Review Journal of International Medical Research 2019, Vol. 47(8) 3559–3568 Effect of hypothermia on ! The Author(s) 2019 Article reuse guidelines: haemostasis and bleeding sagepub.com/journals-permissions DOI: 10.1177/0300060519861469 risk: a narrative review journals.sagepub.com/home/imr Thomas Kander and Ulf Schott€ Abstract It must be remembered that clinically important haemostasis occurs in vivo and not in a tube, and that variables such as the number of bleeding events and bleeding volume are more robust measures of bleeding risk than the results of analyses. In this narrative review, we highlight trauma, surgery, and mild induced hypothermia as three clinically important situations in which the effects of hypothermia on haemostasis are important. In observational studies of trauma, hypothermia (body temperature <35C) has demonstrated an association with mortality and morbidity, perhaps owing to its effect on haemostatic functions. Randomised trials have shown that hypothermia causes increased bleeding during surgery. Although causality between hypothermia and bleeding risk has not been well established, there is a clear association between hypothermia and negative outcomes in connection with trauma, surgery, and accidental hypothermia; thus, it is crucial to rewarm patients in these clinical sit- uations without delay. Mild induced hypothermia to 33C for 24 hours does not seem to be associated with either decreased total haemostasis or increased bleeding risk. Keywords Hypothermia, coagulopathy, haemostasis, bleeding, trauma, surgery, injury Date received: 20 March 2019; accepted: 13 June 2019 Introduction Many studies have been conducted to inves- Lund University, Ska˚ne University Hospital, Department tigate the effects of hypothermia on haemo- of Clinical Sciences Lund, Intensive and Perioperative stasis, and these have yielded contradictory Care, Lund, Sweden results. These varying outcomes may be Corresponding author: Thomas Kander, Ska˚ne University Hospital, Intensive and explained by differences in the methods Perioperative Care, Getingev, 221 85 Lund, Sweden. used to study platelet function and Email: [email protected] Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). 3560 Journal of International Medical Research 47(8) coagulation. Furthermore, some of these tests are performed at 37C, which means studies have only investigated mild hypo- that any temperature-dependent coagula- thermia whereas others have tested a tion disturbances may be overlooked.7 broader spectrum of temperature ranges, Previously, hypothermia was always including deep hypothermia. treated because it affects many biological Over the course of evolution, animals systems, e.g., coagulation and platelet func- have developed different methods of tion. In modern medicine, hypothermia is maintaining an ideal body temperature. used as a treatment in some situations, Cold-blooded animals, also known as ecto- such as after cardiac arrest, to protect the thermic animals, cannot regulate their body brain from further damage after ischaemia. temperature internally so their body Research has also been conducted on the temperature varies according to their envi- potential of therapeutic hypothermia to ronment. In contrast, warm-blooded, or protect organs other than the brain from endothermic, animals, including humans, ischaemic organ injury via protective mito- maintain a constant body temperature via chondrial effects.8 endogenous mechanisms. Such mechanisms The aim of this review was to describe include the internal generation of heat, how hypothermia may affect bleeding risk, which is mainly an incidental effect of coagulation, and platelet function in the animal’s routine metabolism. Under trauma, surgery, and mild induced hypo- conditions of excessive cold or low activity, an endotherm may utilise special mecha- thermia, three clinically important situa- nisms adapted specifically for heat produc- tions in which the effects of hypothermia tion. Examples include special-function on haemostasis are important. muscular exertion, such as shivering, and uncoupled oxidative metabolism within Materials and methods brown adipose tissue.1,2 It is thought that We performed a PubMed/MEDLINE and endothermic animals need to keep their body temperature constant to ensure Embase search using the search terms enzyme activity and complex homeostasis, “hypothermia,” “coagulopathy,” “bleeding,” such as haemostasis.3 In humans, hypother- and “bleeding risk,” which were combined mia has been demonstrated to slow with “surgery,” “trauma,” “injury,” and