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 and the initial guide- lines40 on hypothermia after cardiac arrest minor bleeding. In fact, surgery provides a excluded patients with bleeding diathesis. useful potential research model for rando- Several studies have investigated how mised interventional studies to determine mild induced hypothermia affects coagula- whether mild hypothermia constitutes a tion and platelet function. Conventional risk factor for blood loss and/or transfusion coagulation tests (i.e., prothrombin time/ requirements in comparison with normo- international normalised ratio) suggest thermia. Several studies have provided evi- that activated partial thromboplastin time dence of the manner in which mild and platelet count seem unaffected by hypothermia affects the haemostatic mild hypothermia when analysed under system during surgery. In an initial study, normothermia, but these show a progres- hypothermia was found to increase both 25 sively hypocoagulative response when ana- blood loss and transfusion requirements. lysed at the temperature of the patient.41 These findings were not confirmed in a later Wohlberg et al.5 performed similar study, which reported that hypothermia did experiments and only demonstrated a hypo- not increase either blood loss or transfusion thermic effect at temperatures below 33C. 26 requirements. Since then, various studies Using the Sonoclot instrument, Shimokawa have reported that mild hypothermia et al.42 demonstrated a significant hypocoa- increases blood loss and/or transfusion gulative response upon analysing the 27–32 21,33–35 requirements, does neither, and patient’s own hypothermic body tempera- even reduces blood loss.36 ture. Other visco-haemostatic assays, such In a meta-analysis including investiga- as thromboelastography or rotational tions of how hypothermia during surgery thromboelastometry, have also been used affects bleeding and transfusions, it was to investigate hypothermia applied both in concluded that even mild hypothermia vivo and in vitro. The overall results of (<1C) significantly increases blood loss these studies have shown delayed clot initi- by approximately 16% (4%–26%) and ation and propagation if the analyses are Kander and Sch€ott 3563 performed with instruments set to the multiple-electrode aggregometry and flow temperature of the hypothermic patient cytometry. However, given that there is no but not if performed under normothermic perfect coagulation or platelet measurement conditions.38,43–51 capable of evaluating the risk of bleeding, it Investigations of how platelet function, would be extremely interesting to investi- with or without platelet inhibitors, is affect- gate the number of bleeding events that ed by hypothermia have yielded divergent occur during mild induced hypothermia, results. Some authors have described as a clinically relevant surrogate measure decreased platelet function in response to of bleeding risk. In fact, this was done in deep hypothermia.4,5,17,52,53 We have previ- the Targeted Temperature Management ously shown markedly increased platelet (TTM) trial.58 In that study, 950 comatose activity, measured via flow cytometry, in survivors of out-of-hospital cardiac arrest response to mild hypothermia to 33C were randomised into body temperature applied in vitro in whole blood from conditions of either 33Cor36C for patients with acute coronary syndrome 24 hours. The TTM study was sufficiently who were treated with ticagrelor and aspi- powered to detect differences in mortality rin.45 This finding is in agreement with sev- and neurological outcomes but also eral other studies, in which in vitro showed that there were no differences in incubation at mild hypothermia of whole serious bleeding complications between the blood taken from healthy volunteers groups. Furthermore, in a sub-study of the resulted in increased platelet reactivity. TTM trial, we recently demonstrated that Scharbert et al.54,55 used multiple-electrode there was no difference in the incidence of aggregation to demonstrate increased plate- bleeding during the first 3 days of intensive let aggregability in response to in vitro care after cardiac arrest between the 33C application of mild hypothermia (33C). and 36C groups.59 This can be considered Hogberg€ et al.56 found an increase in indicative of the safety of mild induced ADP-stimulated platelet aggregation after hypothermia to 33C with regard to temporary clopidogrel treatment in hypo- bleeding complications. thermic (33C) blood compared with nor- mothermic blood. Ferreiro et al.57 used multiple-electrode aggregation testing to Discussion investigate the effect of in vitro application In this narrative review, we highlight of hypothermia in blood from clopidogrel- trauma, surgery and mild induced hypo- treated patients; those authors concluded thermia as three clinically important situa- that mild therapeutic hypothermia is asso- tions in