Acute Decompensated Heart Failure: New Strategies for Improving Outcomes

Table of Contents

 

1. Abstract
2. Case Presentations
3. Introduction
4. Critical Appraisal of the Literature
5. Etiology And Pathophysiology
6. Differential Diagnosis
7. Prehospital Care
8. Emergency Department Evaluation
   1. History
9. Diagnostic Studies
   1. Electrocardiogram
   2. Diagnostic Imaging
      1. Chest X-Ray
      2. Echocardiography
      3. Pulmonary Ultrasound
   3. Laboratory Testing
      1. Cardiac Biomarkers
      2. Complete Blood Cell Count
      3. Chemistry Panel
      4. Supplementary Testing
10. Treatment
    1. Airway and Ventilation Management
       1. Vasodilators
          • Nitroglycerin
          • Clevidipine
          • Angiotensin-Converting Enzyme Inhibitors
          • Nesiritide
          • Vasodilator Therapy Recommendations
       2. Inotropes
          • Digoxin
          • Dopamine
          • Dobutamine
          • Norepinephrine
          • Milrinone
          • Inotrope Therapy Recommendations
       3. Diuretics
    2. Mechanical Circulatory Support
    3. Further Management
11. Controversies and Cutting Edge
    1. Novel Drug Therapies
       1. Levosimendan
       2. Serelaxin
       3. Human Natriuretic Peptides
       4. Omecamtiv Mecarbil
    2. Ultrafiltration
    3. Novel Biomarkers
12. Disposition
13. Time- and Cost-Effective Strategies
14. Summary
15. Risk Management Pitfalls for Management Acute Decompensated Heart Failure
16. Case Conclusions
17. Clinical Pathway for Unstable Patients in Decompensated Heart Failure (Reduced and Preserved Ejection Fraction)
18. Tables and Figures
    1. Table 1. Precipitants of Acute Decompensation in Heart Failure Patients
    2. Table 2. Differential Diagnosis for Patients Presenting With Dyspnea
    3. Table 3. Pitting Edema Scale
    4. Table 4. Treatment Options in Acute Decompensated Heart Failure
    5. Figure 1. Diastolic and Systolic Heart Failure
    6. Figure 2. Electrocardiogram Demonstrating an Acute Inferior STEMI
    7. Figure 3. Mild Pulmonary Congestion Demonstrating Cephalization
    8. Figure 4. Pulmonary Congestion Demonstrating Kerley B-Lines
    9. Figure 5. Pulmonary Congestion With Cardiomegaly
    10. Figure 6. Normal and Increased E-point Septal Separation
    11. Figure 7. Lung Ultrasound Demonstrating B-Lines
19. References

Abstract

Acute decompensated heart failure is a common emergency department presentation with significant associated morbidity and mortality. Heart failure accounts for more than 1 million hospitalizations annually, with a steadily increasing incidence as our population ages. This issue reviews recent literature regarding appropriate management of emergency department presentations of acute decompensated heart failure, with special attention to newer medication options. Emergency department management and appropriate interventions are discussed, along with critical decision-making points in resuscitation for both hypertensive and hypotensive patients.

Case Presentation

As you arrive for your ED shift, an ambulance pulls in, carrying a patient struggling to breathe. The paramedics quickly brief you: your patient is a 76-year-old woman with a history of heart failure. She has been compliant with all of her medications but has had progressively worsening, difficult breathing. You notice coarse, wet-sounding lungs with poor air movement at the lung bases. You also notice significant pitting edema in both of her legs. She describes orthopnea and states that she has been sitting up in a chair to sleep for “a while.” When you examine her medications, you note that she is on a low dose of a beta blocker and an ACE inhibitor, despite a stated history of low blood pressure. She was also prescribed spironolactone and furosemide, and you can feel an implant under the skin of her left chest wall, which she confirms as an AICD. You attach your patient to the cardiac monitor and notice she is tachycardic, with a heart rate of 115 beats/min, and her blood pressure is 80/40 mm Hg. You wonder if she would be best treated with fluids or diuretics, and your medical student asks, “How do we decide?”

While nurses are establishing IV access for your first patient, another nurse pulls you into a nearby room with a patient who just arrived via EMS. The patient is an overweight middle-aged man who is also struggling to breathe. Paramedics report that his blood pressure was 220/130 mm Hg at the scene. You immediately attach the patient to the cardiac monitor and obtain vital signs. His blood pressure is now 240/140 mm Hg. You listen to his lungs and again notice coarse, wet breath sounds. Your patient is tachypneic, leaning forward in bed, and saturating 70% on room air. His oxygen saturation improves to 88% on a 100% nonrebreather mask. His legs are edematous, and he has marked conversational dyspnea. Respiratory failure seems certain unless appropriate action is taken, and you wonder if there is anything that can change this patient’s course.

