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Three Part Question

For [adult patients presenting to the emergency department or the intensive care unit] do [epinephrine, dopamine, dobutamine, or vasopressin] produce better [28 and 90 day mortality rates] than norepinephrine alone?

Clinical Scenario

A seventy four year old female presents from a nursing home with altered mental status and recent diagnosis of pneumonia. She is febrile, tachypnoeic, tachycardic, anuric, and has a blood pressure of 72/35. Your attending physician suggests you start her on an infusion of norepinephrine, however epinephrine has more inotropic effect. You wonder what is the best vasopressor for your patient?

Search Strategy

Medline 1950 - 3/10 using Ovid interface, Cochrane Library (2010), PubMed clinical queries
[(exp shock, septic/ drug therapy) AND (exp vasocontrictor agents or vasopressors.mp)] Limit to human and English.

Search Outcome

Trials were excluded if they were not designed to investigate mortality but rather surrogate measures such as blood pressure and cardiac index. A total of 120 papers were found of which 5 were relevant to the three part question. These studies included a meta-analysis that reported results of controlled trials through November 2003. We also identified 4 randomized, controlled trials that were not included in the meta-analysis.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Annane et. al. 2007 France	330 Patients with septic shock.	Prospective, multicenter, randomized, double-blind study comparing infusion of epinephrine alone versus norepinephrine plus dobutamine to achieve MAP greater than or equal to 70 mmHg.	28 day mortlity	40% epinephrine, 34% norepinephrine plus dobutamine, p=0.31	Patients allocated epinephrine were slightly older on average.
			90 day mortality	epinephrine 52%, norepinephrine plus dobutamine 50%, p=0.73
Myburgh et. al. 2008 Australia	280 patients requiring vasopressors for any reason with a subgroup of 158 patients requiring vasopressors for severe sepsis.	Prospective, randomized, double-blind, controlled trial.	28 day mortality	22.5% epinephrine, 26.1% norepinephrine, p=0.48	MAP goal assigned by treating physician. No restriction on other vasopressors, inotropes, inodilators, or catecholamine sparing agents. Finally, the authors do not include data on key confounding co-interventions(e.g., intravenous fluid volumes in subgroups, etc.).
			90 day mortailty	30.4% epinephrine, 34.3% norepinephrine, p=0.49
Russell, et. al. 2008 United States, Canada, Australia	778 patients older than 16 who had septic shock resistant to fluids and low-dose norepinephrine.	Prospective, multi-center, randomized, double-blind trial. Paients were randomized to vasopressin or norepinephrine in addition to open-label vasopressors.	28 day mortality	35.4 % vasopressin, 39.3% norepinephrine, p=0.26	A range of doses of vasopressin and norepinephrine were permittted by the study protocol. Long mean time from study enrollment to time of administration of drug (12 hours).
			90 day mortality	43.9% vasopressin, 49.6% norepinephrine, p=0.11
Müllner et al. 2004 Austria	Blinded and unblinded, parallel-group RCTs that compared various vasopressors, vasopressors with placebo, or vasopressors with intravenous fluids for the treatment of shock. Mortality was the main outcome.	Meta-analysis of 8 RCTs	Two studies compared norepinephrine plus dobutamine with epinephrine alone in patients with septic shock (52 patients)	Relative risk of death 0.98 (95% CI 0.57-1.67)	All 8 studies were methodologically poor, had small sample sizes, wide confidence intervals, and failed to investigate patient-oriented outcomes. Only two studies reported allocation concealment.
			Three studies compared norepinephrine with dopamine in patients with septic shock (62 patients)	Relative risk of death 0.88 (95% CI 057-1.36)
			Two studies compared vasopressin with placebo in patients with septic shock (58 patients)	Relative risk of death 1.04 (95% CI 0.06-19.33)
			One study compared terlipressin with norepinephrine in patients with refractory hypotension after general anaesthesia but there were no deaths (20 patients)
De Backer et al. 2010 Belgium	1679 adult patients with shock (signs of tissue hypoperfusion and systolic blood pressure <100 mm Hg or mean arterial pressure <70 mm Hg) that persisted after treatment with "adequate" fluids (at least 1000 mL of crystalloids or 500 mL of colloids) were randomized to receive dopamine or norepinephrine. Septic shock occurred in 1044 patients.	Prospective, multicenter, randomized, clinical trial	28 day mortality	51% dopamine, 56% norepinephrine, p=0.19	The type and amount of volume resuscitation may have affected the outcomes. The authors do not clearly state how they defined the resolution of shock. “Equipotent” doses of vasopressors were used; however, evidence that these doses of the two vasopressors are equipotent does not exist.