enzyme activity.4,5 “induced hypothermia.” Both authors car- It must be remembered that clinically ried out electronic searches and reviewed important haemostasis occurs in vivo and the bibliographies of retrieved articles to not in a tube. All analyses of coagulation identify further studies of interest. The and platelet function have limitations and authors conducted additional searches, con- measure only part of the total haemostatic tent revision, and discussion until agreement system. To evaluate bleeding risk or deter- was reached. mine the cause of bleeding, clinicians must recognise which part of the total haemo- Results static system is being analysed and, perhaps more importantly, which part is not being Figure 1 presents an overview of the analysed with the methods used. The usual study findings regarding the manner in testing systems have no natural flow, which which hypothermia affects outcomes and means that the natural intersection of blood haemostasis under clinical conditions flow with the endothelium cannot be mea- of trauma, surgery, and mild induced sured.6 Furthermore, many coagulation hypothermia. Kander and Sch€ott 3561 Figure 1. Summary of how hypothermia affects outcomes and haemostasis in three clinical conditions. Trauma Many observational studies have demonstrat- ed an association between trauma-induced Undesirable hypothermia, along with aci- hypothermia, defined as body temperature dosis and coagulopathy, is part of the <35C, and morbidity and mortality.11–17 lethal triad that worsens the prognosis of The effects of undesired hypothermia in patients with severe trauma.9 Heat is lost trauma are many;18 hypothermia may alter at the scene of trauma in the emergency department when the clothing is removed myocardial contractions, induce arrhyth- and when room-temperature fluids are mias, or cause trauma-associated coagulop- administered. Furthermore, patients who athy. From an immunological perspective, are in shock have disrupted body tempera- hypothermia may diminish the inflammato- ture regulation and lower tissue metabo- ry response and increase the risk of pneu- 19 lism, which decrease the amount of heat monia. Because hypothermia is more that they produce. During surgery, heat common in severely injured patients, it is loss is exacerbated by the exposure of the difficult to determine whether it contributes peritoneum. It has been estimated that a to mortality independently of injury severi- patient undergoing damage-control lapa- ty. Thus, even if there is a strong associa- rotomy loses as much as 4.6C of core tion between accidental hypothermia after body heat per hour.10 trauma and mortality or morbidity, causal- An impressive number of observational ity between hypothermia and bleeding risk studies have examined the effects of hypo- has not been convincingly established. The thermia after trauma. Unfortunately, increased risk of death and morbidity may but for obvious reasons, prospective rando- be dependent on any of the negative effects mised trials are largely unavailable. of hypothermia or increased bleeding risk. 3562 Journal of International Medical Research 47(8) Surgery increases the relative risk of transfusion by approximately 22% (3%–37%).37 General anaesthesia inhibits the thermoreg- ulatory system20 and may cause undesired hypothermia in unwarmed patients. Several Mild induced hypothermia studies have described how hypothermia Conventional wisdom holds that hypother- causes complications such as morbid myo- mia reduces coagulation and platelet func- cardial outcomes,21 surgical wound infec- tion and impairs primary and secondary tion,22 prolonged recovery,23 and haemostasis. Whether this is also true of hospitalisation.24 Furthermore, patients mild induced hypothermia (33 C) has 38 who undergo long major operations are been debated. Concerns have been raised more likely to become hypothermic than regarding whether mild induced hypother- those undergoing shorter minor procedures; mia can be applied safely after cardiac these patients are also likely to lose more arrest because external chest compressions, blood. Consequently, retrospective correla- dual anti-platelet inhibition after primary tions between hypothermia and blood loss percutaneous coronary intervention, and are especially likely to be confounded and the insertion of arterial and venous lines should be interpreted carefully. are frequent in such situations. Bleeding issues were among the reasons that the During surgery, it is crucial that the hae- 39 mostatic system functions properly, to stop first clinical study