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Three Part Question

In [an adult presenting with decompensated heart failure and pulmonary oedema] are [phosphodiesterase inhibitors superior to dobutamine] for [reduction in mortality and morbidity]?

Clinical Scenario

It's 6 a.m. The standby phone goes and the ambulance service tell you there bringing in a chap with severe heart failure, low sats and a low BP. You attempt to stabilise him in resus. BIPAP is instituted to compensate for the respiratory failure; a small dose of IV nitrates is infused and a catheter is passed. Despite your best efforts, he remains dyspnoeic and hypotensive. You call up to ICU looking to steal some enoximone or milrinone, having previously used these agents with success, but a consultant intensivist suggests using dobutamine instead as "it does the same job". After initiating dobutamine therapy and successful transfer to CCU, you resolve to go home and find out if he's right or not.

Search Strategy

Medline 1950 - November week 1 2009 using the Ovid interface.
{cardiac failure.mp. OR exp Heart Failure/ OR exp Cardiac Output, Low/ OR cardiogenic shock.mp. OR exp Shock, Cardiogenic/ OR ventricular failure, left.mp.OR decompensated heart failure.mp. } AND {enoximone.mp. OR exp Enoximone/ OR milrinone.mp. OR exp Milrinone/ OR phosphodiesterase inhibitor.mp. OR exp Phosphodiesterase Inhibitors/ OR inodilator.mp. OR perfan.mp. OR primacor.mp.} AND {dobutamine.mp. OR exp Dobutamine/}
LIMIT to Human and English Language

Search Outcome

The search as detailed above returned 202 hits. Reviewing the abstracts of these allowed 7 papers to be retrieved. Review of the references of these revealed one paper not included by the search strategy. As all but 2 papers reviewed the effect of dobutamine or phosphodiesterase inhibitors in stable hospitalised patients, they were not included in the report.
The two relevant papers are included below.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Yamani, M.H., et al. 2001 US	329 patients admitted to a heart failure unit with acute exacerbation of CHF.	Retrospective analysis. Patients had 6/12 history of CHF and were in NYHA class IV. Patients treated with dobutamine (D) (n=269) or Milrinone (M) (n=60). Additional drugs (e.g. nitroglycerin and dopamine) given as needed.	Cardiac index	D increased from 1.6 +/- 0.3 to 2.5 +/- 02; M incresed from 1.6 +/-0.2 to 2.6 +/-0.5 (p=0.02)	Not randomised and retrospective. Drugs given at physicians discretion; milrinone drug of choice in patients with worse pulmonary hypertension, hence possibly sicker. Milrinone group had better haemodynamic improvement in short term. No long term follow up.
			Inhospital mortality	D=21 (7.8%); M 6 (10%); p= n/s
			Length of stay in heart failure unit (days)	D=3.3 +/-1.5; M=3.2 +/-1.5; p=n/s
			Drug cost ($)	D=45+/-10; M=1855+/-350; p<0.0001
Flammang, D., et al. 1990 France	44 patients hospitalised with acute pulmonary oedema.	RCT, 22 in each arm. Bolus 1mg/kg enoximone (E) every 8 hours for 48 hours versus conventional treatment (C) including dobutamine, dopamine, frusemide and nitrates.	"Favourable outcome"	E=17; C=11; p=0.06	Preliminary report of trial aiming for 100 patients in total. Ethical improvement not stated. Enoximone usually given as infusion. Bolus enoximone had to be repeated in 11 (50%) patients. No haemodynamic data given. No long term follow up. Side effects not reported.
			Unfavourable (additional Rx required)	E=4; C=9; p<0.05
			Death	E=1; C=2; p=n/s

Comment(s)

Patients presenting with acute pulmonary oedema on a background of congestive cardiac failure from any cause form a very high-risk group with significant short-term mortality (Nohria, et al., J Am Coll Card 2003; 41: 1797 -1804). When these patients have poor cardiac output then mortality is increased. Management is difficult as nitrates, diuretics and NIV all have the possibility to reduce cardiac output more. Traditional inotropic agents, whilst increasing haemodynamic variables, have the propensity to increase myocardial work and hence oxygen demand. The phosphodiesterase inhibitors enoximone and milrinone act to increase myocardial cAMP and therefore increasing inotropy shilst decreasing systemic and pulmonary vascular resistance causing an increase in both stroke volume and cardiac output (Barnard, M.J. and Linter S.P.K., BMJ 1993; 307: 35-41). Despite this theoretical benefit, large placebo controlled trials have shown increased mortality with milrinone (Cuff, M.F., et al. JAMA 2002; 287: 1541-1547)and also with dobutamine (O'Connor, C.M., et al. Am Heart J 1999; 138: 78-86). The ADHERE (Acute Decompensated Heart Failure National Registry) registry (Abraham, W.T., et al., J Am Coll Card 2005; 46: 57-64) in analysing mortality in 65 180 patient episodes shows that the 2 021 patients treated with milrinone, 248 died (12.3%); of 4 226 treated with dobutamine, 589 died (13.9%). Both these groups had worse SBP, DBP and LVEF than comparative patients not treated with these agents. The OR in the ADHERE registry for an SBP < 115 mmHg was 3.09, that for DBP =< 55 2.87, indicating that patients presenting with pulmonary oedema and decompensated heart failure are likely to have a very poor outcome whatever modality of treatment is employed. It remains to be seen whether newer agents such as nesiritide (recombinant B-type natriuretic peptide) or levosimendan (a calcium sensitizer) have any benefit. Although there are some concerns over nesiritide and increased mortality and risk of renal failure, levosimendan seems promising and large trials are awaited.

Clinical Bottom Line

Patients who present with acute pulmonary oedema and hypotension have a bleak outcome whatever their emergency physician does. This BET suggests that either phosphodiesterase inhibitors or dobutamine may be tried with comparable efficacy, with a slight balance in favour of the former, if available. Patients should have invasive monitoring and be admitted to critical care areas due to their increased risk of mortality.

References

1. Yamani, M.H., et al. Comparison of dobutamine-based and milrinone-based therapy for advanced decompensated congestive heart failure: hemodynamic efficacy, clinical outcome and economic impact. American Heart Journal 2001; 142 (6): 999-1002
2. Flammang, D., et al. Acute pulmonary oedema: preliminary results of a randomised trial of the intravenous phosphodiesterase inhibitor, enoximone vs conventional therapy. International Journal of Cardiology. 1990; 28: S3-S6