Signal of harm in morphine use in adults with acute pulmonary oedema: A rapid systematic review

Authors

  • C Hendrikse Division of Emergency Medicine, Department of Family, Community and Emergency Care, Faculty of Health Sciences, University of Cape Town, South Africa; Ministerially appointed PHC/Adult Hospital Level Expert Review Committee of the National Essential Medicines List Committee, National Department of Health (2019 - 2023), Pretoria, South Africa
  • V Ngah Centre for Evidence-based Health Care, Division of Epidemiology and Biostatistics, Department of Global Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
  • I I Kallon Centre for Evidence-based Health Care, Division of Epidemiology and Biostatistics, Department of Global Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
  • G Thom Ministerially appointed PHC/Adult Hospital Level Expert Review Committee of the National Essential Medicines List Committee, National Department of Health (2019 - 2023), Pretoria, South Africa; Amajuba District Clinical Specialist Team, KwaZulu-Natal Department of Health, Pretoria, South Africa
  • T D Leong Secretariat to the PHC/Adult Hospital Level Expert Review Committee (2020 - 2023); Secretariat to the National Essential Medicines List Committee, National Department of Health (2021 - 2022), Durban, South Africa; Cochrane South Africa, South African Medical Research Council, Cape Town, South Africa
  • K Cohen Ministerially appointed PHC/Adult Hospital Level Expert Review Committee of the National Essential Medicines List Committee, National Department of Health (2019 - 2023), Pretoria, South Africa; Division of Clinical Pharmacology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa
  • M McCaul Ministerially appointed PHC/Adult Hospital Level Expert Review Committee of the National Essential Medicines List Committee, National Department of Health (2019 - 2023), Pretoria, South Africa; Centre for Evidence-based Health Care, Division of Epidemiology and Biostatistics, Department of Global Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa; South African GRADE Network, Centre for Evidence-based Health Care, Department of Global Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa

DOI:

https://doi.org/10.7196/SAMJ.2023.v113i8.348

Keywords:

Essential Medicines, Review, cardiopulmonary disease

Abstract

Background. Heart failure affects nearly 65 million people globally, resulting in recurrent hospital admissions and substantial healthcare expenditure. The use of morphine in the management of acute pulmonary oedema remains controversial, with conflicting guidance and significant variation in practice. Synthesised evidence is needed to inform standard treatment guidelines and clinical practice.

Objective. To determine whether morphine should be used in the treatment of acute pulmonary oedema (APE) in adults.

Methods. A rapid review of systematic reviews of randomised controlled trials or observational studies, and then randomised controlled trials, was conducted searching three electronic databases (PubMed, Embase, Cochrane Library) and one clinical trial registry on 12 February 2022. We used a prespecified protocol following Cochrane rapid review methods and aligned to the National Standard Treatment Guidelines and Essential Medicines List methodology. We first considered relevant high-quality systematic reviews of randomised controlled trials or observational studies, then (if required) randomised controlled trials to inform time-sensitive or urgent evidence requests, clinical practice, policy, or standard treatment guidelines.

Results. We identified four systematic reviews of observational studies. The two most relevant, up-to-date, and highest-quality reviews were used to inform evidence for critical outcomes. Morphine may increase in-hospital mortality (odds ratio (OR) 1.78; 95% confidence interval (CI) 1.01 - 3.13; low certainty of evidence; six observational studies, n=151 735 participants), resulting in 15 more per 1 000 hospital deaths, ranging from 0 to 40 more hospital deaths. Morphine may result in a large increase in invasive mechanical ventilation (OR 2.72; 95% CI 1.09 - 6.80; low certainty of evidence; four observational studies, n=167 847 participants), resulting in 45 more per 1 000 ventilations, ranging from 2 more to 136 more. Adverse events and hospital length of stay were not measured across reviews or trials.

Conclusion. Based on the most recent, relevant and best-available quality evidence, morphine use in adults with APE may increase in-hospital and all-cause mortality and may result in a large increase in the need for invasive mechanical ventilation compared to not using morphine. Recommending against the use of morphine in pulmonary oedema may improve patient outcomes. Disinvesting in morphine for this indication may result in cost savings, noting the possible accrued benefits of fewer patients requiring invasive ventilation and management of morphine-related side-effects.

