Epinephrine Tied to Greater Mortality in Pediatric Septic Shock Than Norepinephrine

A recent study showed children with septic shock on epinephrine had a greater 30-day mortality but no difference in major adverse kidney events by 30 days (MAKE30) than those receiving norepinephrine as the first vasoactive medication.1

“Our findings suggest that norepinephrine was associated with a benefit in terms of the mortality component, but not the renal component, of MAKE30,” wrote investigators, led by Matthew A. Eisenberg, MD, MPH, Boston Children’s Hospital.

The 2020 Surviving Sepsis Campaign International Guidelines recommend epinephrine or norepinephrine over dopamine for children with septic shock.2 The revised guidelines followed 2 clinical trials showing lower mortality and fewer organ failure days when on epinephrine versus dopamine.

However, epinephrine and norepinephrine have limited head-to-head comparisons in pediatric septic shock. While norepinephrine is the first-line agent for adult septic shock, no consensus exists for children. Investigators aimed to determine whether either agent was associated with better outcomes in pediatric septic shock without known cardiac dysfunction.1

They conducted a single-center, retrospective cohort study with 231 children aged 1 month to 18 years (mean age, 11.4 years; 54.6% females) diagnosed with septic shock and requiring a vasoactive infusion within 24 hours of emergency department arrival. Participants received either epinephrine (63.6%) or norepinephrine (36.4%) at a freestanding quaternary care children’s hospital between June 1, 2017, and December 31, 2023. Among them, 61.5% had a medical history that predisposed them to sepsis.

Investigators analyzed the data from March to December 2024. The primary outcome was MAKE30. Secondary outcomes included 30-day in-hospital mortality, 3-day mortality, need for kidney replacement therapy or persistent kidney dysfunction, endotracheal intubation, mechanical ventilation days, extracorporeal membrane oxygenation, and hospital and ICU length of stay.

The study found 6.1% (n = 9) of patients on epinephrine reached MAKE30, compared with 3.6% on norepinephrine. Although more patients on epinephrine had major adverse kidney events, inverse probability of treatment weighting showed no significant differences between groups for MAKE30.

However, with 2:1 propensity matching, epinephrine was linked to a greater 30-day mortality with 6 deaths (3.7%) versus none in the norepinephrine arm (risk difference, 3.7%; 95% confidence interval [CI], 0.2 – 7.2%).

The mechanism linking norepinephrine to lower mortality remains unclear. Investigators noted that norepinephrine and epinephrine both stimulate the peripheral α-1 adrenergic receptors, although epinephrine has a stronger affinity for the B-1 and B-2 receptors. Due to this, norepinephrine is a stronger vasoconstrictor, and epinephrine is a stronger inotropic agent.

Additionally, norepinephrine increases the preload and cardiac output, while epinephrine may raise metabolic and cardiac complication risk.

Findings suggest a survival benefit of using norepinephrine as a first-line treatment in pediatric septic shock.

“Notably, the findings align with a recent open-label randomized clinical trial of children with fluid-refractory septic shock and clinical signs of cold shock (cool extremities, delayed capillary refill time, diminished pulses, narrow pulse pressure) that found first-line norepinephrine (combined with dobutamine) led to a shorter time to shock resolution than first-line epinephrine,” wrote Scott L. Weiss, MD, MSCE, from Nemours Children’s Hospital in Delaware, in a commentary paper.2

Weiss noted patients on norepinephrine received medication later in resuscitation compared with those receiving epinephrine (median, 7.5 hours vs 3.6 hours). Additionally, patients on norepinephrine were more frequently in the ICU (65% vs 22%).

“It is possible that the norepinephrine group was enriched with patients who presented with lower severity of illness for whom vasoactive initiation could be delayed,” Weiss wrote.

Weiss emphasized there may not be a universal first-line vasoactive treatment for children, as sepsis pathophysiology varies—hypovolemic, cardiogenic, distributive, or dysoxic.

“For now…it remains reasonable to initiate either epinephrine or norepinephrine as a first-line vasoactive medication in children with septic shock without known cardiac dysfunction,” Weiss wrote. “Perhaps more important than the initial vasoactive agent is close attention to the physiologic response to that agent so that the chosen treatment plan is not blindly pushed forward without consideration of alternative approaches if the expected clinical improvement is not observed. After all, it is how you finish that counts, not how you start.”

References

1. Eisenberg MA, Georgette N, Baker AH, Priebe GP, Monuteaux MC. Epinephrine vs Norepinephrine as Initial Treatment in Children With Septic Shock. JAMA Netw Open. 2025;8(4):e254720. doi:10.1001/jamanetworkopen.2025.4720

2. Weiss SL. Vasoactive Selection for Pediatric Septic Shock—Where to Begin? JAMA Netw Open. 2025;8(4):e254726. doi:10.1001/jamanetworkopen.2025.4726