<scp>EBNEO</scp> Commentary: Review of the ‘Norepinephrine Versus Dopamine for Septic Shock in Neonates: A Randomised Controlled Trial’

The randomised controlled trial by Mazhari et al. provides valuable comparative data on norepinephrine versus dopamine as first-line agents in neonatal fluid-refractory septic shock [1]. 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 judgement, 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. Standardised 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 min—may not be physiologically meaningful in neonates, where haemodynamic responses are dynamic and may evolve over a longer period [2]. 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 characterise shock phenotypes is another key limitation. Neonatal septic shock is often haemodynamically complex, involving a mix of vasodilatory and cardiogenic features, sometimes exacerbated by persistent fetal shunts or elevated pulmonary vascular resistance [2, 3]. Without phenotypic stratification, it is difficult to determine whether either drug was more effective for specific shock subtypes. Methodologically, the trial used appropriate randomisation and blinding strategies, but lacked standardisation in critical aspects of drug delivery. Practical variables—such as 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 utilisation. Although CrSO2 at 24 h 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 signalling adverse neurological effects [4, 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. Generalisability is another concern. All patients were enrolled at a single tertiary centre 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 aetiologies. URL LINK: https://ebneo.org/ebneo-commentary-norepi-vs-da-for-septic-shock. Gabriel Altit: conceptualization, writing – original draft, writing – review and editing, resources, validation. The author declares no conflicts of interest. The author has nothing to report.

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