Introduction

The incidence of in-hospital mortality among patients admitted to the hospital for decompensated heart failure is 6.4%.¹ Although there are many management options available, some therapies offer innovative approaches to improve patient outcomes, while others may increase cost without improving outcomes.

In the United States, acute decompensated heart failure (ADHF) is the number one cause of hospital admission in patients over the age of 65 and accounts for more than 1 million hospital admissions and $30.7 billion in healthcare expenditure annually.² In individuals aged 65 to 69 years, the prevalence of heart failure is roughly 20 per 1000, and prevalence jumps to more than 80 per 1000 in individuals older than 85 years.³ The prevalence of heart failure varies by sex and ethnicity, with men demonstrating a higher prevalence than women, and blacks having a higher prevalence than whites.² With the aging of the United States population, heart failure is expected to become a more common emergency department (ED) presentation. Projections estimate an increase in the prevalence of heart failure by 46% from 2012 to 2030, with a predicted 8 million adult cases in the United States by 2030.²

Not all heart failure is the same. Heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF) represent distinct underlying pathophysiologies that require different approaches in treatment. HFpEF and HFrEF are essentially equal in terms of occurrence, morbidity, and mortality.⁴ The underlying volume status of heart failure patients is difficult to assess, yet time is often limited, and the interventions chosen can change the course for better or for worse. In addition, ADHF patients may present with either hypertension or hypotension, which can make management challenging.

This issue of Emergency Medicine Practice examines the medical management of ADHF, with a focus on new therapies that may alter conventional management. This issue will enable the emergency clinician to quickly recognize the clinical presentations of the varying types of decompensated heart failure, understand the underlying pathophysiology, and formulate the most appropriate management plan.

Critical Appraisal Of The Literature

A literature search was performed via PubMed using the terms acute heart failure and decompensated heart failure. The search returned 1710 articles; 350 articles from 2014 to present were screened for relevance, and a total of 190 were reviewed based on clinical applicability in the ED. The Cochrane Database of Systematic Reviews was searched for reviews using the terms decompensated heart failure and acute heart failure, which identified 10 reviews; 108 were identified with the more general search terms of heart failure. The majority of these reviews focused on chronic heart failure management and were excluded. Guidelines released jointly by the American Heart Association and American College of Cardiology Foundation were also reviewed.

The available data that focus on the management of ADHF are, overall, of lower quality than that for chronic heart failure management, and the literature behind newer interventions is even more limited. Studies looking at newer treatment modalities would benefit from the improved generalizability associated with multicenter studies that enroll larger patient populations. The paucity of data on the vasodilator nesiritide is a prime example – the only available studies are small, underpowered, and tend to show nonsignificant trends in terms of efficacy and harm compared with older modalities.^5,6 Even basic interventions (such as nitrate administration) have limited data supporting their use.⁷ Less commonly performed rescue therapies, such as extracorporeal membrane oxygenation (ECMO), have even lower-quality data supporting their use, largely due to small sample sizes.⁸ The literature behind the management of HFpEF is also weaker than that supporting the management of HFrEF.

Risk Management Pitfalls for Management Acute Decompensated Heart Failure

1. “The patient looked comfortable, so I didn’t immediately check his pulse oximetry.”

Vital signs are truly vital in these patients. Blood pressure and pulse oximetry must be checked immediately. A low pulse oximetry level requires immediate intervention with supplemental oxygen or respiratory support.

2. “I wasn’t sure what was going on, but I didn’t know how to use the ultrasound machine.”

Bedside echocardiogram is a crucial diagnostic tool to help confirm the diagnosis of heart failure. The onus is on the emergency clinician to learn to use ultrasound as a diagnostic tool for diagnosis of heart failure and other ED presentations.

3. “The patient was short of breath, so I started treatment for heart failure.”

There are many diagnostic entities that can cause dyspnea and mimic the symptoms of heart failure. Particularly in obese patients who are poorly conditioned at baseline, many other causes of dyspnea can be mistaken for heart failure. Examples include pulmonary embolism, pneumonia, pericardial effusion, and COPD. Treatment can be started quickly if the diagnosis is clear, but alternative etiologies should be actively sought.

4. “The patient was wheezing, so I knew it was COPD and did not worry about heart failure.”

While heart failure traditionally presents with rales on the pulmonary examination, cardiac wheezes can also occur and are not necessarily indicative of obstructive pulmonary disease as the primary etiology. Additionally, patients may have coexisting obstructive pulmonary disease and heart failure, which can complicate the clinical picture.

5. “There was a focal infiltrate on the chest x-ray, so I knew it couldn’t be heart failure.”

Patients can present with multiple coexisting etiologies, and heart failure can be exacerbated by secondary assaults, such as sepsis. Additionally, pulmonary congestion can present as bilateral consolidation on chest x-ray.