Comment(s)

Septic Shock is a condition of acute organ dysfunction due to severe infection, with a mortality of up to 50%. Current efforts to improve care are limited by little practical evidence regarding the interventions and timing of sepsis therapies. For example, there are very few RCTs of vasopressors for the treatment of shock which assess outcomes that matter to patients. Many existing trials were not designed to investigate such outcomes but rather surrogate measures such as blood pressure and cardiac index. Vasopressin is commonly used as an adjunct to catecholamines to support blood pressure in refractory septic shock, but it did not reduce mortality rates as compared with norepinephrine. However, the average time from meeting the diagnostic criteria to infusion of the study drug was approximately 12 hours. Studies by Kumar et al and Rivers et al conclude that antimicrobial and cardiovascular and other therapies initiated earlier (preferably within 1 or 2 hours) result in the highest survival rates. Treatment initiated at an average of 12 hours after the onset of septic shock may be too late for any vasopressor agent to show a significant effect on mortality. Mortality rates did not differ between epinephrine and norepinephrine. In addition, rates of severe arrhythmias, stroke and myocardial events, limb ischemia, and other adverse effects were similar between groups. Although dopamine is the natural precursor of norepinephrine one RCT suggests that there is no significant difference in 28 day mortality and that dopamine administration may be associated with more arrhythmias in patients with shock. One observational study confirmed that dopamine administration was associated with a worse outcome from shock due to any cause.

Clinical Bottom Line

No clinical study has definitely indicated that one catecholamine is superior to another, so that at present no agent should be preferred over the other. If simplicity is best, then using one drug (epinephrine) over two (norepinephrine plus dobutamine) creates less opportunity for error. Data in this field to date suggest that it is the timing of vasopressor (and other) therapy, rather than the specific agent, that is decisive. In both clinical practice and clinical trials, once hypotension occurs in septic shock, clinicians need to initiate immediate antimicrobial therapy, cardiovascular support, and other effective therapies recommended by current guidelines.

References

1. Annane D, Vignon P, Renault A, et. al. Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomised trial The Lancet 2007; 370:676-684
2. Myburgh JA, Higgins, A, Jovanovska A, et. al. A comparison of epinephrine and norepinephrine in critically ill patieints Intensive Care Medicine 2008;34:2226-2234.
3. Russell JA, Walley KR, Singer J, et.al. Vasopressin versus norepinephrine infusion in patients with septic shock New England Journal of Medicine 2008; 358:877-887
4. Müllner M, Urbanek B, Havel C, Losert H, Gamper G, Herkner H Vasopressors for shock Cochrane Database of Systematic Reviews 2004; Issue 3. Art. No.: CD003709
5. De Backer D, Biston P, Devriendt J, et al. Comparison of Dopamine and Norepinephrine in the Treatment of Shock. N Engl J Med 2010; 362:779-789.
6. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345:1368-1377.
7. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 2006;34:1589-1596.
8. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock. Crit Care Med 2008;36:296-327.
9. Sakr Y, Reinhart K, Vincent J, et al. Does dopamine administration in shock influence outcome? Results of the Sepsis Occurrence in Acutely Ill Patients (SOAP) Study. Crit Care Med 2006;34:589-597.