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Foundational Trials

SOAP II

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Publication

  • Title: Comparison of Dopamine and Norepinephrine in the Treatment of Shock
  • Acronym: SOAP II
  • Year: 2010
  • Journal published in: New England Journal of Medicine
  • Citation: 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(9):779-789.

Context & Rationale

  • Background
    Dopamine and norepinephrine (noradrenaline) were both widely used as first-line vasopressors for shock, but with different pharmacology and adverse-effect profiles (chronotropy/arrhythmias with dopamine vs potent vasoconstriction with norepinephrine).
    Prior comparative randomised evidence was limited, while observational data suggested potential harm with dopamine exposure in shock (including higher mortality after adjustment). 1
  • Research Question/Hypothesis
    In adults with shock requiring vasopressor support in ICU, does dopamine (compared with norepinephrine) reduce 28-day mortality, without excess adverse events?
  • Why This Matters
    Vasopressor selection affects survival-critical physiology (perfusion pressure, cardiac output, rhythm stability) and is near-universal in shock care; even modest differences in mortality or harm would have major population impact.
    A definitive, blinded, adequately powered trial could resolve long-standing equipoise and standardise practice.

Design & Methods

  • Research Question: Among ICU adults with shock requiring vasopressors, does dopamine versus norepinephrine change 28-day all-cause mortality?
  • Study Type: Multicentre, randomised, double-blind trial in eight ICUs (Belgium, Austria, Spain); sequential (triangular-test) monitoring design; enrolment Dec 2003 to Oct 2007.
  • Population:
    • Setting: ICU patients with shock requiring vasopressor initiation.
    • Inclusion: Age ≥18 years; shock defined as MAP <70 mmHg or SBP <100 mmHg despite “adequate fluid resuscitation” (≥1000 mL crystalloids or ≥500 mL colloids, unless CVP >12 mmHg or PAOP >14 mmHg), plus signs of tissue hypoperfusion (altered mental state, mottled skin, urine output <0.5 mL/kg for 1 hour, or lactate >2 mmol/L).
    • Shock strata (at enrolment): Septic (542 dopamine vs 502 norepinephrine), cardiogenic (135 vs 145), hypovolaemic (126 vs 118), other (55 vs 56).
    • Key exclusions: Vasopressor therapy for >4 hours in current shock episode; serious arrhythmia (rapid atrial fibrillation >160/min, ventricular tachycardia); brain death; age <18 years.
  • Intervention:
    • Dopamine infusion (weight-based), increased in increments of 2 μg/kg/min to a maximal dose of 20 μg/kg/min, titrated to a clinician-defined target blood pressure.
    • If hypotension persisted at maximal study dose: open-label norepinephrine could be added.
    • Rescue vasopressors permitted: epinephrine and vasopressin; inotropes permitted to raise cardiac output.
  • Comparison:
    • Norepinephrine (noradrenaline) infusion (weight-based), increased in increments of 0.02 μg/kg/min to a maximal dose of 0.19 μg/kg/min, titrated to a clinician-defined target blood pressure.
    • If hypotension persisted at maximal study dose: open-label norepinephrine could be added.
    • Same rescue-vasopressor and inotrope allowances as dopamine group; open-label dopamine was not permitted.
  • Blinding: Double-blind: allocation via sealed, opaque envelopes; study drug prepared by an unblinded individual not involved in care; clinicians, investigators, and research personnel remained unaware of assignment.
  • Statistics: Power calculation: 765 patients per group to detect a 15% relative difference in 28-day mortality with 80% power at a two-sided 5% significance level (assumed 43% mortality with dopamine vs 36% with norepinephrine); primary analysis by intention-to-treat; sequential interim analyses (after 50, 100, then every 100 patients) using a triangular test with stopping boundaries for superiority of either drug or “no difference.”
  • Follow-Up Period: Primary endpoint at 28 days; additional mortality follow-up at ICU discharge, hospital discharge, 6 months, and 12 months (long-term follow-up incomplete).

Key Results

This trial was stopped early. Per prespecified sequential monitoring, enrolment stopped after interim analysis of the first 1600 patients crossed the boundary indicating no difference in 28-day mortality; 1679 patients had been randomised in total.

