Inadvertent hypothermia and mortality in critically ill adults: Systematic review and meta-analysis

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Review Paper

Inadvertent hypothermia and mortality in critically ill adults: Systematic review and meta-analysis Panagiotis Kiekkas RN, PhD a,∗ , Fotini Fligou MD, PhD b , Michael Igoumenidis RN, PhD a , Nikolaos Stefanopoulos RN, PhD a , Evangelos Konstantinou RN, PhD c , Vasilios Karamouzos MD b , Diamanto Aretha MD, PhD b a

Nursing Department, Technological Educational Institute of Western Greece, Patras, Greece Department of Anesthesiology and Critical Care Medicine, Patras University Hospital, Patras, Greece c Nursing Department, National and Kapodistrian Athens University, Athens, Greece b

article information Article history: Received 21 September 2016 Received in revised form 23 January 2017 Accepted 25 January 2017 Keywords: Hypothermia Core temperature Mortality Intensive care unit Critically ill Outcome

a b s t r a c t Objective: Considering that inadvertent hypothermia (IH) is common in Intensive Care Unit (ICU) patients and can be followed by severe complications, this systematic review identified, appraised and synthesized the published literature about the association between IH and mortality in adults admitted to the ICU. Data sources: By using key terms, literature searches were conducted in Pubmed, CINAHL, Cochrane Library, Web of Science and EMBASE. Review methods: According to PRISMA guidelines, articles published between 1980–2016 in Englishlanguage, peer-reviewed journals were considered. IH was defined as core temperature of <36.5 ◦ C or lower, present on ICU admission or manifested during ICU stay. Outcome measure included ICU, hospital or 28-day mortality. Selected cohort studies were evaluated with the Newcastle–Ottawa Scale. Extracted data were summarized in tables and synthesized qualitatively and quantitatively, with adjusted odds ratios (ORs) for mortality being combined in meta-analyses. Results: Eighteen observational studies met inclusion criteria. All of them had high methodological quality. In twelve out of fifteen studies, unadjusted mortality was significantly higher in hypothermic patients compared to non-hypothermic ones. Likewise, in thirteen out of sixteen studies, IH or lowest core temperature was independently associated with significantly higher mortality. High severity and long duration of IH were also associated with higher mortality. Mortality was significantly higher in patients with core temperature <36.0 ◦ C (pooled OR 2.093, 95% CI 1.704–2.570), and in those with core temperature <35.0 ◦ C (pooled OR 2.945, 95% CI 2.166–4.004). Conclusions: These findings indicate that IH predicts mortality in critically ill adults and pose suspicion that this may contribute to adverse patient outcome. © 2017 Australian College of Critical Care Nurses Ltd. Published by Elsevier Ltd. All rights reserved.

1. Introduction Inadvertent hypothermia (IH) refers to the uncontrolled, nontherapeutic core temperature (Tc ) decrease below normal. In

∗ Corresponding author at: 76 Stratigou Konstantinopoulou Str., Aroi, Patras 26331, Greece. E-mail address: [email protected] (P. Kiekkas).

contrast to fever, which constitutes a regulated Tc elevation in response to infectious or non-infectious noxious stimuli, IH generally comes as a result of increased heat loss, attributed to cold environment exposure and/or the dysfunction of normal thermoregulatory mechanisms.1 IH not only lacks the adaptive value of fever, but even mild Tc decrease below normal can be followed by potentially severe complications.2 Cold-induced shivering and increased catecholamine secretion results in vasoconstriction and the increase of heart, respiratory and metabolic rate. These effects

http://dx.doi.org/10.1016/j.aucc.2017.01.008 1036-7314/© 2017 Australian College of Critical Care Nurses Ltd. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Kiekkas P, et al. Inadvertent hypothermia and mortality in critically ill adults: Systematic review and meta-analysis. Aust Crit Care (2017), http://dx.doi.org/10.1016/j.aucc.2017.01.008

