A103-22 Optimal Vasopressor Choice in Septic Shock With Tachycardia: A Target Trial Emulation Determining the Comparative Effectiveness of Phenylephrine vs. Norepinephrine

Rationale

Norepinephrine (NE) is the recommended first-line vasopressor for septic shock. However, clinicians often substitute phenylephrine (PE) in patients with significant tachycardia (sinus tachycardia or atrial fibrillation), hypothesizing that PE’s lack of beta-adrenergic activity will mitigate arrhythmia risk and improve hemodynamic stability. Despite this common physiologic rationale, high-quality evidence comparing these agents specifically in the “tachycardia phenotype” is scarce. We aimed to determine if initiating PE improves 28-day mortality compared to NE in patients with septic shock presenting with tachycardia.

Methods

We performed a target trial emulation using the Medical Information Mart for Intensive Care IV (MIMIC-IV) database (v3.1). We identified adult patients meeting Sepsis-3 criteria requiring vasopressors who exhibited a “Tachycardia Phenotype,” defined as a median heart rate >100 bpm in the 2 hours preceding vasopressor initiation. The primary exposure was the initial vasopressor selected (PE vs. NE). The primary outcome was 28-day mortality; secondary outcomes included new-onset arrhythmia, renal replacement therapy (RRT) use, and ventilator-free days. To rigorously adjust for confounding by indication, we employed Targeted Maximum Likelihood Estimation (TMLE) with SuperLearner ensemble learning to estimate the Adjusted Risk Difference (RD).

Results

The final cohort included 2,281 patients (1,558 NE, 723 PE). In the primary TMLE analysis shown, phenylephrine use was not associated with a reduction in 28-day mortality compared to norepinephrine (Adjusted RD 0.5%; 95% CI -4.0% to 5.1%; p = 0.816). Consistent with this, adjusted survival curves showed overlapping trajectories with no significant separation between groups (p = 0.14). Conversely, phenylephrine was associated with a statistically significant increase in the risk of arrhythmia events (Adjusted RD + 5.2%; 95% CI 0.6% to 9.9%; p = 0.026). Phenylephrine was also associated with significantly fewer ventilator-free days (Mean Difference -1.28 days; p = 0.021). Results are summarized in the accompanying Figure.

Conclusions

In this target trial emulation of septic shock patients with tachycardia, the use of phenylephrine as a first-line vasopressor provided no survival benefit compared to norepinephrine. Phenylephrine was associated with a significantly higher risk of arrhythmia events and worse respiratory outcomes, challenging the widespread physiologic assumption that alpha-only agonism is protective in tachycardic patients. These findings support the continued use of norepinephrine as the standard of care, regardless of baseline heart rate.

This abstract is funded by: None