Heterogeneity in the response to a high vs low mean arterial pressure target in patients with septic shock a post hoc analysis of a randomized controlled trial

Abstract

Background: The best blood pressure target in sepsis is a matter of debate. SEPSIS-PAM, a large multicenter pragmatic randomized controlled trial, compared two mean arterial pressure targets (65-70 mmHg vs 80-85 mmHg) in septic shock and did not find any difference in mortality. The goal of this study was to assess whether (i) heterogeneity of treatment effect (HTE) exists in the response to different targets and (ii) the initial clinical trajectory can inform the optimal blood pressure target.

Methods: The primary outcome was mortality at day 28. Secondary outcomes included mortality at day 90, acute kidney injury (AKI), and severe AKI based on the KDIGO classification, need for renal replacement therapy, renal replacement therapy, and vasopressor-free days. The presence of HTE was tested for and, if present, quantified. The interaction between post-randomization evolution of the MAP, norepinephrine requirements, lactate, mottling score, and urine output was estimated using a multimediation analysis.

Results: 776 patients were enrolled and analyzed in this study. There was no evidence of significant treatment effect heterogeneity based on baseline characteristics (sweep p-value = 0.664; 95% CI: 0.633-0.673). The direct effect of a higher MAP target on mortality, holding 24 h mediators at their control-level values, was not significant (RD = 0.017; 95% CI - 0.052 to 0.086; p = 0.62). However, if reaching a higher MAP required high norepinephrine doses and/or did not result in mottled skin resolution at 24 h, the effect transmitted through those mediators was associated with higher mortality (risk difference = 0.027; 95% CI 0.012-0.047 and 0.012; 95% CI 0.001-0.026).

Conclusion: Our results suggest the absence of heterogeneity of the response to different blood pressure targets in patients with septic shock. Targeting a higher MAP target may be associated with harm when high norepinephrine doses are required or when mottled skin is present.

Trial registration: SEPSISPAM ClinicalTrials.gov number, NCT01149278.

Keywords: Blood pressure; Heterogeneity; Indivisualized; Sepsis; Shock; Target.