outcomes included use of a rescue medication, persistent cognitive impairment, length of hospitalization, institutionalization, mortality, cost of intervention, early departure from the study, and quality of life.
• There was no clear difference between the rivastigmine group and the placebo group in terms of the use of rescue medications, mortality, or early departure from the study. The included study did not report on persistent cognitive impairment, length of hospitalization, institutionalization, cost of intervention, or quality of life.

Conclusion

• This literature review did not find any evidence to support the use of cholinesterase inhibitors for treating delirium. However, because this review included only a single small study, limited conclusions can be drawn from this research.

In summary, delirium is common, especially among patients who are acutely medically ill, and it is associated with poor physical and cognitive clinical outcomes. Because of these poor outcomes, it is important to identify delirium early and intervene aggressively. Clearly, there is a need for further research into short- and long-term treatments for delirium.