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predispose to myocardial ischaemia in patients with coronary heart disease, due to the decrease of coronary blood flow and the increase of myocardial oxygenation needs.3,4 IH further contributes to coagulation disorders, such as decreased fibrinolytic activity and the inhibition of normal function of platelets and clotting factor enzymes, leading thus to the increase of blood loss and allogeneic transfusion requirements.5,6 In postoperative patients, IH can be followed by impaired wound healing and increased risk for surgical infections, triggered by local tissue vasoconstriction and the suppression of the immune system activity.7,8 Especially in patients who receive general anesthesia, IH often results in delayed emergence from anesthesia and prolonged recovery time, due to decreased metabolism of anesthetic medications in combination with decreased cerebral blood perfusion.9 Although IH is generally common among patients admitted to the Intensive Care Unit (ICU),10–12 its incidence may vary considerably according to IH definition used and patient groups admitted to each ICU. Although there is no consensus about IH definition, previous authors have used Tc of 35.0–35.9 ◦ C, 32.0–34.9 ◦ C, and <32.0 ◦ C for defining mild, moderate, and severe hypothermia respectively in the ICU population.13,14 Conditions predisposing to IH in ICU patients mainly include low ambient temperature (in postoperative or trauma patients), drug effects, severe infections, endocrine abnormalities, as well as the critical illness per se.15–17 Irrespective from severity and etiology of IH, patients who need intensive care are expected to be particularly susceptible to the complications following IH, considering their limited physiological reserve. In this context, there is an imperative need to investigate whether IH manifested during ICU stay can be an indicator, or even a mediator, of adverse patient outcomes. In the literature, a review on the association between IH and hospital mortality published in 2011 was limited to surgical ICU patients and included only seven observational studies.18 Considering that surgical patients admitted to the ICU are not representative of the entirety of the critically ill population, as well as that five out of the seven studies included in this review were conducted between 1985–2003, the need for an updated, more extensive, systematic review was identified.

2. Aim The aim of this systematic literature review and meta-analysis was to identify, critically appraise and synthesize qualitatively and quantitatively the existing empirical evidence on the association between IH and mortality of adults admitted to the ICU.

3. Methods 3.1. Design and inclusion criteria To ensure consistent reporting of findings in this review article, guidelines set out in the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement were used.19 Fulltext articles published between January 1980 and September 2016 in English-language, peer-reviewed, medical and nursing journals were considered for inclusion. Specific inclusion criteria were: - Study subjects: Adult patients admitted to any ICU (medical, surgical, mixed, neurological/neurosurgical or trauma). Studies not enrolling adult ICU patients (pediatric patients, or critically ill patients not admitted to the ICU) were excluded. - Study design: Observational cohort, prospective or retrospective, single- or multi-center. Interventional design studies were excluded.

- Exposure: IH manifested at any time point during ICU stay (from ICU admission to discharge or death), and measured by any appropriate thermometry method (invasive or non-invasive) at any site. Considering that its definition is arbitrary, IH was defined according to the Tc threshold of <36.5 ◦ C or lower, since Tc of 36.5 ◦ C is generally considered as the lowest normothermia value among studies conducted in the ICU. Alternatively, studies that used lowest Tc without defining a particular Tc threshold for IH were also included. Studies on therapeutic (induced) hypothermia were excluded. - Outcome measure: Mortality during ICU or hospital stay, or 28day mortality. - Reported associations: In the univariate level, mortality of hypothermic patients was compared to mortality of nonhypothermic ones (normothermic, febrile or both). In the multivariate level, independent associations between IH or lowest Tc and mortality were considered. 3.2. Database search and study selection Two reviewers (NS and MI) independently and systematically searched for clinical studies indexed in the Cumulative Index for Nursing and Allied Health Literature (CINAHL), the US National Library of Medicine (PubMed), the Web of Science, the Cochrane Library, and the Excerpta Medica Database (EMBASE). Combinations of the following search terms were used: “hypothermia”, “body temperature”, “mortality”, “outcome”, “intensive care unit”, “ICU/CCU”, “critically ill”. Database searches initially took place at the first week of July 2016 and were updated at the first week of September 2016. Study selection was conducted in three steps. In the first step, retrieved studies were screened for inclusion according to their titles and abstracts. In the second step, the full text of selected articles was obtained and read for a final determination regarding eligibility for inclusion. In the third step, reference lists contained in the eligible articles were checked for identifying other potentially relevant articles (not found in the online searches). The full text of these additional articles was also obtained and read for determining eligibility for inclusion. Inter-rater agreement was calculated by the use of percent agreement and Cohen’s kappa coefficient with 95% confidence intervals (CIs). Discrepancies between reviewers were discussed until consensus was reached. 3.3. Data extraction, quality appraisal and bias assessment Two reviewers (DA and FF) with long clinical experience in critical care independently extracted data from included studies by using a standardized data collection form, which included: - study characteristics: age range, gender, admission type and diagnosis of patients, study design, thermometry devices and sites used, IH definitions, - study findings: hypothermia incidence, mortality differences between hypothermic and non-hypothermic patients, mortality differences according to IH severity or duration, independent associations between IH or lowest Tc and mortality (multivariate regression). Although methodological quality was not a criterion for study inclusion in this review, the reviewers appraised quality of selected studies with the use of Newcastle–Ottawa Scale (NOS).20 NOS has been developed for evaluating quality of non-randomized studies and, for cohort studies, NOS comprises nine items categorized into three groups: selection (exposed cohort representativeness, nonexposed cohort selection, exposure ascertainment, demonstration that the outcome of interest was not present at the beginning),