6. “The patient had chest pain and obvious heart failure, so we treated for heart failure but did not do any additional diagnostic testing.”

Don’t miss secondary causes of heart failure. Coronary ischemia, pulmonary embolism, and pericardial effusion can all contribute to the heart's inability to pump effectively. These secondary reversible or treatable causes are crucial to identifying and effectively managing these patients.

7. “The patient was hypotensive but had a history of heart failure, so I did not give any IV fluids.”

Patients with heart failure can be intravascularly depleted and may require gentle fluid resuscitation in the setting of hypotension. The fluids should be given in smaller aliquots, but fluid should not be withheld in these patients, particularly in hypotensive patients who do not look grossly fluid overloaded.

8. “I wasn’t sure what to do for my unstable patient, so I just gave furosemide and waited.”

These patients respond well to aggressive, early interventions. Failure to quickly intervene can allow clinical deterioration, requiring more-invasive airway and circulatory support. Furosemide is an inadequate sole intervention in an unstable patient.

9. “My patient was having difficulty breathing, so I immediately intubated.”

While the decision to intubate is always a clinical one, a trial of NIPPV is often appropriate in patients with ADHF. NIPPV is a useful temporizing measure that can stabilize the patient until more definitive interventions have taken effect. The appropriate contraindications for NIPPV should always be considered, but in the appropriate patient, it can be a useful adjunct.

10. “My patient was looking much better on the nitroglycerin drip, so I weaned her off and discharged her home.”

Heart failure patients have a high risk of clinical deterioration and require close observation. Patients requiring nitroglycerin or pressor drips require ICU-level care and close monitoring. Any patient with respiratory symptoms should be admitted for diuresis and close observation.

Tables and Figures

References

Evidence-based medicine requires a critical appraisal of the literature based upon study methodology and number of subjects. Not all references are equally robust. The findings of a large, prospective, randomized, and blinded trial should carry more weight than a case report.

To help the reader judge the strength of each reference, pertinent information about the study is included in bold type following the reference, where available. The most informative references cited in this paper, as determined by the authors, are noted by an asterisk (*) next to the number of the reference.

