Therapeutic Hyperthermia Is Associated With Improved Survival in Afebrile Critically Ill Patients With Sepsis: A Pilot Randomized Trial

Abstract

Objectives: To test the hypothesis that forced-air warming of critically ill afebrile sepsis patients improves immune function compared to standard temperature management.

Design: Single-center, prospective, open-label, randomized controlled trial.

Setting: One thousand two hundred-bed academic medical center.

Patients: Eligible patients were mechanically ventilated septic adults with: 1) a diagnosis of sepsis within 48 hours of enrollment; 2) anticipated need for mechanical ventilation of greater than 48 hours; and 3) a maximum temperature less than 38.3°C within the 24 hours prior to enrollment. Primary exclusion criteria included: immunologic diseases, immune-suppressing medications, and any existing condition sensitive to therapeutic hyperthermia (e.g., brain injury). The primary outcome was monocyte human leukocyte antigen (HLA)-DR expression, with secondary outcomes of CD3/CD28-induced interferon gamma (IFN-γ) production, mortality, and 28-day hospital-free days.

Interventions: External warming using a forced-air warming blanket for 48 hours, with a goal temperature 1.5°C above the lowest temperature documented in the previous 24 hours.

Measurements and main results: We enrolled 56 participants in the study. No differences were observed between the groups in HLA-DR expression (692 vs 2,002; p = 0.396) or IFN-γ production (31 vs 69; p = 0.678). Participants allocated to external warming had lower 28-day mortality (18% vs 43%; absolute risk reduction, 25%; 95% CI, 2-48%) and more 28-day hospital-free days (difference, 2.6 d; 95% CI, 0-11.6).

Conclusions: Participants randomized to external forced-air warming did not have a difference in HLA-DR expression or IFN-γ production. In this pilot study, however, 28-day mortality was lower in the intervention group. Future research should seek to better elucidate the impact of temperature modulation on immune and nonimmune organ failure pathways in sepsis.

Trial registration: ClinicalTrials.gov NCT02706275.

Figure 1.. Temperature in the treatment and control groups.

The curves shown demonstrate the separation of temperatures between the therapeutic hyperthermia (squares) group and the usual care (circles) group. The points represent the group mean temperature at each time point, and the error bars represent standard deviation. deg C, degrees Celsius.

Figure 2.. Immune Outcomes.

This figure details the differences in immune parameters between the therapeutic hyperthermia (Warming) and usual care (Control) groups. All bars show the mean value for each group, and the error bars represent the standard deviation. A. HLA-DR expression. B. Lymphopenia observed on each day of observation (among participants who had an absolute lymphocyte count recorded on any given day. C. IFN-γ spot number (representing number of cells producing IFN-γ). D. IFN-γ spot area. HLA, human leukocyte antigen; IFN, interferon; SFU, spot-forming unit.

Figure 3.. Survival curve.

This Kaplan-Meier plot shows the proportion of participants in each group alive at each time point through 28 days. The a priori defined secondary outcome was the dichotomous variable 28-day mortality (18% vs. 43%, absolute risk reduction 25%, 95% CI 2–48%).