References

Groenewegen A, Rutten FH, Mosterd A, Hoes AW. Epidemiology of heart failure. Eur J Heart Fail

;22(8):1342-1356. https://doi.org/10.1002/ejhf.1858

Gil V, Domínguez-Rodríguez A, Masip J, Peacock WF, Miró Ò. Morphine use in the treatment of acute

cardiogenic pulmonary edema and its effects on patient outcome: A systematic review. Curr Heart Fail

Rep 2019;16(4):81-88. https://doi.org/10.1007/s11897-019-00427-0

Bleumink G, Knetsch A, Sturkenboom M, et al. Quantifying the heart failure epidemic: Prevalence,

incidence rate, lifetime risk and prognosis of heart failure. The Rotterdam Study. Eur Heart J

;25(18):1614-1619. https://doi.org/10.1016/j.ehj.2004.06.038

Mosterd A, Hoes AW. Clinical epidemiology of heart failure. Heart 2007;93(9):1137-1146. https://doi.

org/10.1136/hrt.2003.025270

Kraus S, Ogunbanjo G, Sliwa K, Ntusi NAB. Heart failure in sub-Saharan Africa: A clinical approach.

S Afr Med J 2015;106(1):23. https://doi.org/10.7196/samj.2016.v106i1.10325

McMurray JJV, Adamopoulos S, Anker SD, et al. ESC Guidelines for the diagnosis and treatment of

acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and

Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with

the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012;33(14):1787-1847. superscript 2

Gao D, David C, Rosa MM, Costa J, Pinto FJ, Caldeira D. The risk of mortality associated with opioid

use in patients with acute heart failure: Systematic review and meta-analysis. J Cardiovasc Pharmacol

;77(2):123-129. https://doi.org/10.1097/fjc.0000000000000954

Adams KF, 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

,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE). Am Heart J

;149(2):209-216. https://doi.org/10.1016/j.ahj.2004.08.005

Masip J, Peacock WF, Price S, et al. Indications and practical approach to non-invasive ventilation in

acute heart failure. Eur Heart J 2018;39(1):17-25. https://doi.org/10.1093/eurheartj/ehx580

Sosnowski MA. Lack of effect of opiates in the treatment of acute cardiogenic pulmonary oedema.

Emerg Med Australasia 2008;20(5):384-390. https://doi.org/10.1111/j.1742-6723.2008.01113.x

Allison RC. Initial treatment of pulmonary edema: A physiological approach. Am J Med Sci

;302(6):385-391. https://doi.org/10.1097/00000441-199112000-00013

Agewall S. Morphine in acute heart failure. J Thorac Dis 2017;9(7):1851-1854. https://doi.org/10.21037/

jtd.2017.06.129

Vatner SF, Marsh JD, Swain JA. Effects of morphine on coronary and left ventricular dynamics in

conscious dogs. J Clin Invest 1975;55(2):207-217. https://doi.org/10.1172/JCI107923

Lin Y, Chen Y, Yuan J, et al. Intravenous morphine use in acute heart failure increases adverse outcomes:

A meta-analysis. Rev Cardiovasc Med 2021;22(3):865. https://doi.org/10.31083/j.rcm2203092

Peacock WF, Hollander JE, Diercks DB, Lopatin M, Fonarow G, Emerman CL. Morphine and

outcomes in acute decompensated heart failure: An ADHERE analysis. Emerg Med J 2008;25(4):205-

https://doi.org/10.1136/emj.2007.050419

Yancy CW, Jessup M, Bozkurt B, et al. 2016 ACC/AHA/HFSA focused update on new pharmacological

therapy for heart failure: An update of the 2013 ACCF/AHA Guideline for the Management of Heart

Failure: A report of the American College of Cardiology/American Heart Association Task Force

on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation 2016;134(13).

https://doi.org/10.1161/cir.0000000000000435

Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of

acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic

heart failure of the European Society of Cardiology (ESC). Developed with the special contribution

of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016;37(27):2129-2200. https://doi.

org/10.1093/eurheartj/ehw128

Hitzeroth J, Mpe M, Klug E, et al. 2020 Heart Failure Society of South Africa perspective on the 2016

