ReviewMorphine in the treatment of acute pulmonary oedema — Why?
Introduction
Acute pulmonary oedema is a common condition in the emergency room, associated with considerable mortality [1], [2]. The oedema develops when the left ventricle fails, making the hydrostatic pressure in the pulmonary circulation increase, and therefore fluid builds up in the pulmonary insterstitium and alveoli. The condition is defined by severe respiratory distress that worsens in supine position, crackles over the lung and signs of pulmonary congestion on chest X-ray [3]. Peripheral oxygen saturation is usually below 90% prior to treatment.
Pharmacological treatment of pulmonary oedema aims at treating the increased hydrostatic pressure in the pulmonary circulation, primarily by lowering filling pressure (preload), and by lowering the peripheral arterial pressure (afterload) — achieved through venous and arterial dilation [4]. Traditionally there has also been emphasis on removing excess fluid through increased diuresis [5].
Since the 1960s, three drugs have been most frequently used to achieve these effects, alongside oxygen treatment. It is furosemide, which inhibits reabsorption of sodium in Henle's loop and distal tubuli and thereby increasing excretion of fluids through the kidney. Then there is nitroglycerin, which via cGMP and smooth muscle relaxation induces vasodilatation — at low doses only venous, at high doses also causing arterial relaxation [6], [7].
The third drug, morphine, has been used due to its anticipated anxiolytic and vasodilatory properties. During the last decade, a discussion about the benefits and especially the risks accompanying the use of morphine in cases of pulmonary oedema has been raised [1], [4], [8], [9], [10], [11]. In a retrospective study from 2008 based on the ADHERE registry, morphine given in acute decompensated heart failure was an independent predictor of increased hospital mortality, with an odds ratio of 4.8 (95% CI: 4.52–5.18, p < 0.001) [2].
A literature search in Medline using the keywords “pulmonary oedema” OR “lung oedema” OR “acute heart failure” AND “morphine” was performed. The search was conducted in February 2014 and gave 263 results. A similar search was performed in Embase, where Medline articles were excluded and the search was limited to articles written in English (191 results). We were particularly interested in studies that documented the outcome after using morphine in the treatment of acute pulmonary oedema as well as studies and review articles in which the physiological effects of the drug were discussed. A total of 24 articles were discretionarily picked out after reviewing abstracts [2], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26].
Section snippets
Guidelines
The European heart failure guideline from 2012 state that one can consider giving 4–8 mg of morphine intravenously (repeated as needed) if the patient suffers from severe anxiety or distress caused by pulmonary oedema (Fig. 1) [27]. The American Heart Failure Society does not include morphine in its recommendations from 2010 and comments that the drug should be used with caution if administered [28]. The collaboration American College of Cardiology Foundation/American Heart Association does not
Physiological effects of morphine
Morphine induces depression of the central nervous system via opiate receptors in the brain, which causes both sedation and analgesia [12]. In addition to this, morphine has a supposed anxiolytic effect, which together with the sedative effect reduces the activity of the sympathetic nervous system and causes a reduction of both the filling pressure and the arterial pressure [4].
It is believed that morphine has a vasodilating effect in pulmonary oedema [3], [13], [28]. The background of this
Adverse physiological effects
The most common adverse effects of morphine are constipation and nausea. While constipation has no significance in acute medical context, it is described that between one-fifth and one-third of patients experience nausea when using opioids [35], [36]. Vomiting occurs about half as frequently as nausea. European guidelines recommend the addition of 10 mg of metoclopramide to counteract nausea if morphine is administered [27]. Nausea in pulmonary oedema is a disadvantageous side effect because of
Heterogeneous prognoses
In a review article from 2008 Sosnowski [11] emphasises that there seems to be a correlation between the use of morphine and worsening of the patient's condition, based on five studies from 1987 to 2003 [10], [21], [22], [23], [24]. One of these is a small trial of prehospital treatment of pulmonary oedema. It showed that 38% of patients treated with morphine and furosemide, experienced subjective deterioration compared with none of the patients who received nitroglycerin and furosemide [10].
Conclusion
Morphine is still used for pulmonary oedema in spite of relatively poor scientific background data. A randomised, controlled study is necessary in order to determine the effect – and especially the risk – when using morphine for pulmonary oedema. Since the positive effects are not sufficiently documented, and since the risk for increased mortality cannot be ruled out, one can advocate that the use should be avoided.
Conflict of interest
C. Ellingsrud: No conflict of interest. S. Agewall: Speaker fees, Honoraria, Consultancy, Advisory Board fees from AstraZeneca, ThermoFischer, Boehringer Ingelheim.
References (42)
- et al.
Modern management of cardiogenic pulmonary edema
Emerg. Med. Clin. North Am.
(2005) - et al.
Randomised trial of high-dose isosorbide dinitrate plus low-dose furosemide versus high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary oedema
Lancet
(1998) - et al.
Comparison of nitroglycerin, morphine and furosemide in treatment of presumed pre-hospital pulmonary edema
Chest
(1987) Initial treatment of pulmonary edema: a physiological approach
Am. J. Med. Sci.
(1991)- et al.
Mechanisms of action of morphine in the treatment of experimental pulmonary edema
Am. J. Cardiol.
(1966) - et al.
Nitrate therapy is an alternative to furosemide/morphine therapy in the management of acute cardiogenic pulmonary edema
J. Card. Fail.
(1998) - et al.
Effect of ED management on ICU use in acute pulmonary edema
Am. J. Emerg. Med.
(1999) - et al.
Comparative effects of morphine, meperidine and pentazocine on cardiocirculatory dynamics in patients with acute myocardial infarction
Am. J. Med.
(1976) - et al.
Opioid induced nausea and vomiting
Eur. J. Pharmacol.
(2014) Opioids and the control of respiration
Br. J. Anaesth.
(2008)
Present state of extradural and intrathecal opioid analgesia in Sweden. A nationwide follow-up survey
Br. J. Anaesth.
The use of benzodiazepines in the treatment of chest pain: a review of the literature
J. Emerg. Med.
Diuretic, opiate and nitrate use in severe acidotic acute cardiogenic pulmonary oedema: analysis from the 3CPO trial
QJM
Morphine and outcomes in acute decompensated heart failure: an ADHERE analysis
Emerg. Med. J.
Executive summary of the guidelines on the diagnosis and treatment of acute heart failure: the Task Force on Acute Heart Failure of the European Society of Cardiology
Eur. Heart J.
CHF treatment: is furosemide on the way out? Rethinking the pulmonary edema cocktail
EMS World
Pharmacotherapy for acute heart failure syndromes
Am. J. Health Syst. Pharm.
Is morphine indicated in acute pulmonary oedema?
Emerg. Med. J.
Opiates should be avoided in acute decompensated heart failure
Emerg. Med. J.
Review article: lack of effect of opiates in the treatment of acute cardiogenic pulmonary oedema
Emerg. Med. Australas.
Acute pulmonary edema
Curr. Treat. Options Cardiovasc. Med.
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