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]?
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.
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].
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
|Author, date and country
||Study type (level of evidence)
|Sharon A et al.|
|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
|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.|
|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,|
|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%|
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.
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.
- 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.
- 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.
- 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.