European Society of Cardiology Chronic Heart Failure Guidelines. S Afr Med J 2020;110(9b):935-951.

https://doi.org/10.7196/SAMJ.2020.v110i8.14681

Purvey M, Allen G. Managing acute pulmonary oedema. Aust Prescr 2017;40(2):59-63. https://doi.

org/10.18773/austprescr.2017.012

National Department of Health, South Africa. Hospital Level (Adults) Standard Treatment Guidelines

and Essential Medicines List. 2nd ed. https://knowledgehub.health.gov.za/elibrary/hospital-leveladults-standard-treatment-guidelines-and-essential-medicines-list-2nd (accessed 20 June 2023).

Gray A, Suleman F, Pharasi B. South Africa’s national drug policy: 20 years and still going? S Afr Health

Rev 2017;2017(1):49-58. https://doi.org/10.10520/EJC-c80c69129

National Department of Health, South Africa. National Drug Policy for South Africa Pretoria: NDoH,

https://www.gov.za/documents/national-drugs-policy (accessed 22 June 2023).

World Health Organization. Essential medicines, health product policy and standards, medicines

selection, IP and affordability. WHO model list of essential medicines, Geneva: WHO, 2019. https://

www.who.int/publications-detail-redirect/WHOMVPEMPIAU2019.06 (accessed 22 June 2023).

Leong TD, McGee SM, Gray AL, et al. Essential medicine selection during the COVID-19 pandemic:

Enabling access in uncharted territory. S Afr Med J 2020;110(11):1077. https://doi.org/10.7196/

samj.2020.v110i11.15271

South Africa GRADE Network. The Centre for Evidence-based Health Care (CEBHC). https://www.

cebhc.co.za/research-what-we-do/south-africa-grade-network/ (accessed 20 June 2023).

Garritty C, Gartlehner G, Nussbaumer-Streit B, et al. Cochrane Rapid Reviews Methods Group offers

evidence-informed guidance to conduct rapid reviews. J Clin Epidemiol 2021;130:13-22. https://doi.

org/10.1016/j.jclinepi.2020.10.007

Cochrane. Collaborating in response to COVID-19: Editorial and methods initiatives across Cochrane.

Cochrane Database Syst Rev 2020;12(Suppl 1):CD202002. https://doi.org/10.1002/14651858.CD202002

Tricco AC, Garritty CM, Boulos L, et al. Rapid review methods more challenging during COVID-19:

Commentary with a focus on 8 knowledge synthesis steps. J Clin Epidemiol 2020;126:177-183. https://

doi.org/10.1016/j.jclinepi.2020.06.029

Akl EA, Morgan RL, Rooney AA, et al. Developing trustworthy recommendations as part of an

urgent response (1 - 2 weeks): A GRADE concept paper. J Clin Epidemiol 2021;129:1-11. https://doi.

org/10.1016/j.jclinepi.2020.09.037

McCaul M, Tovey D, Young T, et al. Resources supporting trustworthy, rapid and equitable evidence

synthesis and guideline development: Results from the COVID-19 evidence network to support

decision-making (COVID-END). J Clin Epidemiol 2022;151:88-95. https://doi.org/10.1016/j.

jclinepi.2022.07.008

Sterne JA, Hernán MA, Reeves BC, et al. ROBINS-I: A tool for assessing risk of bias in non-randomised

studies of interventions. BMJ 2016;355:i4919. https://doi.org/10.1136/bmj.i4919

Sterne JAC, Savović J, Page MJ, et al. RoB 2: A revised tool for assessing risk of bias in randomised trials.

BMJ 2019:l4898. https://doi.org/10.1136/bmj.l4898

Guyatt GH, Oxman AD, Vist GE, et al. GRADE: An emerging consensus on rating quality of

evidence and strength of recommendations. BMJ 2008;336(7650):924-926. https://doi.org/10.1136/

bmj.39489.470347.AD

Zhang D, Lai W, Liu X, Shen Y, Hong K. The safety of morphine in patients with acute heart failure:

A systematic review and meta-analysis. Clin Cardiol 2021;44(9):1216-1224. https://doi.org/10.1002/

clc.23691

Caspi O, Naami R, Halfin E, Aronson D. Adverse dose-dependent effects of morphine therapy in acute

heart failure. Int J Cardiol 2019;293:131-136. https://doi.org/10.1016/j.ijcard.2019.06.015