Outcome Dopamine (n=858) Norepinephrine (n=821) Effect p value / 95% CI Notes
28-day mortality (primary) 450/858 (52.5%) 398/821 (48.5%) OR 1.17 95% CI 0.97 to 1.42; P=0.10 Intention-to-treat; sequential design stopped for “no difference.”
ICU mortality 431/858 (50.2%) 377/821 (45.9%) OR 1.19 95% CI 0.98 to 1.44; P=0.07 Secondary endpoint.
Hospital mortality 503/858 (59.4%) 460/821 (56.6%) OR 1.12 95% CI 0.92 to 1.37; P=0.24 Secondary endpoint.
6-month mortality 548/858 (63.8%) 516/821 (62.9%) OR 1.06 95% CI 0.86 to 1.31; P=0.71 Follow-up incomplete overall (data available for 1443/1679).
12-month mortality 566/858 (65.9%) 517/821 (63.0%) OR 1.15 95% CI 0.91 to 1.46; P=0.34 Follow-up incomplete overall (data available for 1036/1679).
Arrhythmia (any) 207/858 (24.1%) 102/821 (12.4%) Not reported P<0.001 Driven largely by atrial fibrillation (20.5% vs 11.0%).
Study drug discontinued due to severe arrhythmia 52/858 (6.1%) 13/821 (1.6%) Not reported P<0.001 A major mechanism of protocol “contamination” via mandated therapy changes.
Days without need for open-label vasopressors (mean ± SD) 12.6 ± 12.5 14.2 ± 12.3 Not reported P=0.007 Secondary endpoint; consistent with more rescue therapy in dopamine group.
Days without need for trial drug (mean ± SD) 11.0 ± 12.1 12.5 ± 12.1 Not reported P=0.01 Secondary endpoint.
28-day mortality in cardiogenic shock subgroup Not reported (n=135) Not reported (n=145) Not reported Log-rank P=0.03; interaction P=0.87 Pre-specified subgroup; interaction test did not support differential treatment effect by shock type.
  • There was no statistically significant difference in 28-day mortality: 52.5% (dopamine) vs 48.5% (norepinephrine); OR 1.17; 95% CI 0.97 to 1.42; P=0.10.
  • Dopamine caused substantially more arrhythmia: 24.1% vs 12.4% (P<0.001), and more drug discontinuation for severe arrhythmia: 6.1% vs 1.6% (P<0.001).
  • In cardiogenic shock, dopamine was associated with higher 28-day mortality by Kaplan–Meier analysis (P=0.03), but the interaction test for shock type was not significant (P=0.87).

Internal Validity

  • Randomisation and allocation concealment: Computer-generated sequence in permuted blocks (size 6–10), stratified by ICU; allocation via sealed, opaque envelopes; drug prepared by an unblinded person not involved in care (reducing selection and performance bias).
  • Follow-up completeness: Primary outcome (28-day mortality) reported for all randomised patients (858 vs 821). Longer-term mortality follow-up was incomplete (6 months data available for 1443/1679; 12 months for 1036/1679), introducing attrition risk for late endpoints.
  • Performance/detection bias: Mortality endpoints are objective; double-blinding limits differential co-interventions, though titration targets (clinician-defined blood pressure goals) introduce pragmatic variability.
  • Protocol adherence and contamination: Rescue open-label norepinephrine was permitted at maximal study dose and occurred more often in the dopamine arm (26% vs 20%; P<0.001), reducing separation between strategies; severe arrhythmia led to study-drug discontinuation more often with dopamine (52 vs 13 patients).
  • Baseline comparability: Groups were broadly well matched in severity (median APACHE II 20 vs 20; median SOFA 9 vs 9) and shock aetiology distribution (e.g., septic shock 63.2% vs 61.1%). Some baseline treatment differences existed (e.g., open-label norepinephrine at enrolment 18.3% vs 13.0%; dobutamine 14.8% vs 19.4%), consistent with clinician physiology-driven practice in a pragmatic ICU population.
  • Timing: Exclusion of patients already on vasopressors for >4 hours selected for earlier shock, aligning with the mechanistic window where vasopressor choice might matter.
  • Separation of the variable of interest: Process and harm outcomes indicate meaningful pharmacologic separation (arrhythmias 24.1% vs 12.4%; drug discontinuation for arrhythmia 6.1% vs 1.6%), but rescue norepinephrine use (26% vs 20%) attenuated pure between-arm vasopressor exposure differences.
  • Statistical rigour: Prespecified sequential monitoring with objective primary endpoint reduces risks of arbitrary early stopping; however, multiple subgroup comparisons and pragmatic titration targets complicate mechanistic inference (while leaving the pragmatic mortality/harm question well addressed).

Conclusion on Internal Validity: Overall, internal validity is strong for the primary mortality comparison (blinded randomisation, objective endpoint, near-complete 28-day follow-up), with the main threat being protocol-permitted rescue norepinephrine and therapy changes after arrhythmias, which likely biased towards smaller between-group differences.

External Validity

  • Population representativeness: Broad ICU shock population (septic, cardiogenic, hypovolaemic, and other shock) with relatively few exclusions (notably serious arrhythmias and prolonged pre-enrolment vasopressor exposure), enhancing real-world relevance.
  • Applicability across systems: Conducted in European ICUs (2003–2007); co-interventions reflect contemporary ICU practice for that era (e.g., activated protein C use in a minority of septic shock patients), so baseline care has evolved, but catecholamine physiology and arrhythmia risk remain directly applicable.
  • Clinical translation: Findings generalise best to ICU shock requiring catecholamine vasopressors with clinician-titrated blood pressure targets; extrapolation to prehospital/ED-only cohorts or very late shock (already on vasopressors >4 hours) is limited.

Conclusion on External Validity: External validity is moderate-to-strong for ICU shock care: inclusion was broad and pragmatic, though changing sepsis care bundles over time and the European ICU context slightly constrain direct transportability to all contemporary settings.

