September 2013 FAQs

What is the recommended treatment for shivering related to therapeutic hypothermia?

Therapeutic hypothermia, also known as therapeutic temperature modulation, is recommended by the American Heart Association for patients who have been successfully resuscitated after cardiac arrest.1 It has also been used for neuroprotection in patients with traumatic brain injury or stroke. 2 Although the exact mechanism by which therapeutic hypothermia is protective is unknown, it is believed to minimize the effects of ischemia-reperfusion injury. Generally it is mild hypothermia that is desired with a body temperature between 32⁰ and 34⁰C for a duration of 12 to 24 hours.3,4 Inducing hypothermia is not without risk. Shivering, abnormal coagulation, electrolyte abnormalities, and cardiac membrane changes can occur.5,6

Shivering

Shivering occurs as a thermoregulatory mechanism and is characterized by involuntary mechanical oscillatory muscle movements.4 Shivering in the setting of therapeutic hypothermia may negatively impact outcomes.7,8 It may impede attainment of adequate hypothermia, be uncomfortable for the patient, as well as increase intracranial pressure and metabolic demand. Thus, prevention and treatment of shivering is a vital part of any therapeutic hypothermia protocol.

A number of nonpharmacologic and pharmacologic strategies for shivering have been employed; however, at this time, no method of treatment or prevention is globally preferred. A recent meta-analysis found that 27 different pharmacologic agents for shivering have been studied with clonidine, meperidine, tramadol, nefopam, and ketamine the most frequently studied.9 The efficacy of these agents was calculated using a risk:benefit ratio (e.g., a risk benefit of 2 means that patients receiving the treatment are 2 times less likely to shiver compared with placebo) and the number needed to treat (number of patients who need to be treated with the agent for 1 patient to benefit). The results are summarized in Table 1. Unfortunately, these studies were not conducted in the patient population of interest, and some were conducted in healthy volunteers. In addition, both prophylactic and treatment studies were included in the analysis, but these strategies were not delineated.

Table 1. Efficacy of agents for shivering.9

a Studies conducted with intravenous formulation (not available in United States).

b Not available in the United States.

Shivering related to therapeutic hypothermia

One protocol developed specifically for the prophylaxis and treatment of shivering in patients undergoing therapeutic hypothermia is known as the Columbia Anti-Shivering Protocol, and its use has been described by a number of authors.8 The protocol uses the Bedside Shivering Assessment Scale (BSAS) to guide treatment (see Table 2).10 The goal of therapy is little to no shivering, which is indicated by a score ≤ 1. This protocol calls for the use of pharmacologic and nonpharmacologic agents at initiation of the cooling period (i.e., prophylaxis). Stepwise therapy is initiated when prophylactic therapy fails to maintain the desired BSAS score. The interventions are described in Table 3.

Table 2. The Bedside Shivering Assessment Scale.10

Table 3. The Columbia Anti-Shivering Protocol.8

a To maintain a serum concentration of 3-4 mg/dL.

Abbreviations: IM, intramuscular; IV, intravenous.

The authors of this protocol found that 18% of patients did not require additional therapy when prophylaxis was employed, while 29% received 1 additional agent, 35% received 2 additional agents, 15% received 3 additional agents, and 2.4% required 4 additional agents. Several of the agents in the above algorithm are not traditionally considered agents for the treatment of shivering, but have a role specific to therapeutic hypothermia. Magnesium, for example, leads to peripheral vasodilation and can assist in decreasing body temperature.8,11 It is also reported to improve discomfort associated with therapeutic hypothermia.

Seder and colleagues have published a similar protocol, but with separate protocols for intubated and nonintubated patients.3 For nonintubated patients they recommend acetaminophen, buspirone plus meperidine, or dexmedetomidine or clonidine in addition to a magnesium infusion (target level of 2.5 to 3.5 mg/dL). They also recommend cautious use of a benzodiazepine for comfort of the patient. For intubated patients, they recommend acetaminophen, sedation, and neuromuscular blockade; however, these recommendations are less specific than those provided in the Columbia Anti-Shivering Protocol.

Another protocol developed by Logan and colleagues recommends dexmedetomidine and fentanyl as the first-line sedative and analgesic agents for patients undergoing therapeutic hypothermia with the addition of meperidine and skin counterwarming for shivering.11 Magnesium sulfate and neuromuscular blockade are recommended for refractory cases.

