The inflammatory response after out-of-hospital cardiac arrest is not modified by targeted temperature management at 33 °C or 36 °C☆
Introduction
Patients successfully resuscitated after out-of-hospital cardiac arrest (OHCA) are exposed to whole body ischemia during the period of cardiac arrest and to reperfusion injury after achievement of return of spontaneous circulation (ROSC). Ischemic reperfusion injury is partially related to activation of neutrophils with release of pro-inflammatory cytokines.1, 2 Reperfusion after cardiac arrest has been shown to activate cascades of immunological and coagulation pathways, resembling severe sepsis or septic shock with elevated serologic markers of global inflammation.3, 4, 5 This systemic ischemia/reperfusion response is part of the post-cardiac arrest syndrome (PCAS), which includes post-cardiac arrest brain injury and myocardial dysfunction.6 Severity of PCAS is related to the extent of organ dysfunction, but whether excessive levels of inflammation are associated with severity of PCAS or may exacerbate organ dysfunction is poorly studied.7
In comatose post-cardiac arrest patients, targeted temperature management (TTM) is applied to attenuate PCAS related neurological injury and improve outcome.8, 9, 10 Whether the use of TTM may interfere with the systemic inflammatory response after OHCA has not been fully elucidated. Our current knowledge is based on animal studies or observational studies where findings have been conflicting.11, 12, 13
We investigated the association between level of inflammation and severity of PCAS in a single center study from the TTM trial [14]. Furthermore, we aimed to investigate the influence of TTM at 33 °C (TTM33) and 36 °C (TTM36) on the inflammatory response. We hypothesized that TTM33 compared to TTM36 would decrease systemic inflammation assessed by a battery of inflammatory markers, including pro-inflammatory cytokines interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α and anti-inflammatory cytokines, IL-4, IL-10, IL-13 together with C-reactive protein (CRP) and procalcitonin (PCT).
Section snippets
Study design
This investigation was a single center secondary study of the prospective investigator-initiated, multi-center, randomized, parallel-group, and assessor-blinded clinical Target Temperature Management (TTM) trial.14 Patients were randomized in a 1:1 fashion to TTM33 or TTM36 for 24 h after cardiac arrest. The TTM protocol was approved in Denmark by the Ethics Committee of the Capital Region Copenhagen (H-1-2010-059) and the Danish Data Protection Agency. Written informed consent was obtained from
Patients
A total of 169 patients were included in the analysis with a mean age of 61.5 years, 88% male and 87% had an initial rhythm of ventricular fibrillation. Detailed demographics, co-morbidities and pre-hospital data are provided in Table 1, stratified by temperature allocation with 86 patients in the TTM33 group and 83 patients in the TTM36 group. Time from OHCA to randomization was median 135 (103–170) min. Mortality at 180 day was 40% compared to 30% in the TTM33 and TTM36 group, plog–rank = 0.18,
Discussion
This study confirms that survivors after OHCA exhibit an acute release of systemic inflammatory cytokines. We demonstrate, for the first time in a prospective randomized clinical study, that targeted temperature management at 33 °C compared with 36 °C does not significantly influence key mediators of the inflammatory response. In addition, we found that both pro- and anti-inflammatory cytokines were associated with severity of PCAS. IL-6 levels at randomization was strongly associated with
Limitations
TTM was initiated within two hours after OHCA and thus this study cannot exclude that the inflammatory response could be altered by initiating induction of hypothermia at an earlier time point as some inflammatory markers have been shown to peak within the first hour after cardiac arrest.12 In a trauma model, immediate induction of hypothermia decreased the pro-inflammatory response,40 but whether this also applies for OHCA is not known. Furthermore, the results may be influenced by a relative
Conclusions
Level of inflammatory cytokines are associated with severity of PCAS with the pro-inflammatory cytokine IL-6 being consistently and more strongly associated with severity of PCAS than classical inflammatory markers as CRP and PCT. The systemic inflammatory response after cardiac arrest was not modified by targeted temperature management at 33 °C or 36 °C.
Conflict of interest statement
All authors have reported that they have no financial relationships relevant to the contents of this paper to disclose.
Acknowledgement
The work of Hans Friberg, Jesper Kjaergaard and Christian Hassager are supported by the EU Interreg IV A programme as part of the grant for establishing the Centre for Resuscitation Science in the Oresund Region. The study was supported by unrestricted grants for co-funding the analysis of biomarkers from The Danish Foundation TrygFonden (grant no. 7-12-0454).
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A Spanish translated version of the summary of this article appears as Appendix in the final online version at http://dx.doi.org/10.1016/j.resuscitation.2014.08.007.