1. Wakabayashi K, Sato N, Kajimoto K, et al. Incidence and predictors of in-hospital non-cardiac death in patients with acute heart failure. Eur Heart J Acute Cardiovasc Care. 2015 Jul 2. (Retrospective observational cohort study; 4842 patients)
2. * Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics-2016 update: a report from the American Heart Association. Circulation. 2016;133(4):e38-e360. (Cross-sectional analysis)
3. Curtis LH, Whellan DJ, Hammill BG, et al. Incidence and prevalence of heart failure in elderly persons, 1994-2003. Arch Intern Med. 2008;168(4):418-424. (Retrospective cohort study; 622,789 patients)
4. Karrowni W, Chatterjee K. Diastolic heart failure: the current understanding and approach for management with focus on intensive care unit patients. J Intensive Care Med. 2014;29(3):119-127. (Review article)
5. Miller AH, Nazeer S, Pepe P, et al. Acutely decompensated heart failure in a county emergency department: a double-blind randomized controlled comparison of nesiritide versus placebo treatment. Ann Emerg Med. 2008;51(5):571-578. (Randomized blinded placebo-controlled trial; 101 patients)
6. Peacock WF 4th, Holland R, Gyarmathy R, et al. Observation unit treatment of heart failure with nesiritide: results from the proaction trial. J Emerg Med. 2005;29(3):243-252. (Multicenter randomized double-blind placebo-controlled pilot study)
7. * Wakai A, McCabe A, Kidney R, et al. Nitrates for acute heart failure syndromes. Cochrane Database Syst Rev. 2013 Aug 6;(8):CD005151. (Cochrane review)
8. Tramm R, Ilic D, Davies Andrew R, et al. Extracorporeal membrane oxygenation for critically ill adults. Cochrane Database Syst Rev. 2015 Jan 22;1:CD010381. (Cochrane review)
9. Gloschat CR, Koppel AC, Aras KK, et al. Arrhythmogenic and metabolic remodelling of failing human heart. J Physiol. 2016;594(14):3963-3980. (Review article)
10. Irizarry Pagan EE, Vargas PE, Lopez-Candales A. The clinical dilemma of heart failure with preserved ejection fraction: an update on pathophysiology and management for physicians. Postgrad Med J. 2016;92(1088):346-355. (Review article)
11. Paulus WJ, Tschope C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol. 2013;62(4):263-271. (Review article)
12. Maalouf R, Bailey S. A review on B-type natriuretic peptide monitoring: assays and biosensors. Heart Fail Rev. 2016;21(5):567-578. (Review article)
13. Williams TA, Finn J, Perkins GD, et al. Prehospital continuous positive airway pressure for acute respiratory failure: a systematic review and meta-analysis. Prehosp Emerg Care. 2013;17(2):261-273. (Meta-analysis; 5 studies, 1002 patients.)
14. Clemency BM, Thompson JJ, Tundo GN, et al. Prehospital high-dose sublingual nitroglycerin rarely causes hypotension. Prehosp Disaster Med. 2013;28(5):477-481. (Retrospective cohort study; 75 patients)
15. Pan A, Stiell IG, Dionne R, et al. Prehospital use of furosemide for the treatment of heart failure. Emerg Med J. 2015;32(1):36-43. (Multicenter review; 330 patients)
16. Jaronik J, Mikkelson P, Fales W, et al. Evaluation of prehospital use of furosemide in patients with respiratory distress. Prehosp Emerg Care. 2006;10(2):194-197. (Retrospective cohort study; 144 patients)
17. Maisel AS, Shah KS, Barnard D, et al. How B-type natriuretic peptide (BNP) and body weight changes vary in heart failure with preserved ejection fraction compared with reduced ejection fraction: secondary results of the HABIT (HF Assessment With BNP in the Home) trial. J Card Fail. 2016;22(4):283-293. (Retrospective cohort study)
18. Rizzi MA, Torres Bonafonte OH, Alquezar A, et al. Prognostic value and risk factors of delirium in emergency patients with decompensated heart failure. J Am Med Dir Assoc. 2015;16(9):799.e791-e796. (Prospective observational cohort study; 239 patients)
19. Anker SD, Sharma R. The syndrome of cardiac cachexia. Int J Cardiol. 2002;85(1):51-66. (Review)
20. Martindale JL, Wakai A, Collins SP, et al. Diagnosing acute heart failure in the emergency department: a systematic review and meta-analysis. Acad Emerg Med. 2016;23(3):223-242. (Meta-analysis)
21. Unluer EE, Karagoz A, Akoglu H, et al. Visual estimation of bedside echocardiographic ejection fraction by emergency physicians. West J Emerg Med. 2014;15(2):221-226. (Prospective cohort study; 146 patients)
22. Ehrman RR, Russell FM, Ansari AH, et al. Can emergency physicians diagnose and correctly classify diastolic dysfunction using bedside echocardiography? Am J Emerg Med. 2015;33(9):1178-1183. (Prospective observational study; 62 patients)
23. Holst JM, Kilker BA, Wright S, et al. Heart failure with preserved ejection fraction: echocardiographic VALVE protocol for emergency physicians. Eur J Emerg Med. 2014;21(6):394-402. (Review)
24. Secko MA, Lazar JM, Salciccioli LA, et al. Can junior emergency physicians use E-point septal separation to accurately estimate left ventricular function in acutely dyspneic patients? Acad Emerg Med. 2011;18(11):1223-1226. (Prospective observational study; 58 patients)
