Elsevier

Resuscitation

Volume 85, Issue 10, October 2014, Pages 1359-1363
Resuscitation

Clinical paper
Minimal effects on ex vivo coagulation during mild therapeutic hypothermia in post cardiac arrest patients

https://doi.org/10.1016/j.resuscitation.2014.06.009Get rights and content

Abstract

Objectives

Mild therapeutic hypothermia (MTH) is being used to improve neurological outcome and survival in patients successfully resuscitated after cardiac arrest. The impact on coagulation may be difficult to assess since most coagulation parameters are measured at 37 °C and not at actual body core temperature. Therefore we investigated the effects of MTH both at body core (target) temperature of 32 °C and at 37 °C.

Methods

Patients admitted at the ICU after cardiac arrest treated with MTH. Baseline blood samples, measured at 37 °C were taken directly at arrival. The second and third samples were drawn within 1 h and 24 h after reaching target temperature and were measured at 32 °C and 37 °C. A final sample was drawn when the patient returned to normotemperature (measured at 37 °C). Clotting time (CT) and maximum clotting formation (MCF) were measured with thromboelastometry.

Results

Upon reaching target temperature (32 °C) Extem and Intem CT were increased compared to baseline with 57 s (49–75) to 65 s (59–72) and 165 s (144–183) to 193 s (167–212) respectively (median with IQR; P < 0.05), with a further significant increase after 24 h of hypothermia with 68 s (57–80) and 221 s (196–266). Samples analyzed at 32 °C showed a significant longer CT of 12 s in Extem and 33 s in Intem compared to 37 °C. MCF was not affected by MTH or adjustment of temperature.

Conclusion

The mild effect of MTH on coagulation parameters remains unidentified when measured at 37 °C. Although measurements at 32 °C differ from those at 37 °C, this does not appear to be of clinical relevance as all values were still within the reference range.

Introduction

Mild therapeutic hypothermia (MTH) with body core temperatures between 32 and 34 °C is being used for many years to improve neurological outcome and survival in patients successfully resuscitated after cardiac arrest. The optimal target temperature for MTH is still controversial. Recently two large RCT's showed that hypothermia at a target temperature of 33 °C had no benefit compared to a target temperature of 36 °C in terms of survival or neurological outcome.1, 2 These findings were criticized, but a shared conclusion was that hyperthermia should be avoided and that more research is needed before abandoning any temperature management from daily care.

MTH may lead to alterations in hemostasis and coagulopathy. Hypothermia below 33 °C affects the synthesis and kinetics of clotting enzymes, thrombin generation, plasminogen activator inhibitors and is related to dysfunction of platelets.3, 4 A prolonged clotting time (CT) was observed in healthy cooled animals and in externally cooled blood of healthy volunteers.5, 6 In post cardiac arrest patients treated with MTH only a slightly prolonged CT was demonstrated (measured at 37 °C) after the induction of hypothermia with a maximum clot formation identical to normothermic baseline samples, measured before cooling.7 The risk of bleeding associated with MTH seems to be relatively small in patients after cardiac arrest even when these patients are treated with anticoagulants and infusion of cold crystalloids.8 This might be related to concomitant activation of coagulation. Post cardiac arrest patients typically receive MTH after a period of hypoperfusion and reperfusion, which causes a pro-inflammatory response and activation of coagulation.9 After regaining spontaneous circulation, tissue factor increases which leads eventually to increased thrombin and fibrin formation.10, 11 The real impact of hypothermia on coagulation however, may be difficult to assess since most coagulation parameters are routinely measured at 37 °C and not at the actual patients core temperature.6, 7 The aim of this study is to investigate the effects of MTH on coagulation parameters tested by thromboelastometry both at body core (target) temperature of 32 °C and at 37 °C.

Section snippets

Study design and population

We conducted a prospective non-interventional study in a tertiary care hospital mixed medical-surgical intensive care unit. Post cardiac arrest patients were enrolled when they were older than 18 years, comatose upon the admission to the hospital, and with a presumed cardiac etiology of the cardiac arrest and return of spontaneous circulation. Exclusion criteria were: pregnancy, non-cardiac causes of cardiac arrest, traumatic brain injury, use of coumarin derivates, pre-existing coagulopathy

Demographic and clinical data

From April 2011 until June 2012 during daytime, 22 patients with an out-of-hospital cardiac arrest were included. In four patients cardiac arrest appeared to be of non-cardiac origin (pneumosepsis) and one patient had an additional subarachnoidal bleeding. These patients were excluded from analysis. One patient died during the study, but the first two measurements were included in the analysis. In total 17 patients were used for analysis. Patient characteristics are presented in Table 1.

Influence of hypothermia on thromboelastometry parameters

MTH led

Discussion

In this study the effects of MTH on coagulation in post cardiac arrest patients during all phases of therapeutic hypothermia and rewarming were determined by using thromboelastometry measurements at both 32 °C and 37 °C. The optimal target temperature for MTH is still controversial. Recently, a large RCT comparing two target temperatures, both intended to prevent fever, showed that in 939 post cardiac arrest patients hypothermia at a target temperature of 33 °C had no benefit compared to a target

Conclusion

The effects of MTH on coagulation are underestimated when measurements are performed at 37 °C instead of the patients’ actual body temperature of 32 °C. However, the minimal changes in CT are within reference range and not likely to be of clinical relevance.

Conflict of interest statement

The authors have no conflicts of interest to declare.

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      Both standard laboratory investigations, ROTEM® and thrombin generation analyses were performed at 37 °C regardless of core temperature. Previous studies have found that by running the APTT, INR and ROTEM® analyses on hypothermic patients at 37 °C, prolonged clot initiation and clot propagation were overseen [11,18,19,29–31]. Thus, the affected clot formation observed in hypothermic patients was probably underestimated in the present study.

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      MTH has been proposed to preserve neurological status in these patients.4 MTH has been associated with haemostasis and coagulopathy disorders.5,6 The relationship between a higher risk of stent thrombosis (ST) and OHCA is however very controversial.

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      However, post resuscitation syndrome and MTH may produce alterations in haemostasis and coagulopathy.4 Hypothermia below 33° affects the synthesis and kinetics of clotting enzymes, thrombin generation, and plasminogen activator inhibitors and is related to platelet dysfunction, and this may be associated with an increased risk of both thrombotic and bleeding events.5,6 In this regard, Orban et al. reported an increase in major bleeding in patients in cardiogenic shock treated with primary PCI and MTH compared to those without MTH.7

    • European Resuscitation Council and European Society of Intensive Care Medicine Guidelines for Post-resuscitation Care 2015. Section 5 of the European Resuscitation Council Guidelines for Resuscitation 2015.

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      Hypothermia decreases insulin sensitivity and insulin secretion, and causes hyperglycaemia,188 which will need treatment with insulin (see glucose control). Mild induced hypothermia impairs coagulation and may increase bleeding, although this effect seems to be negligible256 and has not been confirmed in clinical studies.7,31,187 In one registry study, an increased rate of minor bleeding occurred with the combination of coronary angiography and mild induced hypothermia, but this combination of interventions was the also the best predictor of good outcome.20

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    A Spanish translated version of the abstract of this article appears as Appendix in the final online version at http://dx.doi.org/10.1016/j.resuscitation.2014.06.009.

    1

    These authors contributed equally to this work.

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