Buspirone

One concern with the use of buspirone in the Columbia Anti-Shivering Protocol is the fact that buspirone has not been studied as monotherapy for shivering. Clinical trials with buspirone typically combine the agent with meperidine or dexmeditomidine.12,13 Although the combination studies support its efficacy, it is unknown whether it is effective as monotherapy.

Meperidine

Many institutions wish to avoid meperidine based on its adverse event profile and seek alternative opioid analgesics for shivering. Unfortunately, studies with other opioid analgesics are limited and, when available, show little or no efficacy for other opioid agents.9 The efficacy of meperidine for shivering is likely separate from its effect on opioid receptors and may involve its monoamine reuptake inhibition, N-methyl-D-aspartate (NMDA) receptor antagonism, or stimulation of the α2 receptor.14 Thus, meperidine is the most useful opioid for shivering.

Conclusion

A number of pharmacologic agents have been studied for the prevention or treatment of shivering. However, no well-designed studies exist for shivering in patients undergoing therapeutic hypothermia. Although protocols have been published, there is no standard treatment at this time.

References

1. Peberdy MA, Callaway CW, Neumar RW, et al; American Heart Association. Part 9: post-cardiac arrest care: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2010;122(18 Suppl 3):S768-S786.

2. Presciutti M, Bader MK, Hepburn M. Shivering management during therapeutic temperature modulation: nurses’perspective. Crit Care Nurse. 2012;32(1):33-42.

3. Seder DB, Van der Kloot TE. Methods of cooling: practical aspects of therapeutic temperature management. Crit Care Med. 2009;37(7):S211-S222.

4. Choi HA, Badjatia N, Mayer SA. Hypothermia for acute brain injury – mechanisms and practical aspects. Nat Rev Neurol. 2012;8(4):214-222.

5. Abella BS, Hoek TL, Becker LB. Therapeutic Hypothermia. In: Hall JB, Schmidt GA, Wood LD, eds. Principles of Critical Care. 3rd ed. New York: McGraw-Hill; 2005.

6. John J, Ewy GA. Cardiopulmonary and Cardiocerebral Resuscitation. In: Fuster V, Walsh RA, Harrington RA, eds. Hurst's The Heart. 13th ed. New York: McGraw-Hill; 2011. http://www.accessmedicine.com/content.aspx?aID=7817210. Accessed August 12, 2013.

7. Pitoni S, Sinclair HL, Andrews PJD. Aspects of thermoregulation physiology. Curr Opin Crit Care. 2011;17(2):115-121.

8. Choi HA, Ko SB, Presciutti M, et al. Prevention of shivering during therapeutic temperature modulation: The Columbia Anti-Shivering Protocol. Neurocrit Care. 2011;14(3):389-394.

9. Park SM, Mangat HS, Berger K, Rosengart AJ. Efficacy spectrum of antishivering medications: meta-analysis of randomized controlled trials. Crit Care Med. 2012;40(11):3070-3082.

10. Badjatia N, Strongilis E, Gordon E, et al. Metabolic impact of shivering during therapeutic temperature modulation: the Bedside Shivering Assessment Scale. Stroke. 2008;39(12):3242-3247.

11. Logan A, Sangkachand P, Funk M. Optimal management of shivering during therapeutic hypothermia after cardiac arrest. Crit Care Nurse. 2011;31(6):e18-e30.

12. Lenhardt R, Orhan-Sungur M, Komatsu R, et al. Suppression of shivering during hypothermia using a novel drug combination in healthy volunteers. Anesthesiology. 2009;111(1):110-115.

13. Mokhtarani M, Mahgoub AN, Morioka N, et al. Buspirone and meperidine synergistically reduce the shivering threshold. Anesth Analg. 2001;93(5):1233-1239.

14. De Witte J, Sessler DI. Perioperative shivering: physiology and pharmacology. Anesthesiology. 2002;96(2):467-484.

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What data support the addition of metronidazole to empiric antibiotic regimens in the treatment of aspiration pneumonia?

Metronidazole has been used to provide coverage for anaerobic microorganisms in the treatment of aspiration pneumonia since the 1970s.1,2 Its exclusively anaerobic spectrum of activity provides a means to introduce or expand anti-anaerobic therapy of an existing empiric antimicrobial regimen. 3 Theoretical benefits of metronidazole include its low cost, availability as intravenous and oral formulations, generally mild adverse effect profile, and extremely low levels of resistance.4 Despite this, limited information is available to fully define its effect when added to empiric regimens for treatment of aspiration pneumonia.