Please cite this article in press as: Kiekkas P, et al. Inadvertent hypothermia and mortality in critically ill adults: Systematic review and meta-analysis. Aust Crit Care (2017), http://dx.doi.org/10.1016/j.aucc.2017.01.008

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Records identified through database searching (n=750)

Records (n=551)

after

Additional records identified through other sources (n=3)

duplicates

Records screened by title (n=551)

removed

Records excluded (n=345)

Records screened by abstract (n=206)

Records excluded (n=164)

Full-text articles assessed for eligibility (n=42)

Full-text articles excluded, with reasons (n=24) (n=10, no data on ICU pts) (n=6, no observational design) (n=5, data on pt mortality not provided or inconsistent) (n=3, no comparisons according to Tc only hypothermic pts enrolled)

Studies included in qualitative synthesis (n=18)

Studies included synthesis (n=10)

in

3

quantitative

Fig. 1. Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) flow diagram.

Fig. 2. Funnel plot for the assessment of publication bias among studies that reported adjusted odds ratios for mortality. Circles represent odds ratios coming from published studies (some studies reported separate odds ratios for different patient groups).

comparability (based on design or analysis), and outcome (outcome assessment, adequacy of follow-up length and of cohort follow-up). Studies of highest quality receive NOS score of 9, with NOS score >5 indicating high methodological quality.

Beyond NOS evaluation, the reviewers assessed each selected study for the following, which would increase risk for bias: singlecenter design, retrospective design, small population size (<300 patients), included patients limited to one admission type (e.g. surgical), exclusion criteria not reported, Tc measured only by

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thermometer or thermometry method not defined, multivariate regression for mortality not conducted. One point was attributed for each of these seven criteria, with risk for bias ranging between 0 (no risk) and 7 (highest risk). In case data extraction, quality appraisal or assessment of the risk for bias was discordant between reviewers, the articles were re-examined until differences were resolved by consensus. 3.4. Data synthesis and analysis Study characteristics and findings, quality appraisal and bias assessment were presented in tables and narratively summarized within the text. Comprehensive Meta Analysis 3.3 software (Biostat, Englewood, NJ) was used for the quantitative synthesis of studies that provided adjusted odds ratios (ORs) for mortality according to IH. Pooled adjusted ORs with 95% CIs were calculated according to IH definitions (Tc thresholds) and forest plots were constructed to present the range and distribution of effects across studies. Heterogeneity among studies included in meta-analyses was assessed by calculating I2 statistic and Cochran’s Q test. An I2 value >75.0% was considered as evidence of substantial heterogeneity. A fixed effects model approach was used but in case of substantial heterogeneity, a random effects model was preferred.21 Publication bias was assessed by constructing a funnel plot, in which the vertical axis represented study size (standard error) and the horizontal axis represented effect size (log risk ratio), while Egger’s test was used for evaluating small-study effects. 4. Results 4.1. Search outcome Online searches revealed 750 potentially relevant citations, while reference list searches revealed three additional citations (Fig. 1). Removal of duplicates along with screening of titles and abstracts yielded 42 articles for full-text review. Of them, 18 published articles (conducted on 18 unique study populations) met eligibility criteria for inclusion in the qualitative synthesis. Percent agreement and Cohen’s kappa coefficient (with 95% CIs) were 94.2% and  = 0.89 (0.83–0.95) for abstract review, 95.2% and  = 0.90 (0.82–0.98) for full-text review, and 88.0% and  = 0.76 (0.67–0.84) for data extraction respectively. 4.2. Study characteristics, quality appraisal and bias assessment Characteristics of included studies are presented in Table 1. Fourteen studies were published between 2005–2015, and four studies were published between 1995–2005.21,23,24,29 Eight studies employed prospective data collection22,24,25,27,29,30,31,34 and nine had multi-center design.11,14,23,29,30,32–35 Among multicenter studies, patient population ranged between 450–636,051 patients. Among single-center studies, patient population ranged between 184–5701 patients, with four of them enrolling <300 patients.17,22,24,27 Two studies enrolled any ICU admission type,34,35 while medical/surgical patients were enrolled in four studies,11,14,29,31 and only surgical patients in six studies.12,22,24–27 Patients with trauma,23 traumatic brain injury,28 neurological injuries,32 acute lung injury,30 sepsis17 and faecal peritonitis33 were enrolled in one study each. Exclusion criteria were not reported in nine studies.12,22,23,25–28,31,32 All included studies were of high methodological quality, with NOS score >5, while risk for bias was <3 in ten studies.11,14,23,24,29–31,33–35 IH definition was provided in sixteen studies; of them, IH was defined as Tc < 36 ◦ C in nine studies,11,12,14,26,27,30–32,35 Tc < 35 ◦ C in four studies,22,23,25,28 Tc < 36.5 ◦ C in two studies,29,34 and Tc < 34.5 ◦ C in one study.24 Two studies also provided definitions

