De Backer D, Biston P, Devriendt J, Madl C et al; SOAP II Investigators. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med. 2010 Mar 4;362(9):779-89
Introduction
Acute circulatory failure may be of varied etiology and carries a high mortality without expeditious evaluation and timely management. One of the basic tenets of circulatory support is the administration of catecholamines. They act on specific receptors to sustain the circulation, mainly as a temporizing measure, until specific therapeutic measures can take effect. Historically, norepinephrine and dopamine have been widely used as catecholamine support in acute circulatory failure.
Dopamine is a precursor of norepinephrine. Traditionally, several dose-specific effects have been attributed to dopamine, including the so-called “dopaminergic” effect at low doses, believed to increase renal blood flow and urine output. However, these potentially favorable observations have been largely confined to animals and healthy human volunteers (1). The Australian and New Zealand Intensive Care Society group (ANZICS), in a large randomized controlled trial (RCT), demonstrated that dopamine in a “renal-protective” dose did not lower the peak creatinine levels, nor reduce the requirement for renal replacement therapy compared with placebo among patients with the systemic inflammatory response syndrome and early renal dysfunction. Besides, the ICU survival was not different compared with placebo (2).
The SOAP observational study, published in 2006, included 198 ICUs in Europe. This study included 3,147 patients of whom1058 developed shock. Among patients in shock, those who received dopamine had higher ICU and hospital mortality compared with those who did not (49.9% vs. 41.7%, p=0.01). Furthermore, on multivariate analysis, dopamine was one of the independent predictors of ICU mortality in patients with shock (3). However, despite a paucity of supporting evidence, consensus guidelines and expert recommendations continued to recommend dopamine as an initial vasopressor in patients with shock (4,5).
Considering the lack of evidence to support a specific renal-protective effect of dopamine and observational data that supported the use of norepinephrine, the SOAP II investigators compared the two agents as first-line vasopressor in patients with shock (6).
Population and design
The SOAP II trial was conducted between December 2003, and October 2007, across eight ICUs in Belgium, Austria, and Spain. The investigators randomly assigned patients with shock to receive dopamine or norepinephrine as the initial vasopressor. Clinicians and nursing staff who administered the drugs were unaware of the treatment assignment.
Adult patients >18 years who required vasopressors for shock were included.
Patients were considered to be in shock if the mean arterial pressure was <70 mm Hg or systolic BP <100 mm Hg after adequate fluid resuscitation with at least 1000 ml crystalloids or 500 ml colloids. Besides, signs of hypoperfusion were present, characterized by altered sensorium, skin mottling, urine output <0.5 ml/kg for 1 hour, or a lactate level of >2mmol/l.
Exclusions
Patients who had already received a vasopressor for >4 hours, had a severe arrhythmia, and those who had been declared brain dead were excluded.
Dopamine group
The dopamine dose was titrated by 2 mcg/kg/min at a time to a target blood pressure based on clinician judgment. Open-label norepinephrine was administered if the dose exceeded 20 mcg/kg/min.
Norepinephrine group
The dose was titrated by 0.02 mcg/kg/min to attain the target blood pressure. Open-label norepinephrine was administered if a maximal dose of 0.19 mcg/kg/min was reached.
Common management
Open-label dopamine was not allowed. Any vasopressor that was already being infused before study entry was replaced with the trial drug. Epinephrine or vasopressin could be used as rescue therapy based on clinician judgment. Inotropic agents could be administered specifically to improve the cardiac output at clinician discretion. Once hemodynamic stability was achieved, any open-label norepinephrine was weaned down first, followed by the study drug. If hypotension recurred after initial cessation of vasopressors, the study drug was reintroduced as the first option; open-label norepinephrine was added if required. The study protocol was followed for a maximum duration of 28 days. If an adverse event occurred, the patient could be withdrawn from the study and administered open-label vasopressor based on clinician discretion. All other aspects of care were left to clinician judgment.
Sample size
In the earlier SOAP observational trial, the mortality rate in the dopamine group was 43% compared with 36% in the norepinephrine group. Based on this finding, the authors calculated a sample size of 765 patients in each arm, assuming a 15% relative difference in the 28-day mortality. This sample size provided 80% power at a two-sided alpha level of 0.05.
