Early norepinephrine was associated with faster control of septic shock

Three-quarters of patients in a trial group who received norepinephrine soon after ED arrival (a median of 93 minutes) had septic shock controlled within six hours, compared to only about half of those receiving standard care.

Patients with sepsis and hypotension were more likely to have their shock controlled within six hours if they received early norepinephrine therapy, according to a new study.

The single-center trial included 310 patients diagnosed with sepsis with hypotension at a hospital in Thailand. They were randomized to either early norepinephrine (4 mg mixed with 250 mL of 5% dextrose in water) or placebo. If mean arterial blood pressure didn't reach 65 mm Hg after the patient had received at least 30 mL/kg of fluid and the study drug infusion, open-label vasopressors were permitted when no attenuation of shock was observed.

The study's primary outcome was shock control by six hours after diagnosis (defined as mean arterial blood pressure >65 mm Hg and either urine flow >0.5 mL/kg/h for two consecutive hours or serum lactate level decreased >10% from baseline). Results were published by the American Journal of Respiratory and Critical Care Medicine on Feb. 1.

Patients in the early norepinephrine group received the drug a median of 93 minutes after arrival at the ED, compared to 192 minutes in the standard therapy group (P<0.001). Significantly more of them achieved shock control by six hours (118 of 155 [76.1%] vs. 75 of 155 [48.4%]; P<0.001). Early norepinephrine was also associated with lower incidence of cardiogenic pulmonary edema (14.4% vs. 27.7%; P=0.004) and new-onset arrhythmia (11% vs. 20%; P=0.03). The rate of 28-day mortality was 15.5% in the early norepinephrine group and 21.9% in the standard treatment group, a nonsignificant difference (P=0.15).

The authors believe this to be the first study to assess the benefit of early norepinephrine for sepsis-related hypotension that looked at surrogate, short-term, shock control endpoints. They noted that the studied endpoints measure restoration of both macro- and microcirculation. The study had a number of limitations, including the inability to mask the effect of the norepinephrine, lack of control over the fluid resuscitation rates, and uncertain generalizability outside this single center.

“Further studies are needed to confirm these findings before this approach can be introduced in clinical resuscitation practice,” the authors said. Such research should investigate the effect of early norepinephrine on organ dysfunction and on mortality, which was not a prespecified outcome of this trial.