Etiology and bacteriology of aspiration pneumonia

Aspiration pneumonia is a variant of community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP).5 Aspiration pneumonia occurs when oropharyngeal or gastric secretions are inhaled and normal flora of these secretions causes infection. Common risk factors for aspiration pneumonia include gingivitis and conditions that present compromise of normal swallowing functions, such as esophageal lesions (e.g., esophageal diverticula, esophageal reflux, esophageal stricture), anesthesia, history of seizure, drug and alcohol abuse, and neurologic disorders that reduce consciousness or cause dysphagia (e.g., dementia, history of stroke, myasthenia gravis).1,6-8 Clinical findings often considered diagnostic of anaerobic pulmonary infection include putrid discharge associated with lung abscess or empyema.6

Common flora of aspirated secretions includes anaerobic microorganisms that colonize the oropharynx and upper bowel – bacterial species not normally implicated in CAP and HAP.5 Common pathogens associated with CAP include Streptococcus pneumonia, Haemophilus influenzae, andMycoplasma pneumoniae, while those associated with HAP include Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa.9,10 Importantly, these bacteria may still be pathogens in aspiration pneumonia, as most cases are of mixed infection with aerobic and anaerobic bacteria.11,12 Among anaerobes, those most commonly cultured from anaerobic pulmonary infections in 2 studies included Peptostreptococcus species, Bacteroides melaninogenicus, and Fusobacterium nucleatum.11,13

Recommended treatment of aspiration pneumonia

Guidelines dedicated exclusively to the treatment of aspiration pneumonia are not available, although treatment recommendations for the condition are made by the Infectious Diseases Society of America-American Thoracic Society (IDSA-ATS) guidelines for the treatment of CAP.8 Importantly, these guidelines state that the requirement for anaerobic coverage is overestimated and is only indicated in classic aspiration pleuropulmonary syndrome in patients with underlying risk factors for aspiration. Furthermore, any anaerobic bacteria that are aspirated during intubation in severely ill patients likely would be covered by empiric treatment of severe CAP and the high oxygen tension provided by mechanical ventilation.

Preferred antimicrobials for aspiration pneumonia discussed in the IDSA-ATS guidelines include clindamycin and β-lactam/β-lactamase inhibitors (ampicillin/sulbactam, amoxicillin/clavulanic acid, and piperacillin/tazobactam), while alternative antimicrobials include carbapenems.8 Recently, moxifloxacin also has been recommended as a treatment option because of its good in vitro activity against anaerobes and data from clinical trials demonstrating safety and efficacy similar to ampicillin/sulbactam.14

Metronidazole is not included in the IDSA-ATS recommendations.8 However, some sources, including The Sanford Guide to Antimicrobial Therapy, recommend metronidazole in combination with either amoxicillin-clavulanate, penicillin G, or ceftriaxone as an alternative regimen.3,15 However, data supporting recommendations for metronidazole use with these agents come from small, primarily descriptive studies of amoxicillin-clavulanate and penicillin G in pneumonia, while no trials have specifically evaluated metronidazole in combination with ceftriaxone in aspiration pneumonia. 16,17 Combination of metronidazole with levofloxacin or ciprofloxacin was recommended in one review; however, no clinical data were referenced in support of this statement.2

Literature review

Despite references to metronidazole in reviews of aspiration pneumonia treatment, clinica data are lacking to describe its safety and efficacy when added to empiric antimicrobial regimens. Trials performed in the 1970s linked anaerobic bacteria to aspiration pneumonia and contributed to the practice of metronidazole use in this setting.5,11,18-20 However, no trials have compared empiric antimicrobial regimens for aspiration pneumonia with and without metronidazole.5 Importantly, most patients in early descriptive trials responded to treatment with a beta-lactam without concomitant metronidazole, suggesting that the cultured anaerobes may not have been pathogenic.5,18,20

While no definitive data are available to describe the value of add-on metronidazole for aspiration pneumonia, consensus exists that it should not be used as monotherapy.1,15,21 In 2 small prospective trials, failure rates with metronidazole monotherapy approximated 50%.21,22 One prospective observational study found 5 of 11 patients with anaerobic pleuropulmonary infections experienced clinical failure with metronidazole monotherapy. Another prospective, randomized controlled trial compared metronidazole with clindamycin in 16 patients and found clinical failure occurred in 4 of 7 treated with metronidazole, compared with 1 of 10 treated with clindamycin.22 The rationale for high clinical failure rates is hypothesized to be the drug’s lack of activity against microaerophilic and aerobic streptococci, which are present in 40% to 70% of cases of aspiration pneumonia.15

