Seventy-two hours of mild hypothermia after cardiac arrest is associated with a lowered inflammatory response during rewarming in a prospective observational study

Abstract

Introduction: Whole-body ischemia and reperfusion trigger a systemic inflammatory response. In this study, we analyzed the effect of temperature on the inflammatory response in patients treated with prolonged mild hypothermia after cardiac arrest.

Methods: Ten comatose patients with return of spontaneous circulation after pulseless electrical activity/asystole or prolonged ventricular fibrillation were treated with mild therapeutic hypothermia for 72 hours after admission to a tertiary care university hospital. At admission and at 12, 24, 36, 48, 72, 96 and 114 hours, the patients' temperature was measured and blood samples were taken from the arterial catheter. Proinflammatory interleukin 6 (IL-6) and anti-inflammatory (IL-10) cytokines and chemokines (IL-8 and monocyte chemotactic protein 1), intercellular adhesion molecule 1 and complement activation products (C1r-C1s-C1inhibitor, C4bc, C3bPBb, C3bc and terminal complement complex) were measured. Changes over time were analyzed with the repeated measures test for nonparametric data. Dunn's multiple comparisons test was used for comparison of individual time points.

Results: The median temperature at the start of the study was 34.3°C (33.4°C to 35.2°C) and was maintained between 32°C and 34°C for 72 hours. All patients were passively rewarmed after 72 hours, from (median (IQR)) 33.7°C (33.1°C to 33.9°C) at 72 hours to 38.0°C (37.5°C to 38.1°C) at 114 hours (P <0.001). In general, the cytokines and chemokines remained stable during hypothermia and decreased during rewarming, whereas complement activation was suppressed during the whole hypothermia period and increased modestly during rewarming.

Conclusions: Prolonged hypothermia may blunt the inflammatory response after rewarming in patients after cardiac arrest. Complement activation was low during the whole hypothermia period, indicating that complement activation is also highly temperature-sensitive in vivo. Because inflammation is a strong mediator of secondary brain injury, a blunted proinflammatory response after rewarming may be beneficial.

Figure 1

Temperature changes over time. Values represent medians (black lines in boxes), 25th and 75th interquartile ranges (boxes) and minimums and maximums (whiskers).

Figure 2

Cytokine and chemokine profiles of the patients during hypothermia and after rewarming. Graphs show data for ten patients after cardiac arrest with respect to the proinflammatory cytokine interleukin 6 (IL-6) (a) and the chemokines IL-8 (b) and monocyte chemotactic protein 1 (MCP-1) (c) during hypothermia (0 to 72 hours) and after rewarming (72 to 114 hours). Values presented are medians (black lines in boxes), 25th to 75th interquartile ranges (boxes) and minimums and maximums (whiskers). *Statistically significant compared to time 0.

Figure 3

Interleukin 10 levels during hypothermia and after rewarming. Graph shows levels of the anti-inflammatory cytokine interleukin 10 (IL-10) in arterial blood samples from ten patients during hypothermia (0 to 72 hours) and after rewarming (72 to 114 hours). Values are medians (black lines in boxes), 25th to 75 interquartile ranges (boxes) and minimums and maximums (whiskers). *Statistically significant compared to time 0.

Figure 4

Intercellular adhesion molecule 1 concentrations during hypothermia (0 to 72 hours) and after rewarming (72 to 114 hours) in ten patients after cardiac arrest. The medians (black lines in boxes), 25th and 75th interquartile ranges (boxes) and minimums and maximums (whiskers) are depicted for soluble intercellular adhesion molecule 1 in arterial samples (sICAM). *Statistically significant difference compared to time 0.

Figure 5

Terminal complement complex during hypothermia (0 to 72 hours) and after rewarming (72 to 114 hours) in ten patients after cardiac arrest. The medians (black lines in boxes), 25th and 75 interquartile ranges (boxes) and minimums and maximums (whiskers) are depicted for arterial samples. *Statistically significant difference compared to time 0. #Statistically significant difference compared to 72 hours. TCC: Terminal complement complex (terminal pathway).