Cardiac arrest patients have an impaired immune response, which is not influenced by induced hypothermia

Charlotte J Beurskens, Janneke Horn, Anita M Tuip de Boer, Marcus J Schultz, Ester Mm van Leeuwen, Margreeth B Vroom, Nicole P Juffermans, Charlotte J Beurskens, Janneke Horn, Anita M Tuip de Boer, Marcus J Schultz, Ester Mm van Leeuwen, Margreeth B Vroom, Nicole P Juffermans

Abstract

Introduction: Induced hypothermia is increasingly applied as a therapeutic intervention in ICUs. One of the underlying mechanisms of the beneficial effects of hypothermia is proposed to be reduction of the inflammatory response. However, a fear of reducing the inflammatory response is an increased infection risk. Therefore, we studied the effect of induced hypothermia on immune response after cardiac arrest.

Methods: A prospective observational cohort study in a mixed surgical-medical ICU. Patients admitted at the ICU after surviving cardiac arrest were included and during 24 hours body temperature was strictly regulated at 33°C or 36°C. Blood was drawn at three time points: after reaching target temperature, at the end of the target temperature protocol and after rewarming to 37°C. Plasma cytokine levels and response of blood leucocytes to stimulation with toll-like receptor (TLR) ligands lipopolysaccharide (LPS) from Gram-negative bacteria and lipoteicoic acid (LTA) from Gram-positive bacteria were measured. Also, monocyte HLA-DR expression was determined.

Results: In total, 20 patients were enrolled in the study. Compared to healthy controls, cardiac arrest patients kept at 36°C (n = 9) had increased plasma cytokines levels, which was not apparent in patients kept at 33°C (n = 11). Immune response to TLR ligands in patients after cardiac arrest was generally reduced and associated with lower HLA-DR expression. Patients kept at 33°C had preserved ability of immune cells to respond to LPS and LTA compared to patients kept at 36°C. These differences disappeared over time. HLA-DR expression did not differ between 33°C and 36°C.

Conclusions: Patients after cardiac arrest have a modest systemic inflammatory response compared to healthy controls, associated with lower HLA-DR expression and attenuated immune response to Gram-negative and Gram-positive antigens, the latter indicative of an impaired immune response to bacteria. Patients with a body temperature of 33°C did not differ from patients with a body temperature of 36°C, suggesting induced hypothermia does not affect immune response in patients with cardiac arrest.

Trial registration: ClinicalTrials.gov NCT01020916, registered 25 November 2009.

Figures

Figure 1
Figure 1
Cytokine levels in plasma of healthy controls, cardiac arrest patients with a target temperature of 33°C and cardiac arrest patients with a target temperature of 36°C, after reaching target temperature (T = 1), at the end of the target temperature protocol (T = 2) and after reaching 37°C (T = 3).
Figure 2
Figure 2
Cytokine production after whole blood stimulation with LPS or LTA, in plasma of healthy controls, cardiac arrest patients with a target temperature of 33°C and cardiac arrest patients with a target temperature of 36°C, after reaching target temperature (T = 1), at the end of the target temperature protocol (T = 2) and after reaching 37°C (T = 3). Healthy volunteers are marked by white bars; cardiac arrest patients with a target temperature of 33°C are marked by grey bars, cardiac arrest patients with a target temperature of 36°C are marked by black bars. Every measurement is preceded by a blank control stimulation. Data expressed as median with range. *P <0.05; **P <0.01. LPS: lipopolysaccharide; LTA: lipoteicoic acid.
Figure 3
Figure 3
HLA-DR expression on bright and dull monocytes in plasma of healthy controls, cardiac arrest patients with a target temperature of 33°C and cardiac arrest patients with a target temperature of 36°C, after reaching target temperature (T = 1), at the end of the target temperature protocol (T = 2) and after reaching 37°C (T = 3). HLA-DR: human leukocyte antigen-DR.

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