Early Norepinephrine Stabilizes Septic Shock Patients Faster

The early use of norepinephrine in patients with septic shock was associated with increased shock control within 6 hours of diagnosis in a randomized, placebo-controlled trial conducted in Thailand.

Patients treated with early norepinephrine in the single-center, 310-patient study also showed about half the rate of cardiogenic pulmonary edema. But a trend toward improved 28-day survival did not achieve statistical significance.

The phase II randomized trial is the among the first to assess the benefits of early norepinephrine administration during sepsis-related hypotension resuscitation on surrogate shock control endpoints.

Writing in the American Journal of Respiratory and Critical Care Medicine, Chairat Permpikul, MD, of Mahidol University, Bangkok, Thailand, and colleagues, noted that additional studies will be needed to confirm the findings before early norepinephrine is introduced into clinical resuscitation practice.

“Future studies should investigate the effect of early norepinephrine on organ dysfunction and mortality,” they wrote.

In a press release, Permpikul explained that the early use of norepinephrine at the beginning of resuscitation has been widely advocated, including in the “Surviving Sepsis Campaign Bundle.”

“However, firm supporting evidence is lacking: therefore, we conducted a randomized control study to examine the precise benefits of administering norepinephrine at the beginning of sepsis/septic shock resuscitation.”

The study was conducted at a single hospital in Bangkok, Thailand, from October 2013 to March 2017. During this period, adult patients who presented to the emergency department with arterial blood pressure lower than 65 mm Hg and infection as the suspected cause were eligible for enrollment if they met the diagnostic criteria for sepsis according to the Surviving Sepsis Campaign’s 2012 guidelines and met other study entry requirements.

After enrollment, 310 patients were randomized 1:1 to receive either early norepinephrine or placebo along with fluid resuscitation at the initiation of hypotension resuscitation. The primary outcome was shock control rate, defined as achievement of mean arterial blood pressure ≥65 mm Hg, with urine flow ≥0.5 mL/kg/h for 2 consecutive hours, or decreased serum lactate ≥10% from baseline by 6 hours after diagnosis.

Patients in both groups were well matched in background characteristics and disease severity, but median time from emergency room arrival to norepinephrine administration was significantly shorter in the early norepinephrine group (93 vs 192 minutes; P<0.001).

Among the main findings:

• Shock control rate by 6 hours was significantly higher in early norepinephrine group (76.1% vs 48.4%; P<0.001).
• Twenty-eight day mortality was not different between groups: 15.5% in the early norepinephrine group versus 21.9% in the standard treatment group (P=0.15).
• The early norepinephrine group was associated with lower incidences of cardiogenic pulmonary edema (14.4% vs 27.7%; P=0.004) and new-onset arrhythmia (11% vs 20%; P=0.03).

“The results of our study, which is the first randomized controlled trial to investigate the effect of early norepinephrine, revealed a shorter shock interval in the early norepinephrine group than in the standard treatment group,” the researchers wrote.

They addressed the concern that early norepinephrine use could lead to vasoconstriction of abdominal organs leading to splanchnic hypoperfusion.

“Splanchnic hypoperfusion is an important concern when norepinephrine is given early,” they wrote. “Vasoconstriction induced by norepinephrine may aggravate internal organ ischemia and lead to patient deterioration. Recent studies examined this concern and revealed that norepinephrine did not alter perfusion to the gut and kidney. Although no objective measures were made in the present study, there was no difference in prevalence of organ failure between groups.”

Study limitations cited by the researchers include the fact it was conducted at a single hospital, not all patients were treated in the hospital’s ICU, and resuscitation fluid rates were not standardized, resulting in variations that may have biased results.

“Physicians who decide to apply the results of this study to their routine clinical practice should carefully evaluate the context of this study and compare it with their own situation and setting,” they concluded.

“A multicenter trial with a larger population size, control of the rate of fluid resuscitation, and the timing of norepinephrine initiation is certainly required to assess the survival benefit of early norepinephrine as an intervention.”