Spectra of antimicrobial activities

Recommended antimicrobial regimens for the treatment of aspiration pneumonia include at least some coverage of the most commonly implicated anaerobic bacteria; only ceftriaxone and levofloxacin lack known activity against Fusobacterium.3,8 Thus, the excellent activity of metronidazole against anaerobic organisms may only offer meaningful additional coverage in specific situations, such as when there is a high suspicion of resistance to recommended agents or when infection may be due to anaerobes not covered by recommended agents, such as Bacteroides fragilis and Clostridia species.3,23 However, B fragilis and Clostridia species typically colonize the colon and lower bowel and therefore are unlikely to be aspirated from oropharyngeal contents.3,24-26

Conclusion

While anaerobes are commonly isolated in cases of aspiration pneumonia, their risk for causing this condition is generally overestimated, as most cases are of mixed aerobic and anaerobic etiology. The most commonly isolated bacteria (Peptostreptococcus spp., B melaninogenicus, and F nucleatum) may be covered by empiric regimens for CAP and HAP, thus addition of metronidazole may not be necessary; some data indicate that some patients may respond without specific anti-anaerobic therapy. No data are available to define the role of metronidazole when added to empiric regimens in treatment of aspiration pneumonia; however, data suggest it should not be used alone for this indication. Broadening of coverage with anti-anaerobic therapy is appropriate in cases of suspected aspiration pneumonia in patients with risk factors for aspiration or who develop abscesses, empyema, or necrotizing pneumonia. Because of its unique anti-anaerobic spectrum of activity, metronidazole may offer most benefit when anaerobic resistance is high or when uncommon anaerobes are suspected causes of the aspiration pneumonia.

References

1. Bartlett JG. Anaerobic bacterial infection of the lung. Anaerobe. 2012;18(2):235-239.

2. Marik PE. Aspiration pneumonitis and aspiration pneumonia. N Engl J Med. 2001;344(9):665-671.

3. The Sanford Guide to Antimicrobial Therapy 2012 [handheld database]. Sperryville, VA: Antimicrobial Therapy, Inc; 2012. Accessed August 20, 2013.

4. Löfmark S, Edlund C, Nord CE. Metronidazole is still the drug of choice for treatment of anaerobic infections. Clin Infect Dis. 2010;50(Suppl 1):S16-23.

5. Kwong JC, Howden BP, Charles PG. New aspirations: the debate on aspiration pneumonia treatment guidelines. Med J Aust. 2011;195(7):380-381.

6. Bartlett JG. How important are anaerobic bacteria in aspiration pneumonia: when should they be treated and what is optimal therapy. Infect Dis Clin North Am. 2013;27(1):149-155.

7. Donowitz GR. Acute pneumonia. In: Mandell GL, Bennett JE, Dolin, R, eds. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 7th ed. Philadelphia, PA:Churchill Livingston; 2012:591-916.

8. Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44(Suppl 2):S27-72.

9. Marrie TJ, Poulin-costello M, Beecroft MD, Herman-gnjidic Z. Etiology of community-acquired pneumonia treated in an ambulatory setting. Respir Med. 2005;99(1):60-65.

10. Jones RN. Microbial etiologies of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia. Clin Infect Dis. 2010;51(Suppl 1):S81-87.

11. Lorber B, Swenson RM. Bacteriology of aspiration pneumonia. A prospective study of community- and hospital-acquired cases. Ann Intern Med. 1974;81(3):329-331.

12. Bartlett JG, O'keefe P, Tally FP, Louie TJ, Gorbach SL. Bacteriology of hospital-acquired pneumonia. Arch Intern Med. 1986;146(5):868-871.

13. Bartlett JG. Anaerobic bacterial infections of the lung. Chest. 1987;91(6):901-909.

14. Ott SR, Allewelt M, Lorenz J, Reimnitz P, Lode H. Moxifloxacin vs ampicillin/sulbactam in aspiration pneumonia and primary lung abscess. Infection. 2008;36(1):23-30.