Dominguez-Rodriguez A, Avanzas P, Burillo-Putze G, Abreu-Gonzalez P. Influence of morphine

treatment on in-hospital mortality among patients with acute heart failure. Med Intensiva

;41(6):382-384. https://doi.org/10.1016/j.medin.2016.05.007

Gray A, Goodacre S, Seah M, Tilley S. Diuretic, opiate and nitrate use in severe acidotic acute

cardiogenic pulmonary oedema: Analysis from the 3CPO trial. QJM 2010;103(8):573-581. https://doi.

org/10.1093/qjmed/hcq077

Iakobishvili Z, Cohen E, Garty M, et al. Use of intravenous morphine for acute decompensated heart

failure in patients with and without acute coronary syndromes. Acute Card Care 2011;13(2):76-80.

https://doi.org/10.3109/17482941.2011.575165

Miró Ò, Gil V, Martín-Sánchez FJ, et al. Morphine use in the ED and outcomes of patients with

acute heart failure: A propensity score-matching analysis based on the EAHFE registry. Chest

;152(4):821-832. https://doi.org/10.1016/j.chest.2017.03.037

Sacchetti A, Ramoska E, Moakes ME, McDermott P, Moyer V. Effect of ED management on ICU use

in acute pulmonary edema. Am J Emerg Med 1999;17(6):571-574. https://doi.org/10.1016/s0735-

(99)90198-5

Gray A, Goodacre S, Newby DE, Masson M, Sampson F, Nicholl J. Noninvasive ventilation in acute

cardiogenic pulmonary edema. New Engl J Med 200810;359(2):142-151. https://doi.org/10.1056/

nejmoa0707992

Senoglu N, Oksuz H, Dogan Z, Yildiz H, Demirkiran H, Ekerbicer H. Sedation during noninvasive

mechanical ventilation with dexmedetomidine or midazolam: A randomized, double-blind, prospective

study. Curr Ther Res Clin Exp 2010;71(3):141-153. https://doi.org/10.1016/j.curtheres.2010.06.003

Longrois D, Conti G, Mantz J, Faltlhauser A, Aantaa R, Tonner P. Sedation in non-invasive

ventilation: Do we know what to do (and why)? Multidiscip Respir Med 2014;9(1):56. https://doi.

org/10.1186/2049-6958-9-56

Domínguez-Rodríguez A, Suero-Mendez C, Burillo-Putze G, et al. Midazolam versus morphine in

acute cardiogenic pulmonary oedema: Results of a multicentre, open-label, randomized controlled

trial. Eur J Heart Failure 2022;24(10):1953-1962. https://doi.org/10.1002/ejhf.2602

Krantz MJ, Palmer RB, Haigney MCP. Cardiovascular complications of opioid use. J Am Coll Cardiol

;77(2):205-223. https://doi.org/10.1016/j.jacc.2020.11.002

Behzadi M, Joukar S, Beik A. Opioids and cardiac arrhythmia: A literature review. Med Princ Pract

;27(5):401-414. https://doi.org/10.1159/000492616

Molina PE. Opioids and opiates: Analgesia with cardiovascular, haemodynamic and immune

implications in critical illness. J Int Med 2006;259(2):138-154. https://doi.org/10.1111/j.1365-

2005.01569.x

Duarte GS, Nunes-Ferreira A, Rodrigues FB, et al. Morphine in acute coronary syndrome:

Systematic review and meta-analysis. BMJ Open 2019;9(3):e025232. https://doi.org/10.1136/

bmjopen-2018-025232

Downloads

Published

2023-08-03

Issue

Section

Research

How to Cite

1.
Hendrikse C, Ngah V, Kallon II, Thom G, Leong TD, Cohen K, et al. Signal of harm in morphine use in adults with acute pulmonary oedema: A rapid systematic review. S Afr Med J [Internet]. 2023 Aug. 3 [cited 2024 May 19];113(8):39-43. Available from: https://samajournals.co.za/index.php/samj/article/view/348

Similar Articles

1-10 of 151

You may also start an advanced similarity search for this article.