Apr 072019

Guidelines advise physicians give large boluses of intravenous crystalloid infusions (two to three liters, generally) to patients with septic shock. Vasopressors are typically begun only if patients' blood pressure remains low after fluid administration.

A vocal minority of researchers have advised against delaying vasopressors in septic shock, arguing that norepinephrine, not intravenous fluid, is the most effective initial treatment to correct the loss of vascular tone ("vasoplegia") from septic shock. Aggressive intravenous fluids mainly serve to overload patients with volume, precipitating pulmonary edema, respiratory failure, and mechanical ventilation -- complications which might be avoidable in many patients.

A new randomized trial provides food for thought supporting the minority opinion, but its single-center design, conducted outside the U.S. with imbalance between groups limit any meaningful conclusions.

Investigators randomized 310 patients with septic shock at one hospital in Bangkok, Thailand to receive norepinephrine or placebo along with their initial fluid resuscitation. Unfortunately, patients randomized to norepinephrine received the intervention much faster than those receiving placebo (93 vs 192 minutes) -- raising questions as to adequate blinding or other significant methodologic flaws.

That being said, patients receiving early norepinephrine did better:

  • Shock control rate by 6 hours (primary outcome) was significantly higher with early norepinephrine (76% vs 48%; P<0.001).
  • The early norepinephrine group had lower rates of cardiogenic pulmonary edema (14% vs 28%; P=0.004) and arrhythmia (11% vs 20%; P=0.03).

28-day mortality was not statistically different between groups: 15.5% in the early norepinephrine group versus 22% in the standard treatment group (P=0.15).

One theoretical reason to prioritize volume resuscitation prior to vasopressor administration is to avoid hypoperfusion to the gut or kidneys (if inadequate intravascular fluid is present, vasopressors could theoretically deprive these organs of blood flow). In this study, there was no difference in the rate of organ failure between groups.

More reasons not to draw strong conclusions from this study: not all patients were treated in the ICU, and resuscitation methods were not standardized (patients got differing infusion rates).

A much larger U.S-based trial testing early vasopressors in septic shock (CLOVERS) is currently recruiting, with plans to enroll up to 2,300 patients and an expected completion date of June 2021.

Source: Society journal

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Early norepinephrine improved septic shock, prevented pulmonary edema