15. Bartlett JG. Aspiration pneumonia in adults. In: Basow DS, ed. UpToDate. Waltham, MA: UpToDate; 2013.

16. Germaud P, Poirier J, Jacqueme P, et al. Monotherapy using amoxicillin/clavulanic acid as treatment of first choice in community-acquired lung abscess. Apropos of 57 cases. Rev Pneumol Clin. 1993;49(3):137-141.

17. Eykyn SJ. The therapeutic use of metronidazole in anaerobic infection: six years' experience in a London hospital. Surgery. 1983;93(1 Pt 2):209-214.

18. Bartlett JG, Gorbach SL, Finegold SM. The bacteriology of aspiration pneumonia. Am J Med. 1974;56(2):202-207.

19. Cesar L, Gonzalez C, Calia FM. Bacteriologic flora of aspiration-induced pulmonary infections. Arch Intern Med. 1975;135(5):711-714.

20. Bartlett JG, Gorbach SL. Treatment of aspiration pneumonia and primary lung abscess. Penicillin G vs clindamycin. JAMA. 1975;234(9):935-937.

21. Sanders CV, Hanna BJ, Lewis AC. Metronidazole in the treatment of anaerobic infections. Am Rev Respir Dis. 1979;120(2):337-343.

22. Perlino CA. Metronidazole vs clindamycin treatment of anaerobic pulmonary infection. Failure of metronidazole therapy. Arch Intern Med. 1981;141(11):1424-1427.

23. Brook I. Antimicrobial treatment of anaerobic infections. Expert Opin Pharmacother. 2011;12(11):1691-1707.

24. Levinson W. Gram-negative rods related to the enteric tract. In: Levinson W, ed. Review of Medical Microbiology & Immunology. 12th ed. New York, NY: McGraw-Hill; 2012. http://www.accessmedicine.com/content.aspx?aID=56757572. Accessed August 19, 2013.

25. Brooks GF. Infections caused by anaerobic bacteria. In: Brooks GF, ed. Jawetz, Melnick, & Adelberg's Medical Microbiology. 26th ed. New York, NY: McGraw-Hill; 2013. http://www.accessmedicine.com/content.aspx?aID=57033203. Accessed August 19, 2013.

26. Ferri FF. Aspiration pneumonia. In: Ferri FF, Ferri's Clinical Advisor 2014. 1st ed. Philadelphia, PA: Elsevier Mosby; 2013. http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-0-323-08374-4..12001-2&isbn=978-0-323-08374-4&uniqId=421494403-3#4-u1.0-B978-0-323-08374-4..12001-2 . Accessed August 19, 2013.

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Are most classically described side effects of beta-blocker therapy in heart failure actually due to the medication?

Introduction

For over half a century, beta-blocker therapy has been an important component of cardiovascular disease management.1 Initially, this medication class was developed as a treatment for hypertension and angina.2 With continued study, beta-blocker prescribing expanded into other cardiovascular indications including acute myocardial infarction, tachyarrhythmias, and heart failure. Widespread utilization of beta-blocker therapy in patients with heart failure did not occur rapidly. Historically, heart failure was considered to be due to a decline in systolic function only; therefore, any medication with negative inotropic effects was contraindicated for use. This conventional wisdom changed with the publication of several large, randomized, placebo-controlled trials such as the Metoprolol in Dilated Cardiomyopathy (MDC), Metoprolol CR/XL Randomized Intervention Trial in Heart Failure (MERIT-HF), Cardiac Insufficiency Bisoprolol Studies (CIBIS I and II), and Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) studies.3-7 Results of these studies definitively proved that beta-blocker therapy decreases morbidity and mortality among symptomatic patients with class II through IV heart failure and reduced left ventricular ejection fraction.2 Current guidelines from both the American College of Cardiology and the Heart Failure Society of America recommend beta-blockers as an essential treatment for patients with current or prior symptoms of heart failure with reduced ejection fraction unless contraindications exist.8,9

Beta-blocker adverse effects in heart failure

Although beta-blockers have been shown to positively impact morbidity and mortality in heart failure, uptake and compliance remain poor.10 One of the reasons for this is the perception, by patients and healthcare providers, that beta-blockers are associated with a wide range of intolerable adverse effects. Barron and colleagues recently published a systematic review that evaluated the “genuine versus spurious” adverse effects of beta-blockers in heart failure. This review included 13 parallel-group, double-blind, randomized trials of beta-blocker versus placebo therapy in heart failure reporting adverse effects. These trials included 15,383 patients (n = 7,836 beta-blocker; n = 7,547 placebo) and evaluated the effects of 5 beta-blockers: carvedilol (6 trials), metoprolol, bisoprolol, nebivolol (2 trials each), and bucindolol (1 trial). The occurrence of 33 “classically described side effects” with beta-blocker therapy was assessed. Results revealed that “the majority of adverse effects reported with beta-blockers in heart failure are not caused by the beta-blockers per se but arise from either the disease itself, another coincident problem, or from the power of suggestion.”