Results
The study enrolled 1679 of the 2011 patients (83.5%) who were screened. In the dopamine group, 858 patients were included, compared with 821 patients in the norepinephrine group. All patients were followed up for 28 days. The baseline characteristics were similar. The median APACHE score was 20 and the median SOFA score, 9 in both groups. The most common cause of shock was septic (dopamine vs. norepinephrine: 63.2% vs. 61.1%), followed by cardiogenic shock (15.7% vs. 17.6%). In the dopamine group, 71.7% of patients were mechanically ventilated compared with 70.6% in the norepinephrine group. The mean arterial pressure was similar at baseline in both groups. Open-label norepinephrine was more often required in the dopamine group. The mean time taken to attain the target MAP was similar in both groups. The volume of fluid administered was similar in both groups. The urine output was higher in the dopamine group only in the first 24 hours; the fluid balance was similar in both groups. Dopamine-treated patients experienced more tachycardia for up to 36 hours after randomization. Similar changes were observed in the cardiac index, central venous pressure, venous oxygen saturation, and lactate levels in both groups.
Corticosteroids were administered in a similar number of patients in both groups. Recombinant activated protein C (drotrecogin alpha), considered to improve outcomes in sepsis based on the PROWESS trial, was in use during the study period; however, its use was similar in both groups of patients.
The primary outcome: 28-day mortality
There was no significant difference in the 28-day mortality between the dopamine and norepinephrine groups (52.5% vs. 48.5%, p = 0.10). On subgroup analysis, dopamine use was associated with a significantly higher 28-day mortality in patients with cardiogenic shock. There was no difference in mortality among patients with hypovolemic or septic shock.
Secondary outcomes
Among the secondary outcomes, the 6- and 12-month mortality were also similar in both groups. The ICU mortality, hospital mortality, and the length of stay in the ICU and hospital were also similar. The number of ICU-free and organ support-free days were not significantly different. Death from refractory shock was more common among dopamine-treated patients
Adverse events
Arrhythmias occurred in 18.4% of patients, the most common being atrial fibrillation (86%). Patients in the dopamine group revealed a higher incidence of arrhythmia, particularly atrial fibrillation. Dopamine was discontinued in 6.1% of patients compared due to the onset of severe arrythmias while norepinephrine was discontinued in 1.6% of patients. Other adverse events, including myocardial infarction, new-onset infections, arterial occlusion, and ischemic events were similar in both groups.
Strengths
The SOAP II trial was adequately powered to evaluate the primary outcome of 28-day mortality. Of the 2011 patients screened, 1679 were randomized (83.5%); this constitutes a fairly high recruitment rate for a large RCT. Patients were well-matched at baseline, with a fairly high severity of illness, typical of a high acuity ICU. All patients were followed up until 28 days; hospital outcomes were available in 98.6% patients, adding to the strength of the study. The multicentric design also provides a high level of external validity.
The trial was conducted during the period when the American College of Cardiology – American Heart Association guidelines used to recommend dopamine as the preferred drug to increase arterial blood pressure in patients who were hypotensive following acute myocardial infarction (7). In a multicentric, adequately powered RCT, the SOAP II trial vehemently challenged this recommendation – in fact, the 28-day mortality was higher among patients with cardiogenic shock who received dopamine compared with norepinephrine support. Currently, the Surviving Sepsis Guidelines recommend norepinephrine as the first-line vasopressor in patients with septic shock (8). The American Heart Association also supports norepinephrine in cardiogenic shock, with dopamine as a second line agent (9).
Limitations
Initial fluid resuscitation with 1.0 l of crystalloid or 500 ml of colloid was considered adequate. A fixed volume of fluid resuscitation is debatable considering the heterogeneity associated with diverse types of shock. Clearly, hypovolemic or septic patients require a larger, often variable resuscitation volume; in contrast, volume resuscitation would be restricted in cardiogenic shock. However, the authors did not suggest any methodology to specifically evaluate volume responsiveness.
The target mean arterial pressure was based on clinician judgment, and may have cofounded the study findings.
A dose of 20 mcg/kg/min of dopamine was considered equipotent to 0.19 mcg/kg/min of norepinephrine. The authors offered no evidence to support the presumed equivalence of these doses.
