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Three Part Question

In [patients with acute pulmonary oedema] does [high dose versus standard dose nitrate (e.g. glyceryl trinitrate)] [decrease the need for intubation or length of hospital stay]?

Clinical Scenario

A 75-year-old man presents to the emergency department at 06:00 hours sweaty, acutely short of breath and coughing pink frothy sputum. You diagnose acute left ventricular failure/acute pulmonary oedema. You know intravenous nitrates are part of first line therapy but wonder whether a high dose will provide increased benefit.

Search Strategy

OvidSP MEDLINE 1950 to January Week 2 2009.
The Cochrane Library Issue 1 2009
Medline:[exp Pulmonary Edema/OR pulmonary oedema.mp. OR exp Heart Failure/OR left ventricular dysfunction.mp.] AND [exp isosorbide dinitrate/or exp nitrates/OR exp Nitroglycerin/or GTN.mp.] AND [exp Infusions, Intravenous/OR exp Injections, Intravenous/] Limit to English language, Humans and abstracts.

Cochrane: [(pulmonary oedema): ti,ab,kw OR MeSH descriptor Pulmonary Edema explode all trees] AND [MeSH descriptor Nitrates explode all trees OR MeSH descriptor Isosorbide Dinitrate explode all trees OR MeSH descriptor Nitroglycerin explode all trees].

Search Outcome

A total of 57 papers was found, of which 54 were either irrelevant or of insufficient quality for inclusion. The remaining three papers are shown in the table

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Sharon A et al. 2000 Israel	40 consecutive patients with severe pulmonary oedema (oxygen saturation, 90% on room air prior to treatment). All patients received oxygen at a rate of 10 litres/min, intravenous (IV) furosemide 80 mg and IV morphine 3 mg. Repeated boluses of IV ISDN 4 mg every 4 min (n = 20) vs BiPAP ventilation and standard dose nitrate therapy (n = 20). All treatment was delivered by mobile intensive care units before hospital arrival.	RCT	Death	2 deaths in BIPAP group v 0 in the ISDN group	Pre-hospital trial Small numbers
			Intubation	16 in BIPAP group v 4 in ISDN
			AMI	11 in BIPAP v 2 in ISDN
			Combined (death/AMI/IMMV)	17 in BIPAP v 5 in ISDN
			Recovery rate (measured by respiratory rate, oxygen saturation and pulse)	Quicker improvement seen at 1 hour in high dose ISDN group
Cotter et al. 1998 Israel	110 adult patients presenting to mobile emergency units with signs of congestive heart failure were treated with oxygen 10 L/min, intravenous furosemide 40 mg, and morphine 3 mg bolus. ISDN (3 mg bolus administered IV every 5 min (n = 56) vs furosemide (80 mg bolus administered IV every 15 min) as ISDN 1 mg/h, increased every 10 min by 1 mg/h (n = 54).	RCT	Need for mechanical ventilation	9 in high-dose ISDN vs 21 in furosemide group p = 0.004	Pre-hospital study.
			AMI	9 in high-dose ISDN vs 19 in furosemide p = 0.047
Levy et al, 2007, USA	29 Patients in a convenience sample. All patients had failed conventional treatment of high–low oxygen, IV furosemide and sublingual or oral spray bitrates. All had a systolic BP >160 or a MAP >120. GTN infusion titrated on all patients. 2 mg boluses GTN given every 3 min up to 10 doses. Outcomes compared with a retrospectively identified cohort.	Before and after study	Intubation within 6 h	13.8% vs 29.5%	Small study with a retrospective comparator
			BiPAP	6.9% vs 20%
			ICU admission rate	37.9% vs 80%
			LoS	4.1 days vs 6.2 days
			Cardiovascular complications	20.7% vs 28.9%

Comment(s)

There is no well designed study that answers this question directly. Overall, the best evidence available suggests that high-dose nitrates (bolus or infusion) plus low-dose furosemide are effective in acute cardiogenic pulmonary oedema.

Editor Comment

AMI, acute myocardial infarction; BiPAP, bi-level positive airway pressure; BP, blood pressure; GTN, glyceryl trinitrate; ICU, intensive care unit; IPPV, intermittent positive pressure ventilation; ISDN, isosorbide dinitrate; IV, intravenous; LoS, length of stay; MAP, mean arterial pressure; MI, myocardial infarction; RCT, randomised controlled trial, RR, respiratory rate.

Clinical Bottom Line

High-dose glyceryl trinitrate is effective in acute cardiogenic pulmonary oedema.

References

1. Sharon A, Shpirer I, Kaluski , Moshkovitz Y, Milovanov O, Polak R, Blatt A, Simovitz A, Shaham O, Faigenberg Z, Metzger M, Stav D, Yogev R, Golik A. High-Dose Intravenous Isosorbide-Dinitrate is safer and better than BIPAP combined with conventional treatment of severe pulmonary edema. Journal of the American College of Cardiology Vol. 36, No. 3, September 2000:832–7.
2. Cotter G, Metzkor E, Kaluski E, Faigenberg Z, Miller R, Simovitz A ,Shaham O, Marghitay D. 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 Vol 351 • February 7, 1998.
3. 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;50:144–52.