EBNEO COMMENTARY: NOREPINEPHRINE VERSUS DOPAMINE FOR SEPTIC SHOCK IN NEONATES: A RANDOMIZED CONTROLLED TRIAL

Gabriel Altit from Canada www.theneocardiolab.com reviews the April Article of the Month "Mazhari MYA, Priyadarshi M, Singh P, Chaurasia S, Basu S. Norepinephrine versus Dopamine for Septic Shock in Neonates: A Randomized Controlled Trial. J Pediatr 2025;282:114599. https://doi.org/10.1016/j.jpeds.2025.114599. PMID 40252959." for ebneo.org.

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ACTA COMMENTARY:

Acta Paediatrica - 2025 - Altit - EBNEO Commentary Review of the Norepinephrine Versus Dopamine for Septic Shock in.pdf

"The randomized controlled trial by Mazhari et al. provides valuable comparative data on norepinephrine versus dopamine as first-line agents in neonatal fluid-refractory septic shock1. Despite these insights, several important limitations temper the interpretation of the findings. The study population included both term and preterm infants with a wide range of gestational ages and clinical presentations. The diagnosis of septic shock relied largely on clinical judgment, often in the absence of culture confirmation, with nearly half of participants classified as having “clinical sepsis.” This introduces a risk of misclassification bias and limits internal validity. Standardized sepsis scoring systems or objective definitions for endpoints such as “shock reversal” were not applied, raising concerns about subjectivity, particularly given the reliance on variable clinical signs such as capillary refill or pulse quality.

 The primary outcome—shock reversal within 30 minutes—may not be physiologically meaningful in neonates, where hemodynamic responses are dynamic and may evolve over a longer period2. Recruiting infants already in a decompensated state of shock likely contributed to the high mortality rate and may have hindered the ability to assess early treatment effects. The absence of echocardiographic assessment to characterize shock phenotypes is another key limitation. Neonatal septic shock is often hemodynamically complex, involving a mix of vasodilatory and cardiogenic features, sometimes exacerbated by persistent fetal shunts or elevated pulmonary vascular resistance2, 3. Without phenotypic stratification, it is difficult to determine whether either drug was more effective for specific shock subtypes.

 Methodologically, the trial used appropriate randomization and blinding strategies, but lacked standardization in critical aspects of drug delivery. Practical variables—such preparation site (bedside vs. pharmacy), carrier fluid use—were not described, which could introduce variability affecting drug efficacy. While the study measured cerebral regional oxygen saturation (CrSO₂), it did not report fractional tissue oxygen extraction (FTOE), which would have provided a more integrative index of oxygen delivery and utilization. Although CrSO₂ at 24 hours was significantly higher in the norepinephrine group (76.0 ± 7.3% vs. 69.5 ± 7.7%, p < 0.01), its clinical significance is unclear. CrSO₂ is influenced not only by perfusion but also by metabolic demand; higher values may reflect reduced cerebral metabolism rather than improved perfusion, potentially signaling adverse neurological effects4, 5.

 The study also suffers from the common pitfall of multiple unadjusted comparisons, increasing the risk of type I error. Without statistical correction strategies (e.g., Bonferroni adjustment or false discovery rate control), any significant secondary outcome must be interpreted with caution. Ideally, these findings should have been clearly framed as exploratory. Generalizability is another concern. All patients were enrolled at a single tertiary center in India, where microbial epidemiology and clinical practices differ from those in high-income settings. Pathogens were predominantly gram-negative, including Klebsiella pneumoniae, Acinetobacter spp., and E. coli, with no reported cases of Group B Streptococcus. The feasibility of conducting such a trial in this setting is commendable; however, the consent process (e.g., deferred or opt-out strategies) was not detailed, which is an important ethical consideration in acutely ill neonates. The average gestational age of participants was 33.2 weeks in both treatment arms, indicating that extremely preterm infants (<28 weeks’ gestation) were largely excluded. As such, the findings may not apply to this particularly vulnerable subgroup or to neonates with different underlying sepsis etiologies."