Specific criteria, including an altered mental state, mottled skin, oliguria, and high serum lactate levels were employed to define shock. However, the assessment of shock resolution appears to have been more subjective, and perhaps prone to bias.
Details of specific interventions – including supportive measures like use of the intra-aortic balloon pump or coronary revascularization in cardiogenic shock were not available. This may be relevant as 9.6% of patients had acute myocardial infarction. In patients with septic shock, the authors did not provide details on the source control interventions or the appropriateness of antibiotic therapy.
Subsequent studies
In a retrospective cohort study, Fawzy et al. sought to evaluate factors associated with choice and outcomes with dopamine compared with norepinephrine as initial vasopressor in septic shock. Most clinicians preferred norepinephrine as the first line vasopressor (77%). Dopamine seemed to be more in favor with cardiologists and more often used in non-teaching hospitals and in older patients with higher baseline co-morbidities. On propensity-matched analysis, dopamine use was associated with increased hospital mortality (10).
A Cochrane review analyzed 28 studies comparing vasopressors in hypotensive shock. Only four RCTs fulfilled the quality criteria. No difference in mortality was observed when vasopressor regimens were compared. However, arrhythmias were more commonly observed with dopamine compared with norepinephrine.
Summary
Dopamine, an endogenous catecholamine, had been in use for decades for its presumed protective effect on the kidneys. This presumption was based on its potential to induce renal vasodilatation and improve renal blood flow at low doses. However, these favorable findings were largely confined to experimental studies involving animals and human volunteers. A dose-specific effect could not be discerned in critically ill patients. An increase in the urine output was observed in some studies, but not been consistently evident. The ANZICS dopamine trial could identify no kidney-specific effect, with similar peak creatinine levels and no difference in the requirement for renal replacement therapy in dopamine compared with placebo-treated patients. In the SOAP observational trial that followed, dopamine was found to be an independent predictor of mortality. Despite the dubious rationale, many guidelines continued to recommend dopamine as the preferred vasopressor in shock.
The SOAP II study, in a large, multicentric RCT, demonstrated no improvement in survival with dopamine compared with norepinephrine in patients with shock. The most striking finding was the increase in the 28-day mortality with dopamine among patients with cardiogenic shock. The SOAP II trial led to revised guidelines, with many recommending norepinephrine in preference to dopamine, triggering the decline of an all-pervasive, albeit irrational practice.
References
1. Dasta JF, Kirby MG. Pharmacology and therapeutic use of low-dose dopamine. Pharmacotherapy. 1986;6(6):304–10.
2. Bellomo R, Chapman M, Finfer S, Hickling K, Myburgh J. Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Lancet Lond Engl. 2000 Dec 23;356(9248):2139–43.
3. Sakr Y, Reinhart K, Vincent JL, Sprung CL, Moreno R, Ranieri VM, et al. Does dopamine administration in shock influence outcome? Results of the Sepsis Occurrence in Acutely Ill Patients (SOAP) Study. Crit Care Med. 2006 Mar;34(3):589–97.
4. Antman EM, Anbe DT, Armstrong PW, Bates ER, Green LA, Hand M, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction; A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of patients with acute myocardial infarction). J Am Coll Cardiol. 2004 Aug 4;44(3):E1–211.
5. Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Intensive Care Med. 2008 Jan;34(1):17–60.
6. De Backer D, Biston P, Devriendt J, Madl C et al; SOAP II Investigators. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med. 2010 Mar 4;362(9):779-89
7. Antman EM, Anbe DT, Armstrong PW, Bates ER, Green LA, Hand M, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction–executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction). Circulation. 2004 Aug 3;110(5):588–636.
8. Evans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM, French C, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Crit Care Med. 2021 Nov;49(11):e1063.
9. Vahdatpour C, Collins D, Goldberg S. Cardiogenic Shock. J Am Heart Assoc. 2019 Apr 16;8(8):e011991.
10. Fawzy A, Evans SR, Walkey AJ. Practice Patterns and Outcomes Associated with Choice of Initial Vasopressor Therapy for Septic Shock. Crit Care Med. 2015 Oct;43(10):2141–6.
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