25. Liteplo AS, Marill KA, Villen T, et al. Emergency thoracic ultrasound in the differentiation of the etiology of shortness of breath (ETUDES): sonographic B-lines and N-terminal pro-brain-type natriuretic peptide in diagnosing congestive heart failure. Acad Emerg Med. 2009;16(3):201-210. (Prospective observational study; 94 patients)
26. Martindale JL, Noble VE, Liteplo A. Diagnosing pulmonary edema: lung ultrasound versus chest radiography. Eur J Emerg Med. 2013;20(5):356-360. (Prospective blinded observational study; 60 residents)
27. Pivetta E, Goffi A, Lupia E, et al. Lung ultrasound-implemented diagnosis of acute decompensated heart failure in the ED: A SIMEU multicenter study. Chest. 2015;148(1):202-210. (Multicenter prospective cohort study)
28. * Liu ZP, Zhang Y, Bian H, et al. Clinical application of rapid B-line score with lung ultrasonography in differentiating between pulmonary infection and pulmonary infection with acute left ventricular heart failure. Am J Emerg Med. 2015. (Prospective single-blind study; 98 patients)
29. Chiem AT, Chan CH, Ander DS, et al. Comparison of expert and novice sonographers’ performance in focused lung ultrasonography in dyspnea (FLUID) to diagnose patients with acute heart failure syndrome. Acad Emerg Med. 2015;22(5):564-573. (Prospective, cross-sectional study)
30. Gallard E, Redonnet JP, Bourcier JE, et al. Diagnostic performance of cardiopulmonary ultrasound performed by the emergency physician in the management of acute dyspnea. Am J Emerg Med. 2015;33(3):352-358. (Prospective cohort study; 130 patients)
31. Moe GW, Howlett J, Januzzi JL, et al. N-terminal pro-B-type natriuretic peptide testing improves the management of patients with suspected acute heart failure: primary results of the Canadian prospective randomized multicenter IMPROVE-CHF study. Circulation. 2007;115(24):3103-3110. (Prospective randomized interventional study; 500 patients)
32. van Kimmenade RR, Pinto YM, Bayes-Genis A, et al. Usefulness of intermediate amino-terminal pro-brain natriuretic peptide concentrations for diagnosis and prognosis of acute heart failure. Am J Cardiol. 2006;98(3):386-390. (Prospective observational cohort study; 215 patients)
33. Fonarow GC, Peacock WF, Horwich TB, et al. Usefulness of B-type natriuretic peptide and cardiac troponin levels to predict in-hospital mortality from ADHERE. Am J Cardiol. 2008;101(2):231-237. (Retrospective cohort study; 77,467 hospitalizations)
34. Dieplinger B, Gegenhuber A, Kaar G, et al. Prognostic value of established and novel biomarkers in patients with shortness of breath attending an emergency department. Clin Biochem. 2010;43(9):714-719. (Prospective cohort study; 251 patients)
35. Januzzi JL Jr, Sakhuja R, O’Donoghue M, et al. Utility of amino-terminal pro-brain natriuretic peptide testing for prediction of 1-year mortality in patients with dyspnea treated in the emergency department. Arch Intern Med. 2006;166(3):315-320. (Prospective cohort study; 599 patients)
36. Bayes-Genis A, Lopez L, Zapico E, et al. NT-ProBNP reduction percentage during admission for acutely decompensated heart failure predicts long-term cardiovascular mortality. J Card Fail. 2005;11(5 Suppl):S3-S8. (Prospective observational study; 74 patients)
37. Dhaliwal AS, Deswal A, Pritchett A, et al. Reduction in BNP levels with treatment of decompensated heart failure and future clinical events. J Card Fail. 2009;15(4):293-299. (Retrospective cohort study; 203 patients)
38. Nakada Y, Kawakami R, Nakano T, et al. Gender differences in clinical characteristics and long-term outcome in acute decompensated heart failure patients with preserved and reduced ejection fraction. Am J Physiol Heart Circ Physiol. 2016;310(7):H813-H820. (Retrospective observational cohort study; 748 patients)
39. * Horwich TB, Patel J, MacLellan WR, et al. Cardiac troponin I is associated with impaired hemodynamics, progressive left ventricular dysfunction, and increased mortality rates in advanced heart failure. Circulation. 2003;108(7):833-838. (Prospective cohort study; 238 patients)
40. Adams KF Jr, Fonarow GC, Emerman CL, et al. Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE). Am Heart J. 2005;149(2):209-216. (Retrospective analysis; 107,362 patients)
41. Diez M, Talavera ML, Conde DG, et al. High sensitive troponin is associated with high risk clinical profile and outcome in acute heart failure. Cardiol J. 2016;23(1):78-83. (Prospective cohort study; 187 patients)
42. Carson JL, Grossman BJ, Kleinman S, et al. Red blood cell transfusion: a clinical practice guideline from the AABB*. Ann Intern Med. 2012;157(1):49-58. (Clinical practice guidelines)
43. Vakilian F, Rafighdoost AA, Rafighdoost AH, et al. Liver enzymes and uric acid in acute heart failure. Res Cardiovasc Med. 2015;4(4):e22988. (Prospective observational cohort study; 100 patients)
