Update in intensive care medicine: Studies that challenged our practice in the last 5 years
ABSTRACTDuring the last 5 years, new randomized trials in critically ill patients have challenged a number of traditional treatment strategies in intensive care. The authors review eight studies that helped change their medical practices.
KEY POINTS
- In patients with acute respiratory distress syndrome (ARDS), fluid restriction is associated with better outcomes. A pulmonary arterial catheter is not indicated in the routine management of ARDS. Corticosteroid use can result in improved oxygenation but may be associated with worse outcomes if treatment is started late, ie, more than 14 days after the onset of the disease.
- Intensive insulin therapy is associated with hypoglycemia and may be associated with complications in medical patients.
- In patients with septic shock, corticosteroid therapy is associated with faster shock reversal, but its effects on mortality rates remain controversial. Vasopressin improves hemodynamic variables but is not associated with a lower mortality rate.
- Daily interruption of sedation and early awakening of mechanically ventilated patients result in better outcomes.
- Compared with norepinephrine, dopamine is associated with more cardiac adverse events in patients with shock.
VASOPRESSOR THERAPY IN SHOCK
Key points
- Vasopressin use in patients with severe septic shock is not associated with an improvement in mortality rates.
- Vasopressin should not be used as a first-line agent in patients with septic shock.
- Norepinephrine should be considered a first-line agent in patients with shock.
- Compared with norepinephrine, the use of dopamine in patients with shock is associated with similar mortality rates, although its use may result in a greater number of cardiac adverse events.
Background
Vasopressin gained popularity in critical care in the last 10 years because several small studies showed that adding it improves hemodynamics and results in a reduction in the doses of catecholamines in patients with refractory septic shock.22 Furthermore, the Surviving Sepsis Campaign guidelines recommended the use of vasopressin in patients who have refractory shock despite fluid resuscitation and the use of other “conventional” vasopressors.23
Despite these positive findings, it remained unknown if the use of vasopressin increases the survival rate in patients with septic shock.
The Vasopressin and Septic Shock Trial (VASST)
RUSSELL JA, WALLEY KR, SINGER J, ET AL; VASST INVESTIGATORS. VASOPRESSIN VERSUS NOREPINEPHRINE INFUSION IN PATIENTS WITH SEPTIC SHOCK. N ENGL J MED 2008; 358:877–887.
The Vasopressin and Septic Shock Trial (VASST)24 was a multicenter randomized, double-blind, controlled trial that included 778 patients with refractory septic shock. Refractory shock was defined as the lack of a response to a normal saline fluid bolus of 500 mL or the need for vasopressors (norepinephrine in doses of at least 5 μg/minute or its equivalent for 6 hours or more in the 24 hours before randomization).
Two subgroups were identified: those with severe septic shock (requiring norepinephrine in doses of 15 μg/minute or higher) and those with less-severe septic shock (needing norepinephrine in doses of 5 to 14 μg/minute). Patients with unstable coronary artery disease (acute myocardial infarction, angina) and severe congestive heart failure were excluded.
Patients were randomized to receive an intravenous infusion of vasopressin (0.01–0.03 U/minute) or norepinephrine (5–15 mg/minute) in addition to open-labeled vasopressors (excluding vasopressin). The primary outcome was the all-cause mortality rate at 28 days.
Results
At 28 days, fewer patients had died in the vasopressin group than in the norepinephrine group (35.4% vs 39.3%), but the difference was not statistically significant (P = .26). The trend was the same at 90 days (mortality rate 43.9% vs 49.6%, P = .11).
Subgroup analysis showed that in patients with less-severe septic shock, those who received vasopressin had a lower mortality rate at 28 days (26.5% vs 35.7%, P = .05; relative risk 0.74; 95% CI 0.55–1.01) and at 90 days (35.8% vs 46.1%, P = .04; relative risk 0.78, 95% CI 0.61–0.99).
There were no statistically significant differences in any of the other secondary outcomes or in serious adverse events.
Comments
The study has been criticized for several reasons:
- The mean arterial blood pressure at baseline before initiation of vasopressin was 72 mm Hg (and some argue that vasopressin was therefore not needed by the time it was started).
- The time from screening to infusion of the study drug was very long (12 hours).
- The observed mortality rate was lower than expected (37%).
Despite these considerations, the VASST trial showed that vasopressin is not associated with an increased number of adverse events in patients without active cardiovascular disease. The possible benefit in terms of the mortality rate in the subgroup of patients with less-severe septic shock requires further investigation.
Is dopamine equivalent to norepinephrine?
Previously, the Sepsis Occurrence in Acutely Ill Patients (SOAP) study, a multicenter, observational cohort study, found that dopamine use was associated with a higher all-cause mortality rate in the ICU compared with no dopamine.25 This finding had not been reproduced, as few well-designed studies had compared the effects of dopamine and norepinephrine.
The SOAP II study
DE BACKER D, BISTON P, DEVRIENDT J, ET AL; SOAP II INVESTIGATORS.. COMPARISON OF DOPAMINE AND NOREPINEPHRINE IN THE TREATMENT OF SHOCK. N ENGL J MED 2010; 362:779–789.
The SOAP II study,26 a multicenter, randomized trial, compared dopamine vs norepinephrine as first-line vasopressor therapy. In patients with refractory shock despite use of dopamine 20 μg/kg/minute or norepinephrine 0.19 μg/kg/minute, open-label norepinephrine, epinephrine, or vasopressin was added.
The primary outcome was the mortality rate at 28 days after randomization; secondary end points included the number of days without need for organ support and the occurrence of adverse events.
Results
A total of 1,679 patients were included; 858 were assigned to dopamine and 821 to norepinephrine. Most (1,044, 62%) of the patients had a diagnosis of septic shock.
No significant difference in mortality rates was noted at 28 days: 52.5% with dopamine vs 48.5% with norepinephrine (P = .10).
However, there were more arrhythmias in the patients treated with dopamine: 207 events (24.1%) vs 102 events (12.4%) (P < .001). The number of other adverse events such as renal failure, myocardial infarction, arterial occlusion, or skin necrosis was not different between the groups.
A subgroup analysis showed that dopamine was associated with more deaths at 28 days in patients with cardiogenic shock (P = .03) but not in patients with septic shock (P = .19) or with hypovolemic shock (P = .84).
Comments
The study was criticized because the patients may not have received adequate fluid resuscitation (the study considered adequate resuscitation to be equivalent to 1 L of crystalloids or 500 mL of colloids), as different degrees of volume depletion among patients make direct comparisons of vasopressor effects difficult.
Additionally, the study defined dopamine 20 μg/kg/minute as being equipotent with norepinephrine 0.19 μg/kg/minute. Comparisons of potency between drugs are difficult to establish, as there are no available data.
Nevertheless, this study further confirms previous findings suggesting that norepinephrine is not associated with more end-organ damage (such as renal failure or skin ischemia), and shows that dopamine may increase the number of adverse events, particularly in patients with cardiac disease.
