New England Journal of Medicine March 04, 2010

Comparison of Dopamine and Norepinephrine in the Treatment of Shock (SOAP II)

Daniel De Backer, Patrick Biston, Jacques Devriendt, Christian Madl, Didier Chochrad, Cesar Aldecoa, Alexandre Brasseur, Pierre Defrance, Philippe Gottignies, Jean-Louis Vincent (SOAP II Investigators)

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Bottom Line

In patients with shock, dopamine did not significantly differ from norepinephrine in 28-day mortality but was associated with a greater number of arrhythmic events and increased mortality in the cardiogenic shock subgroup.

Key Findings

1. There was no significant difference in the primary outcome of 28-day mortality between the dopamine and norepinephrine groups (52.5% vs. 48.5%; Odds Ratio [OR] 1.17, 95% CI 0.97-1.42; P=0.10).

2. Arrhythmic events (predominantly atrial fibrillation) were significantly more frequent in the dopamine group compared to the norepinephrine group (24.1% vs. 12.4%, P<0.001).

3. In a pre-specified subgroup analysis of patients with cardiogenic shock (N=280), 28-day mortality was significantly higher in the dopamine group compared to the norepinephrine group (P=0.03).

Study Design

Design

Multicenter RCT

Double-Blind

Sample

1,679

Patients

Duration

28 days

Median

Setting

Multicenter, Europe

Population Adult patients requiring vasopressor therapy for shock, defined as a mean arterial pressure <70 mmHg or a systolic blood pressure <100 mmHg with signs of tissue hypoperfusion, despite adequate fluid resuscitation.

Intervention Dopamine administered via identical blinded syringes, titrated up to a maximum dose of 20 µg/kg/min as the first-line vasopressor to restore and maintain target blood pressure.

Comparator Norepinephrine administered via identical blinded syringes, titrated up to a maximum dose of 0.19 µg/kg/min as the first-line vasopressor to restore and maintain target blood pressure.

Outcome Rate of death from any cause at 28 days after randomization.

Study Limitations

• The trial enrolled a highly heterogeneous population comprising septic (62%), cardiogenic (16%), and hypovolemic (16%) shock patients, potentially diluting specific subgroup treatment effects.

• A substantial proportion of patients in the dopamine group (26%) required open-label rescue norepinephrine, which may have confounded the mortality outcomes and narrowed the difference between the two arms.

• The high overall baseline mortality rate (nearly 50%) reflects an exceptionally sick patient population, which might limit the study's power to detect small differences in survival.

• Despite being double-blinded, the distinct physiologic effects of dopamine (such as pronounced tachycardia) could have inadvertently unblinded clinicians.

Clinical Significance

The SOAP II trial was a landmark practice-changing study in critical care medicine. Its findings conclusively overturned the traditional use of dopamine as a benign first-line vasopressor. Because dopamine yielded double the rate of arrhythmias and worsened survival in cardiogenic shock, international guidelines subsequently shifted to strongly recommend norepinephrine as the first-line vasopressor for undifferentiated and septic shock, and relegated dopamine to very select circumstances.

Historical Context

For decades, dopamine and norepinephrine were both accepted as first-line vasopressors. Dopamine was historically favored by many clinicians due to a theoretical benefit of 'renal-dose' vasodilation (a concept debunked by the early 2000s) and fears that norepinephrine caused profound peripheral ischemia. However, observational data from the original SOAP (Sepsis Occurrence in Acutely Ill Patients) cohort study signaled that dopamine might be independently associated with a higher risk of death. The SOAP II trial was designed to directly test this hypothesis in a rigorous randomized controlled trial.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How do the receptor affinities of dopamine and norepinephrine differ at varying doses, and how does this explain the higher rate of arrhythmias observed with dopamine in the SOAP II trial?

Key Response

Dopamine acts on dopaminergic, beta-1, and alpha-1 receptors in a dose-dependent manner. At the high doses required for shock, it heavily stimulates beta-1 receptors, causing pronounced chronotropy and an increased risk of tachyarrhythmias. Norepinephrine primarily acts on alpha-1 receptors with moderate beta-1 activity, providing potent vasoconstriction without excessive heart rate elevation.

Resident

Based on the SOAP II trial findings, how should your initial choice of vasopressor change when managing a patient presenting with undifferentiated shock versus confirmed cardiogenic shock?