which the effects of hypothermia on ciated with impaired response to clopidog- haemostasis are important but remain rel therapy. In conclusion, mild induced under debate. In observational studies of hypothermia to 33C seems to increase trauma, undesirable hypothermia demon- platelet aggregation whereas deep hypo- strates a strong association with mortality thermia (<33C) appears to decrease plate- and morbidity, perhaps owing to the effects let aggregation. of hypothermia on haemostatic function. It is likely that the increased time to clot Randomised trials have shown that initiation and impaired clot propagation undesirable hypothermia causes increased demonstrated in visco-haemostatic tests bleeding during surgery. In mild induced under mild induced hypothermia may be hypothermia, decreased coagulation ability counteracted by increased platelet aggrega- has been shown to be counteracted by tion and that this can be demonstrated with increased platelet aggregation. Moreover, 3564 Journal of International Medical Research 47(8) in a large randomised trial (the TTM When the body temperature drops below study), no differences were observed in 37C, platelets become more predisposed to bleeding events between groups, indicating activation by thrombotic stimuli, an occur- that mild induced hypothermia to 33Cis rence known as priming. The ability to safe, from the standpoint of bleeding. prime at peripheral body sites, where tem- It should be noted that mild induced peratures are lower and the chances of hypothermia to 33C is applied in the hos- trauma higher, is thought to have evolved pital, together with careful optimisation of as a protective effect against bleeding, all other physiological and laboratory whereas more central body sites have great- 67 values. This is a completely different situa- er protection against thrombosis. It can tion than that of hypothermia at the scene also be speculated that, from an evolution- of trauma or during surgery, where hypo- ary perspective, it is appropriate that plate- thermia occurs in an uncontrolled manner lets are activated when they are exposed to and is often accompanied by hypervolemia lower temperatures, as is the case in and acidosis. open bleeding. The increased platelet aggregation seen Increased platelet activity during mild to in mild induced hypothermia is well recog- moderate hypothermia is counteracted by nised in previous studies.45,54–56,60,61 decreased coagulation ability, presumably caused by inferior enzyme activity in the Furthermore, under normal conditions, 4,5 blood flow is maximal at the centre of the coagulation cascade during hypothermia. vessel, and platelets are marginalised to the In an experiment performed in 1960, thromboplastin time was measured at a periphery and close to the scene of injury,   thus promoting platelet–endothelial inter- range of temperatures from 0 Cto40C, in whole blood from both the cold- action.62 Given that the viscosity of blood blooded South African clawed toad is increased in hypothermia, as previously (Xenopus laevis) and from humans. The shown,63 this marginalisation effect is results showed that the thromboplastin more prominent in a hypothermic situation, time for blood from the toad was nearly as is shear-induced platelet aggregation.64 constant at around 30 s between 10C and Higher blood viscosity during hypothermia  40 C and peaked at just over 1 minute at decreases blood flow velocity, which also  0 C. In human blood, the thromboplastin facilitates the formation of a platelet plug time increased exponentially below 20C because the forces that tend to draw the and reached 13 minutes at 0C.68 This illus- platelet plug from the vessel wall are trates how the blood of cold-blooded ani- decreased. These are all pro-coagulative mals adjusts to temperature changes and factors that are not easily measured in how the blood clotting system of warm- vitro but that are present during hypother- blooded animals is considerably more lim- mia in vivo. ited in terms of optimal temperature range. The platelet count drops during hypo- thermia,.51,65 but this decrease in platelet count is reversible when the normal body Conclusion temperature is restored. This phenomenon Even though the causality between hypo- is also observed in hibernating animals, thermia and bleeding risk is not well estab- whose platelet counts increase very quickly lished, there is a clear association between during arousal, indicating a storage- undesirable hypothermia (body tempera- and-release phenomenon rather than ture <35C) and negative outcomes in decreased and increased production.66 connection with trauma, surgery, and Kander and Sch€ott 3565 accidental hypothermia, and it is crucial to prospective observational study. Crit Care rewarm patients in these clinical situations 2014; 18: 495. without delay. Mild induced hypothermia 8. Aslami H and Juffermans NP. 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