44. Samsky MD, Dunning A, DeVore AD, et al. Liver function tests in patients with acute heart failure and associated outcomes: insights from ASCEND-HF. Eur J Heart Fail. 2015;18(4):424-432. (Retrospective cohort study)
45. Takaya Y, Yoshihara F, Yokoyama H, et al. Risk stratification of acute kidney injury using the blood urea nitrogen/creatinine ratio in patients with acute decompensated heart failure. Circ J. 2015;79(7):1520-1525. (Prospective observational cohort study; 371 patients)
46. Grodin JL, Simon J, Hachamovitch R, et al. Prognostic role of serum chloride levels in acute decompensated heart failure. J Am Coll Cardiol. 2015;66(6):659-666. (Retrospective cohort study [1318 patients] followed by prospective cohort study [876 patients])
47. * Tallman TA, Peacock WF, Emerman CL, et al. Noninvasive ventilation outcomes in 2,430 acute decompensated heart failure patients: an ADHERE Registry Analysis. Acad Emerg Med. 2008;15(4):355-362. (Retrospective cohort study; 2430 patients)
48. Sharon A, Shpirer I, Kaluski E, et al. High-dose intravenous isosorbide-dinitrate is safer and better than Bi-PAP ventilation combined with conventional treatment for severe pulmonary edema. J Am Coll Cardiol. 2000;36(3):832-837. (Randomized controlled trial; 40 patients)
49. Park M, Sangean MC, Volpe Mde S, et al. Randomized, prospective trial of oxygen, continuous positive airway pressure, and bilevel positive airway pressure by face mask in acute cardiogenic pulmonary edema. Crit Care Med. 2004;32(12):2407-2415. (Randomized controlled trial; 80 patients)
50. Vital Flávia MR, Ladeira Magdaline T, Atallah Álvaro N. Non-invasive positive pressure ventilation (CPAP or bilevel NPPV) for cardiogenic pulmonary oedema. Cochrane Database System Rev. 2013 May 31;(5):CD005351. (Cochrane review)
51. Mariani J, Macchia A, Belziti C, et al. Noninvasive ventilation in acute cardiogenic pulmonary edema: a meta-analysis of randomized controlled trials. J Card Fail. 2011;17(10):850-859. (Meta-analysis; 34 studies, 3041 patients)
52. Cioffi G, Stefenelli C, Tarantini L, et al. Hemodynamic response to intensive unloading therapy (furosemide and nitroprusside) in patients >70 years of age with left ventricular systolic dysfunction and decompensated chronic heart failure. Am J Cardiol. 2003;92(9):1050-1056. (Prospective interventional analysis; 59 patients)
53. O’Connor CM, Starling RC, Hernandez AF, et al. Effect of nesiritide in patients with acute decompensated heart failure. N Engl J Med. 2011;365(1):32-43. (Double-blind randomized controlled trial; 7141 patients)
54. Levy P, Compton S, Welch R, et al. Treatment of severe decompensated heart failure with high-dose intravenous nitroglycerin: a feasibility and outcome analysis. Ann Emerg Med. 2007;50(2):144-152. (Nonrandomized open-label single-arm study; 29 patients)
55. Peacock WF, Chandra A, Char D, et al. Clevidipine in acute heart failure: results of the study of blood pressure control in acute heart failure-a pilot study (PRONTO). Am Heart J. 2014;167(4):529-536. (Randomized open-label active control study of clevidipine vs SOC; 104 patients)
56. Hamilton RJ, Carter WA, Gallagher EJ. Rapid improvement of acute pulmonary edema with sublingual captopril. Acad Emerg Med. 1996;3(3):205-212. (Prospective randomized double-blind placebo-controlled clinical trial; 57 patients)
57. Annane D, Bellissant E, Pussard E, et al. Placebo-controlled, randomized, double-blind study of intravenous enalaprilat efficacy and safety in acute cardiogenic pulmonary edema. Circulation. 1996;94(6):1316-1324. (Placebo-controlled randomized double-blind study; 20 patients)
58. Xiong B, Wang C, Yao Y, et al. The dose-dependent effect of nesiritide on renal function in patients with acute decompensated heart failure: a systematic review and meta-analysis of randomized controlled trials. PLoS One. 2015;10(6):e0131326. (Meta-analysis; 15 randomized controlled trials, 9623 patients)
59. Gong B, Wu Z, Li Z. Efficacy and safety of nesiritide in patients with decompensated heart failure: a meta-analysis of randomised trials. BMJ Open. 2016;6(1):e008545. (Meta-analysis; 22 trials, 38,064 patients)
60. Alexander P, Alkhawam L, Curry J, et al. Lack of evidence for intravenous vasodilators in ED patients with acute heart failure: a systematic review. Am J Emerg Med. 2015;33(2):133-141. (Systematic review)
61. Silvers SM, Howell JM, Kosowsky JM, et al. Clinical policy: critical issues in the evaluation and management of adult patients presenting to the emergency department with acute heart failure syndromes. Ann Emerg Med. 2007;49(5):627-669. (Clinical practice guidelines)
62. Francis GS, Bartos JA, Adatya S. Inotropes. J Am Coll Cardiol. 2014;63(20):2069-2078. (Review article)
63. * Elkayam U, Tasissa G, Binanay C, et al. Use and impact of inotropes and vasodilator therapy in hospitalized patients with severe heart failure. Am Heart J. 2007;153(1):98-104. (Retrospective cohort study; 433 patients)