Of the 33 adverse effects classically ascribed to beta-blocker therapy, only 5 were significantly more common with beta-blockers than placebo: hyperglycemia, diarrhea, dizziness, claudication, and bradycardia.10 Six adverse effects occurred significantly less frequently with beta-blockers as compared to placebo: tachycardia, palpitations, depression, insomnia, cardiac failure, and chest pain. Of the 5 effects found to be significantly more common with beta-blockers, only 2 effects (bradycardia and intermittent claudication) were definitively caused by the medication in the majority of patients. For the other 3 effects, beta-blockers were the definitive etiology in < 25% of sufferers. Table 1 summarizes the difference in the frequency of adverse effects between beta-blockers and placebo among the included studies.

Table 1. Frequency of adverse effects between beta-blockers and placebo in heart failure.10

Only 2 trials reported the occurrence of serious adverse effects.10 A higher percentage of patients administered placebo experienced a serious adverse effect as compared to beta-blocker therapy (25.6% vs. 22.1%). Randomization to beta-blocker therapy was associated with a reduction in the risk of serious adverse effects by 16% (95% CI: 4% to 27%; p = 0.01). Overall, a greater proportion of adverse effects were reported by patients randomized to placebo. In addition, more patients who “were so overwhelmed by the side effects that they had to stop” were administered placebo not beta-blocker therapy. 11

Conclusion

As noted prior, the results of this systematic review reveal that the majority of adverse effects reported among patients with heart failure receiving beta-blockers are not actually caused by beta-blocker therapy. Rather, these effects may be caused by heart failure itself, another concomitant condition, or the power of suggestion. The authors of the review suggest that clinicians should reconsider informing patients with heart failure about all potential adverse effects of beta-blocker therapy. Instead, the investigators suggest that “physicians might focus the patient’s attention on a much smaller core of reliable information, together with information on the proportion of side effects that are nonpharmacological. Thus, adverse effects, when later experienced, are not automatically assumed to be caused by the drug”.11

References

1. Frishman WH. β-adrenergic blockers: a 50-year historical perspective. Am J Ther. 2008;15(6):565-576.

2. Foody JM, Farrell MH, Krumholz HM. β-blocker therapy in heart failure. JAMA. 2002;287(7):883-889.

3. Waagstein F, Bristow MR, Swedberg K, et al. Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study Group. Lancet. 1993;342(8885)1441-1446.

4. Goldstein S, Hjalmarson A. The mortality effect of metoprolol CR/XL in patients with heart failure: results of the MERIT-HF trial. Clin Cardiol . 1999;22(Suppl 5):V30-V35.

5. CIBIS Investigators and Committees. A randomized trial of beta-blockade in heart failure. The Cardiac Insufficiency Bisoprolol Study (CIBIS). Circulation. 1994;90(4):1765-1773.

6. CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomized trial. Lancet. 1999;353(9146):9-13.

7. Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001;344(22):1651-1658.

8. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013 Jun 5. pii: S0735-1097(13)02114-1. doi: 10.1016/j.jacc.2013.05.019. [Epub ahead of print].

9. Lindenfeld J, Albert NM, Boehmer JP, et al. HFSA 2010 comprehensive heart failure practice guideline. J Card Fail. 2010;16(6):e1-194.

10. Barron AJ, Zaman N, Cole GD, et al. Systematic review of genuine versus spurious side-effects of beta-blockers in heart failure using placebo control: recommendations for patient information. Int J Cardiol. 2013 Jun 21. pii: S0167-5273(13)00996-0. doi: 10.1016/j.ijcard.2013.05.068. [Epub ahead of print].

11. Beta-blockers in HF get bum rap for most “side effects”, says study. Heartwire. http://www.theheart.org/article/1560695.do. Accessed August 22, 2013.

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