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Three Part Question

In [patients with Acute Cardiogenic Pulmonary Oedema], does [the application of opiates] result in [ an improvement in the mortality and morbidity]?

Clinical Scenario

A 65 year old male patient is brought in to your department. He is severely short of breath, sweaty and has sats of 91% on a non rebreather. He is an ex smoker and known to have IHD and suffers from LVF. The standard teaching is that Diamorphine (morphine) should be given to these patients as it is an effective treatment for the condition. You wander if that is true and if there is any evidence for this statement.

Search Strategy

Using Ovid interface- ALL EBM Reviews- Cochrane DSR, ACP Journal Club, DARE, and CCTR
Ovid MEDLINE(R) 1966 to June Week 1 2005
Other sources: GOOGLE and Emergency Medical Abstracts database from the Centre for Medical Education inc.(http://ccme.org).
EMBASE 1980 to 2005 Week 24
Ovid OLDMEDLINE(R) 1950 to 1965
The following phrases were used in the search of opioid use:
opiates.ab,kw,kf,hw,sh,xs,ti.
heroin.ab,kw,kf,hw,sh,xs,ti.
narcotics.ab,kw,kf,hw,sh,xs,ti.
diamorphine.ab,kw,kf,hw,sh,xs,ti.
morphine.ab,kw,kf,hw,sh,xs,ti.
The results were combined using an "OR" command.
The following phrases were used in the search of acute pulmonary oedema: pulmonary oedema.ab,kw,kf,hw,sh,xs,ti.
pulmonary edema.ab,kw,kf,hw,sh,xs,ti.
cardiac failure.ab,kw,kf,hw,sh,xs,ti.
heart failure.ab,kw,kf,hw,sh,xs,ti.
ventricular failure.ab,kw,kf,hw,sh,xs,ti.
Once again the results were combined using an "OR" command.
Both the searches were then combined using the "AND" command and duplicates were removed.
Internet searches were added at the end.

Search Outcome

This MEDLINE search resulted in 1089 publications. A thorough review of all the titles narrowed the search to only 54 publications which potentially might have been important in influencing clinical practice, but only 7 papers, 6 in English and one in Polish, were found which directly investigated or reported the clinically important outcomes of treatment of acute pulmonary oedema. Only 5 of these dealt specifically with the effects of administration of opiates, in Acute Cardiogenic Pulmonary Oedema.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Hoel BL. Bay G. Refsum HE. 1971 Sweden	8 patients with clinical signs of heart failure	Effects on physiology of IM Morphine	Varied	The only significant change in patients' physiology was a decrease in arterial PO2. Some trends in decreased systemic blood pressure, heart rate and pulmonary artery pressures were noted but were neither statistically, nor clinically significant.	Small study, no control, disease orientated evidence
Grendahl H. Andersen A. Muller C. 1973 Sweden	13 patients with congestive cardiac failure and mitral valvular disease	physiological changes following morphpine administration		the only statistically significant change was a drop in both blood pressure and O2 saturations.	Small study, selected patient group, no control, disease orientated
Vismara LA. Leaman DM. Zelis R. 1976 USA	The effects of 0.1mg/kg of IV morphine on the peripheral venous pooling in 13 patients with mild pulmonary oedema.	Physiological effects of opiates		Although a statistically significant degree of venous dilatation occurred, it only reduced the circulating blood volume by about 115 ml, i.e. clinically insignificant.	No control, disease orientated evidence only, small study
Timmis AD. Rothman MT. Henderson MA. Geal PW. Chamberlain DA. 1980 UK	The haemodynamic effects of morphine on patients with APO due to an acute myocardial infarction.	They gave their patients large doses of morphine intravenously, 0.2mg/kg (mean of 15 mg)	Heart rate and mean blood pressure were reduced and they also noted a slight drop in pulmonary end-diastolic pressure, cardiac index and systemic vascular resistance.	a reduction of dyspnoea and increased drowsiness in all the patients	Small Study, no control, disease orientated evidence only
Hoffman et al, 1987 USA	Pre hospital patients with signs of acute pulmonary oedema	Prospective, Sequentially randomised	Immediate changes in physiological values and/or requirement for large fluid volume replacement in 24 hours	Patients receiving morphine had a significantly worsening outcome. Opposite true for GTN	Poorly randomised, Small groups, Non blinded, Groups not evenly matched, 23% of patients did not have APO
Beltrame et al 1998 Australia	69 consecutive patients presenting to the department with APO Interim analysis of 24h	Randomised controlled trial	Clinical score, gas exchange, need for resp. assistance	IV GTN group non different to IV morphine & furosemide	? method of randomisation, Non blinded, Underpowered, Suboptimal drug doses- esp. GTN
Sacchetti et al 1999 USA	181 patients with APO and clinical evidence of respiratory distress/failure. Review of the effectiveness of different pharmacological treatments in ED	Chart review	ICU admission and length of stay, rate of intubation	Patients receiving morphine 3x more likely to need ICU & 5x more likely to need intubation	Retrospective, Poorly defined, Heterogeneous group
Fiutowski et al 2003 Poland	276 patients with APO.	Chart review	Mortality	Patients who received morphine had a higher mortality	Retrospective, heterogeneous group, no causality can be established