Strengths & Limitations

  • Strengths: Large, multicentre, double-blind RCT; objective primary endpoint; prespecified sequential monitoring; broad shock aetiologies; clinically important adverse-event capture (arrhythmias) with clear between-group separation.
  • Limitations: Pragmatic titration (target BP at clinician discretion) and permitted rescue norepinephrine reduced contrast between strategies; heterogeneity of shock types diluted sepsis- or cardiogenic-specific treatment effects; subgroup findings (cardiogenic shock) not supported by interaction testing; incomplete long-term follow-up (especially at 12 months); dosing “equipotency” between maximum dopamine and norepinephrine ranges is uncertain.

Interpretation & Why It Matters

  • Clinical signal
    Mortality was similar at 28 days, but dopamine produced materially more arrhythmias (24.1% vs 12.4%) and more treatment disruption due to severe arrhythmia (6.1% vs 1.6%), shifting the benefit–harm balance toward norepinephrine for most shock patients.
  • Mechanistic coherence
    The excess of tachyarrhythmias with dopamine aligns with its stronger β-adrenergic/chronotropic effects; the trial demonstrates that haemodynamic equivalence (blood pressure targets achieved) does not imply clinical equivalence when rhythm toxicity differs.
  • Practice impact
    SOAP II helped reframe “first-line vasopressor choice” as a safety-driven decision: when efficacy (mortality) is similar, avoid the agent with substantially higher adverse-event burden.

Controversies & Subsequent Evidence

  • Editorial critiques: The accompanying editorial emphasised that many patients had already received open-label catecholamines before randomisation, and highlighted uncertainties around whether the vasopressor dose ranges and titration approaches ensured truly comparable “vasopressor strategies,” as well as the challenges of defining adequate fluid resuscitation in heterogeneous shock. 2
  • Rescue norepinephrine and treatment contamination: Correspondence raised the concern that more frequent use of open-label norepinephrine in the dopamine arm (26% vs 20%) could obscure true differences; in reply, the investigators reported that excluding patients who received open-label norepinephrine did not reveal a significant mortality difference (P=0.45). 3
  • Cardiogenic shock subgroup: Dopamine’s worse Kaplan–Meier outcome in cardiogenic shock (P=0.03) was debated given the non-significant interaction (P=0.87) and potential for unmeasured confounding in cardiogenic shock care pathways (e.g., mechanical support/revascularisation details were not collected). 3
  • Meta-analytic synthesis: Subsequent meta-analysis of randomised trials in septic shock reported higher mortality and substantially increased arrhythmias with dopamine compared with norepinephrine, strengthening the inference that dopamine’s rhythm toxicity is clinically consequential and not offset by outcome benefit. 4
  • Guideline convergence: Modern sepsis guidelines recommend norepinephrine as first-line vasopressor therapy, relegating dopamine to highly selected circumstances (e.g., relative bradycardia and low arrhythmia risk), reflecting the SOAP II safety signal and subsequent syntheses. 5
  • Cardiogenic shock guidance: Contemporary cardiogenic shock guidance similarly positions norepinephrine as a preferred vasopressor, consistent with concern for dopamine-associated tachyarrhythmias in a vulnerable population. 6

Summary

  • In 1679 ICU patients with shock, dopamine did not reduce 28-day mortality compared with norepinephrine (52.5% vs 48.5%; OR 1.17; 95% CI 0.97 to 1.42; P=0.10).
  • Dopamine caused substantially more arrhythmias (24.1% vs 12.4%; P<0.001), predominantly atrial fibrillation (20.5% vs 11.0%).
  • Severe arrhythmias prompting study-drug discontinuation were more frequent with dopamine (6.1% vs 1.6%; P<0.001), increasing rescue-therapy crossover potential.
  • A cardiogenic shock subgroup signal (P=0.03) was not supported by a significant interaction test (P=0.87), limiting causal certainty for shock-type specificity.
  • The trial’s central contribution is reframing vasopressor choice as a safety trade-off when mortality efficacy appears similar, favouring norepinephrine.

Further Reading

Other Trials

Systematic Review & Meta Analysis

Observational Studies

Guidelines

Notes

  • In this trial, “norepinephrine” corresponds to “noradrenaline” in many European formularies.
  • The key practice signal is safety: when mortality is similar, the agent with higher arrhythmia burden is difficult to justify as first-line in most shock phenotypes.

Overall Takeaway

SOAP II demonstrated that dopamine does not improve survival compared with norepinephrine in ICU shock, while substantially increasing tachyarrhythmias and therapy disruption. In modern practice, its enduring legacy is the reorientation of “vasopressor choice” toward norepinephrine as default first-line, with dopamine reserved—if at all—for carefully selected patients where chronotropy is desired and arrhythmia risk is low.

Overall Summary

  • Primary outcome neutral: 28-day mortality 52.5% (dopamine) vs 48.5% (norepinephrine); OR 1.17; 95% CI 0.97 to 1.42; P=0.10.
  • Clear harm signal: arrhythmias 24.1% vs 12.4% (P<0.001), with more severe arrhythmia-related discontinuation (6.1% vs 1.6%).
  • Subgroup caution: cardiogenic shock signal (P=0.03) without interaction support (P=0.87).

Bibliography