64. Felker GM, Benza RL, Chandler AB, et al. Heart failure etiology and response to milrinone in decompensated heart failure: results from the OPTIME-CHF study. J Am Coll Cardiol. 2003;41(6):997-1003. (Randomized controlled trial; 949 patients)
65. Goldhaber JI, Hamilton MA. Role of inotropic agents in the treatment of heart failure. Circulation. 2010;121(14):1655-1660. (Review article)
66. 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;62(16):e147-e239. (Clinical practice guidelines)
67. Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med. 1997;336(8):525-533. (Randomized controlled trial; 6800 patients)
68. Rathore SS, Wang Y, Krumholz HM. Sex-based differences in the effect of digoxin for the treatment of heart failure. N Engl J Med. 2002;347(18):1403-1411. (Post hoc subgroup analysis of a randomized controlled trial; 6800 patients)
69. Chen HH, Anstrom KJ, Givertz MM, et al. Low-dose dopamine or low-dose nesiritide in acute heart failure with renal dysfunction: the ROSE acute heart failure randomized trial. JAMA. 2013;310(23):2533-2543. (Randomized controlled trial; 360 patients)
70. Bellomo R, Chapman M, Finfer S, et al. Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Lancet. 2000;356(9248):2139-2143. (Randomized controlled trial; 328 patients)
71. Akhtar N, Mikulic E, Cohn JN, et al. Hemodynamic effect of dobutamine in patients with severe heart failure. Am J Cardiol. 1975;36(2):202-205. (Case reports; 22 patients)
72. O’Connor CM, Gattis WA, Uretsky BF, et al. Continuous intravenous dobutamine is associated with an increased risk of death in patients with advanced heart failure: insights from the Flolan International Randomized Survival Trial (FIRST). Am Heart J. 1999;138(1 Pt 1):78-86. (Randomized controlled trial; 471 patients)
73. Metra M, Nodari S, D’Aloia A, et al. Beta-blocker therapy influences the hemodynamic response to inotropic agents in patients with heart failure: a randomized comparison of dobutamine and enoximone before and after chronic treatment with metoprolol or carvedilol. J Am Coll Cardiol. 2002;40(7):1248-1258. (Cohort study; 29 patients)
74. De Backer D, Biston P, Devriendt J, et al. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med. 2010;362(9):779-789. (Randomized controlled trial; 1679 patients)
75. Cuffe MS, Califf RM, Adams KF Jr, et al. Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial. JAMA. 2002;287(12):1541-1547. (Prospective randomized double-blind placebo-controlled trial; 951 patients)
76. Hunt SA, Baker DW, Chin MH, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol. 2001;38(7):2101-2113. (Guideline)
77. * Abraham WT AK, Fonarow GC, et al. In-hospital mortality in patients with acute decompensated heart failure requiring intravenous vasoactive medications: an analysis from the Acute Decompensated Heart Failure National Registry (ADHERE). J Am Coll Cardiol. 2005;46:57-64. (Retrospective observational study; 65,180 patients)
78. * Felker GM, Lee KL, Bull DA, et al. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med. 2011;364(9):797-805. (Prospective double-blind randomized trial; 308 patients)
79. Salvador DR, Rey NR, Ramos GC, et al. Continuous infusion versus bolus injection of loop diuretics in congestive heart failure. Cochrane Database Syst Rev. 2005; Jul 20;(3):CD003178. (Cochrane review; 8 trials, 254 patients)
80. Yayla C, Akyel A, Canpolat U, et al. Comparison of three diuretic treatment strategies for patients with acute decompensated heart failure. Herz. 2015;40(8):1115-1120. (Randomized controlled trial; 43 patients)
81. Peacock WF 4th, Fonarow GC, Emerman CL, et al. Impact of early initiation of intravenous therapy for acute decompensated heart failure on outcomes in ADHERE. Cardiology. 2007;107(1):44-51. (Retrospective cohort study; 4300 patients)
82. Truby L, Mundy L, Kalesan B, et al. Contemporary outcomes of venoarterial extracorporeal membrane oxygenation for refractory cardiogenic shock at a large tertiary care center. ASAIO J. 2015;61(4):403-409. (Prospective cohort study; 179 patients)
83. Tanaka A, Tuladhar SM, Onsager D, et al. The subclavian intraaortic balloon pump: a compelling bridge device for advanced heart failure. Ann Thorac Surg. 2015;100(6):2151-2158. (Retrospective cohort study; 88 patients)
84. Nieminen MS, Brutsaert D, Dickstein K, et al. EuroHeart Failure Survey II (EHFS II): a survey on hospitalized acute heart failure patients: description of population. Eur Heart J. 2006;27(22):2725-2736. (Retrospective cohort study; 3580 patients)
85. Hochman JS, Sleeper LA, Webb JG, et al. Early revascularization and long-term survival in cardiogenic shock complicating acute myocardial infarction. JAMA. 2006;295(21):2511-2515. (Randomized controlled trial; 302 patients)
86. Flaherty JD, Rossi JS, Fonarow GC, et al. Influence of coronary angiography on the utilization of therapies in patients with acute heart failure syndromes: findings from Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF). Am Heart J. 2009;157(6):1018-1025. (Prospective cohort study; 48,612 patients)