Comment(s)

There is no good evidence supporting the use of opiates in the treatment of acute cardiogenic pulmonary oedema. It seems to be based mainly on tradition and anecdotal evidence, while their effectiveness is far from proven. The initial, physiological studies failed to show a mechanism which would reliably explain any benefit from administering them. The more recent, more clinically orientated studies, suggest a strong association between opiate administration and a worsening outcome. However, the causality is difficult to prove due to the poor research methodology. Its use as an effective treatment of acute cardiogenic pulmonary oedma is questionable and ought to be more thoroughly investigated by a prospective, properly randomised, double blind, study before its effectiveness can be established.

Clinical Bottom Line

It is difficult to justify the recommendation of opiates as a "first line" or "essential" part of the treatment of Acute Pulmonary Oedema. The author suggests concentrating on other forms of therapy currently available which are more likely to be beneficial to the patient.

References

1. Hoel BL. Bay G. Refsum HE. The effects of morphine on the arterial and mixed venous blood gas state and on the hemodynamics in patients with clinical pulmonary congestion. Acta Medica Scandinavica
2. Grendahl H. Andersen A. Muller C. The effect of intravenous morphine in patients with mitral valvular disease and congestive heart failure. Acta Medica Scandinavica 1-2(1):69-74, 1973 Jul-Aug
3. Vismara LA. Leaman DM. Zelis R. The effects of morphine on venous tone in patients with acute pulmonary edema. Circulation. 54(2):335-7, 1976 Aug
4. Timmis AD. Rothman MT. Henderson MA. Geal PW. Chamberlain DA. Haemodynamic effects of intravenous morphine in patients with acute myocardial infarction complicated by severe left ventricular failure. British Medical Journal. 280(6219):980-2, 1980 Apr 5.
5. Hoffman JR. Reynolds S. Comparison of nitroglycerin, morphine and furosemide in treatment of presumed pre-hospital pulmonary edema. Chest. 92(4):586-93, 1987 Oct.
6. Beltrame JF. Zeitz CJ. Unger SA. Brennan RJ. Hunt A. Moran JL. Horowitz JD. Nitrate therapy is an alternative to furosemide/morphine therapy in the management of acute cardiogenic pulmonary edema. Journal of Cardiac Failure. 4(4):271-9, 1998 Dec
7. Sacchetti A. Ramoska E. Moakes ME. McDermott P. Moyer V. Effect of ED management on ICU use in acute pulmonary edema. American Journal of Emergency Medicine. 17(6):571-4, 1999 Oct.
8. Fiutowski M. Waszyrowski T. Krzeminska-Pakula M. Kasprzak JD. Wp³yw leczenia farmakologicznego na rokowanie krótkoterminowe i d³ugoterminowe u pacjentów po incydencie kardiogennego obrzêku p³uc Polski Przeglad Kardiologiczny. Polski Przeglad Kardiologiczny. Vol. 5(4)(pp 409-414), 2003.