Key Response

While SOAP II showed no overall mortality difference between the two drugs for undifferentiated shock, dopamine caused significantly more arrhythmias. In the cardiogenic shock subgroup, dopamine was actually associated with increased mortality. Therefore, norepinephrine is preferred in undifferentiated shock to avoid arrhythmias, and is strongly indicated over dopamine in cardiogenic shock to prevent excess mortality.

Fellow

The SOAP II trial demonstrated increased mortality with dopamine in the cardiogenic shock subgroup. Given that dopamine provides both inotropy and vasopressor support, why might it be physiologically detrimental compared to norepinephrine in a failing left ventricle?

Key Response

Dopamine's profound beta-1 mediated chronotropy and inotropy significantly increase myocardial oxygen demand. In cardiogenic shock, where coronary perfusion is already compromised, this exacerbates ischemia. Norepinephrine improves mean arterial pressure and coronary perfusion pressure via alpha-1 vasoconstriction with only mild inotropy, offering a better myocardial oxygen supply-demand balance.

Attending

Prior to SOAP II, dopamine was frequently favored for its perceived renal-protective effects. How do the results of SOAP II serve as a critical teaching point regarding the danger of relying on physiological rationale over hard clinical outcomes?

Key Response

The historical preference for renal-dose dopamine was based on the physiological surrogate of increased splanchnic and renal blood flow. SOAP II demonstrated that this physiological theory did not translate to a survival benefit and actually exposed patients to significant harm through arrhythmias, highlighting the necessity of powering large RCTs for patient-centered outcomes like 28-day mortality rather than surrogate endpoints.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The finding of increased mortality in the cardiogenic shock subgroup in SOAP II was a secondary subgroup analysis. How does the lack of alpha adjustment for multiple comparisons impact the statistical confidence of this finding, and how would you design a robust follow-up trial to isolate this effect?

Key Response

Subgroup analyses are inherently prone to Type I errors due to multiple testing and are generally considered hypothesis-generating. A rigorous follow-up would require an RCT specifically designed and powered for patients with isolated cardiogenic shock, stratifying by etiology to robustly test the hypothesis that norepinephrine is superior to dopamine in this specific population.

Journal Editor

The SOAP II trial allowed for open-label norepinephrine as a rescue therapy if the maximum dose of the blinded study drug was reached. As a peer reviewer, how would you evaluate the impact of this rescue design on the primary outcome's validity?

Key Response

Allowing open-label norepinephrine as a rescue vasopressor introduces a significant risk of diluting the treatment effect. If patients deteriorating on dopamine are rescued by norepinephrine, their outcomes may improve, biasing the primary mortality outcome toward the null hypothesis. A rigorous reviewer would flag this as a potential cause for the non-significant p-value of 0.10 for overall mortality, suggesting the true difference might be larger.

Guideline Committee

How did the SOAP II trial findings inform the transition in the Surviving Sepsis Campaign guidelines regarding the specific strength of recommendation and level of evidence for first-line vasopressor use?

Key Response

SOAP II was the pivotal trial that led the Surviving Sepsis Campaign to issue a strong recommendation with high-quality evidence for norepinephrine as the first-line vasopressor over dopamine. Current guidelines specifically recommend against using dopamine except in highly selected patients, such as those with absolute bradycardia and a low risk of tachyarrhythmias, directly citing the increased arrhythmogenic risk and lack of mortality benefit demonstrated in SOAP II.

Clinical Landscape

Noteworthy Related Trials

2008

VASST Trial

n = 778 · NEJM

Tested

Low-dose vasopressin

Population

Patients with septic shock

Comparator

Norepinephrine

Endpoint

28-day mortality

Key result: There was no significant difference in 28-day mortality between vasopressin and norepinephrine overall.

2014

SEPSISPAM Trial

n = 776 · NEJM

Tested

High target mean arterial pressure (80-85 mm Hg)

Population

Patients with septic shock

Comparator

Low target mean arterial pressure (65-70 mm Hg)

Endpoint

28-day mortality

Key result: Targeting a higher MAP did not improve 28-day survival and increased the risk of atrial fibrillation.

2017

ATHOS-3 Trial

n = 321 · NEJM

Tested

Angiotensin II

Population

Patients with vasodilatory shock unresponsive to high-dose vasopressors

Comparator

Placebo

Endpoint

Mean arterial pressure response at 3 hours

Key result: Angiotensin II effectively increased blood pressure in patients failing high doses of conventional vasopressors.

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