87. Uthamalingam S, Kandala J, Selvaraj V, et al. Outcomes of patients with acute decompensated heart failure managed by cardiologists versus noncardiologists. Am J Cardiol. 2015;115(4):466-471. (Prospective observational cohort study; 496 patients)
88. Packer M, Colucci W, Fisher L, et al. Effect of levosimendan on the short-term clinical course of patients with acutely decompensated heart failure. JACC Heart Fail. 2013;1(2):103-111. (Randomized controlled trial; 700 patients)
89. Mebazaa A, Nieminen MS, Packer M, et al. Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE randomized trial. JAMA. 2007;297(17):1883-1891. (Randomized controlled trial; 1327 patients)
90. Unverzagt S, Wachsmuth L, Hirsch K, et al. Inotropic agents and vasodilator strategies for acute myocardial infarction complicated by cardiogenic shock or low cardiac output syndrome. Cochrane Database Syst Rev. 2014; Jan 2;(1):CD009669. (Cochrane review)
91. Gong B, Li Z, Yat Wong PC. Levosimendan treatment for heart failure: a systematic review and meta-analysis. J Cardiothorac Vasc Anesth. 2015;29(6):1415-1425. (Meta-analysis; 25 randomized controlled studies; 5349 patients)
92. Jia Z, Guo M, Zhang LY, et al. Levosimendan and nesiritide as a combination therapy in patients with acute heart failure. Am J Med Sci. 2015;349(5):398-405. (Randomized controlled trial; 120 patients)
93. Wilson SS, Ayaz SI, Levy PD. Relaxin: a novel agent for the treatment of acute heart failure. Pharmacotherapy. 2015;35(3):315-327. (Review article)
94. Teerlink JR, Cotter G, Davison BA, et al. Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial. Lancet. 2013;381(9860):29-39. (Double-blind placebo-controlled randomized controlled trial; 1161 patients)
95. Felker GM, Teerlink JR, Butler J, et al. Effect of serelaxin on mode of death in acute heart failure: results from the RELAX-AHF study. J Am Coll Cardiol. 2014;64(15):1591-1598. (Randomized controlled trial; 1161 patients)
96. Filippatos G, Teerlink JR, Farmakis D, et al. Serelaxin in acute heart failure patients with preserved left ventricular ejection fraction: results from the RELAX-AHF trial. Eur Heart J. 2014;35(16):1041-1050. (Randomized controlled trial; 1161 patients)
97. Kobayashi D, Yamaguchi N, Takahashi O, et al. Human atrial natriuretic peptide treatment for acute heart failure: a systematic review of efficacy and mortality. Can J Cardiol. 2012;28(1):102-109. (Meta-analysis; 4 studies, 220 patients)
98. Anker SD, Ponikowski P, Mitrovic V, et al. Ularitide for the treatment of acute decompensated heart failure: from preclinical to clinical studies. Eur Heart J. 2015;36(12):715-723. (Review)
99. Mitrovic V, Seferovic PM, Simeunovic D, et al. Haemodynamic and clinical effects of ularitide in decompensated heart failure. Eur Heart J. 2006;27(23):2823-2832. (Randomized controlled trial; 221 patients)
100. Emani S, Meyer M, Palm D, et al. Ularitide: a natriuretic peptide candidate for the treatment of acutely decompensated heart failure. Future Cardiol. 2015;11(5):531-546. (Review article)
101. Lee CY, Chen HH, Lisy O, et al. Pharmacodynamics of a novel designer natriuretic peptide, CD-NP, in a first-in-human clinical trial in healthy subjects. J Clin Pharmacol. 2009;49(6):668-673. (Preclinical trial)
102. Cleland JG, Teerlink JR, Senior R, et al. The effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: a double-blind, placebo-controlled, crossover, dose-ranging phase 2 trial. Lancet. 2011;378(9792):676-683. (Double-blind placebo-controlled crossover, dose-ranging, phase 2 trial; 45 patients)
103. Wen H, Zhang Y, Zhu J, et al. Ultrafiltration versus intravenous diuretic therapy to treat acute heart failure: a systematic review. Am J Cardiovasc Drugs. 2013;13(5):365-373. (Meta-analysis; 5 trials, 477 patients)
104. Costanzo MR, Guglin ME, Saltzberg MT, et al. Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure. J Am Coll Cardiol. 2007;49(6):675-683. (Randomized controlled trial; 200 patients)
105. Ebrahim B, Sindhura K, Okoroh J, et al. Meta-analysis of ultrafiltration versus diuretics treatment option for overload volume reduction in patients with acute decompensated heart failure. Arq Bras Cardiol. 2015;104(5):417-425. (Meta-analysis; 9 studies, 613 patients)
106. Teo LY, Lim CP, Neo CL, et al. Ultrafiltration in patients with decompensated heart failure and diuretic resistance: an Asian centre experience. Singapore Med J. 2016. (Retrospective cohort study; 44 patients)
107. Neves FM, Meneses GC, Sousa NE, et al. Syndecan-1 in acute decompensated heart failure--association with renal function and mortality. Circ J. 2015;79(7):1511-1519. (Prospective cohort study; 201 patients)
108. Mueller C, Scholer A, Laule-Kilian K, et al. Use of B-type natriuretic peptide in the evaluation and management of acute dyspnea. N Engl J Med. 2004;350(7):647-654. (Prospective, randomized controlled study; 452 patients)