Effect of a Resuscitation Strategy Targeting Peripheral Perfusion Status vs Serum Lactate Levels on 28-Day Mortality Among Patients With Septic Shock: The ANDROMEDA-SHOCK Randomized Clinical Trial

Abstract

Importance: Abnormal peripheral perfusion after septic shock resuscitation has been associated with organ dysfunction and mortality. The potential role of the clinical assessment of peripheral perfusion as a target during resuscitation in early septic shock has not been established.

Objective: To determine if a peripheral perfusion-targeted resuscitation during early septic shock in adults is more effective than a lactate level-targeted resuscitation for reducing mortality.

Design, setting, and participants: Multicenter, randomized trial conducted at 28 intensive care units in 5 countries. Four-hundred twenty-four patients with septic shock were included between March 2017 and March 2018. The last date of follow-up was June 12, 2018.

Interventions: Patients were randomized to a step-by-step resuscitation protocol aimed at either normalizing capillary refill time (n = 212) or normalizing or decreasing lactate levels at rates greater than 20% per 2 hours (n = 212), during an 8-hour intervention period.

Main outcomes and measures: The primary outcome was all-cause mortality at 28 days. Secondary outcomes were organ dysfunction at 72 hours after randomization, as assessed by Sequential Organ Failure Assessment (SOFA) score (range, 0 [best] to 24 [worst]); death within 90 days; mechanical ventilation-, renal replacement therapy-, and vasopressor-free days within 28 days; intensive care unit and hospital length of stay.

Results: Among 424 patients randomized (mean age, 63 years; 226 [53%] women), 416 (98%) completed the trial. By day 28, 74 patients (34.9%) in the peripheral perfusion group and 92 patients (43.4%) in the lactate group had died (hazard ratio, 0.75 [95% CI, 0.55 to 1.02]; P = .06; risk difference, -8.5% [95% CI, -18.2% to 1.2%]). Peripheral perfusion-targeted resuscitation was associated with less organ dysfunction at 72 hours (mean SOFA score, 5.6 [SD, 4.3] vs 6.6 [SD, 4.7]; mean difference, -1.00 [95% CI, -1.97 to -0.02]; P = .045). There were no significant differences in the other 6 secondary outcomes. No protocol-related serious adverse reactions were confirmed.

Conclusions and relevance: Among patients with septic shock, a resuscitation strategy targeting normalization of capillary refill time, compared with a strategy targeting serum lactate levels, did not reduce all-cause 28-day mortality.

Trial registration: ClinicalTrials.gov Identifier: NCT03078712.

Figure 1.. Flow of Participants Through the Study

^aAmong the 87 patients eligible but not enrolled because of other reasons, 55 were not enrolled because of logistic issues (lack of personnel, multiple simultaneous admissions) and 32 because of delay in transfer from the emergency department to the intensive care unit after meeting criteria and then losing the window of intervention.

Figure 2.. Kaplan-Meier Estimates of Cumulative Mortality Within 28 Days Among Patients Treated With Peripheral Perfusion–Targeted Resuscitation vs Lactate Level–Targeted Resuscitation

Hazard ratio, 95% confidence interval, and P value were calculated with a Cox proportional hazards model that included as covariates baseline Acute Physiology and Chronic Health Evaluation (APACHE) II score, Sequential Organ Failure Assessment (SOFA) score, lactate level, capillary refill time, and source of infection. Median follow-up for peripheral perfusion–targeted resuscitation was 28 days (interquartile range, 8-28 days) and for lactate level–targeted resuscitation was 28 days (interquartile range, 6-28 days).

Figure 3.. Risk of Death Within 28 Days in the Prespecified Subgroups Among Patients Treated With Peripheral Perfusion–Targeted Resuscitation vs Lactate Level–Targeted Resuscitation

The area of the square representing the hazard ratio is proportional to the number of events in each subgroup. Horizontal bars represent 95% CI. P values are for heterogeneity of treatment effect on the primary outcome in each subgroup. Hazard ratios and 95% CIs were calculated with Cox proportional hazards model adjusted for the baseline covariates Acute Physiology and Chronic Health Evaluation (APACHE) II score, Sequential Organ Failure Assessment (SOFA) score, lactate level, capillary refill time, and source of infection. P values were calculated with treatment × subgroup interaction terms. See Table 1 notes for APACHE II and SOFA definitions.

Figure 4.. Organ Dysfunction During the First 72 Hours After Randomization Among Patients Treated With Peripheral Perfusion–Targeted Resuscitation vs Lactate Level–Targeted Resuscitation

This post hoc analysis is a mixed linear regression considering patient as random effect and adjusting for baseline Sequential Organ Failure Assessment (SOFA) score. P < .001 for mean SOFA score treatment × time interaction within 72 hours. Organ dysfunction assessed by SOFA score at baseline and 8, 24, 48, and 72 hours after randomization. SOFA scores range from 0 to 24, with higher scores indicating a greater severity of organ dysfunction and risk of death. Box plots indicate 75th percentile (top edge of box), 25th percentile (bottom edge of box), and 50th percentile (bold horizontal line in box); whiskers indicate minimum and maximum values up to 1.5 times the interquartile range from the quartiles; circles indicate values that exceed 1.5 times the interquartile range.