for moderate (32 ◦ C < Tc < 35 ◦ C) and severe IH (Tc < 32 ◦ C).11,14 IH was defined according to ICU admission Tc in eight studies,11,22–28 Tc within 24 h of ICU admission in five studies,12,14,32,34,35 and Tc during ICU stay in three studies.29–31 Based on the definitions used, IH incidence ranged between 0.4–57.8%. Information about Tc thermometry methods was provided in ten studies.12,14,22–24,26,27,29–31 Both thermistors and thermometers were used in two studies,29,30 only thermistors were used in four studies,23,24,26,31 and only thermometers were used in four studies.12,14,22,27 With regard to patient outcome, hospital mortality was used in eleven studies,12,17,22,24–26,28,30,32,34,35 ICU mortality in four studies,11,14,27,31 and 28-day in two studies,23,29 while one study used hospital, ICU and 28-day mortality.33

4.3. Qualitative synthesis of study findings Findings of included studies are presented in Table 2. Unadjusted mortality was reported to be significantly higher in hypothermic patients compared to normothermic ones in eleven studies,11,12,14,23–26,28,30–32,35 and significantly higher in hypothermic patients compared to non-hypothermic ones (both normothermic and febrile) in one study.26 Four studies investigated unadjusted mortality according to hypothermia severity, that is, for different Tc thresholds.11,12,25,28 In all of them, higher mortality was reported for lower Tc thresholds, while one study reported significantly increased mortality per 1 ◦ C of Tc decrease.12 In three studies, no significant difference in unadjusted mortality was detected between hypothermic and normothermic patients.22,27,29 In three studies, associations between IH and unadjusted mortality were not reported.17,33,34 Unequal distribution of variables that affect risk for death between hypothermic and normothermic patients may confound the association between hypothermia and mortality; thus, multivariate regression with mortality as dependent variable was conducted to address confounding in included studies, with the exception of two of them.22,27 With regard to adjusted mortality, IH was independently associated with higher mortality in ten studies.11,14,23,25,26,28,30,32,34,35 Among these studies, this association was limited to medical ICU patients in one study,11 ORs for mortality were higher for moderate and severe IH compared with those for mild IH in two studies,11,14 and only IH lasting >2 days was associated with higher mortality in one study.30 In one study, IH or fever was independently associated with higher adjusted mortality,31 while in one study IH was independently associated with multiple organ dysfunction, which in turn was a significant predictor of higher adjusted mortality.24 In three studies, lowest Tc was independently associated with higher adjusted mortality.12,17,33 In one study, hypothermia was not associated with adjusted mortality.29

4.4. Quantitative synthesis of study findings Ten studies reported adjusted ORs for mortality according to IH and could be included in the meta-analysis. Among these studies, IH was defined as Tc < 36.0 ◦ C in six of them,11,14,26,30,32,35 as Tc < 35.0 ◦ C in three of them,23,25,28 and as Tc < 36.5 ◦ C in one of them.34 Five studies did not report adjusted ORs for the entire ICU patient population; instead, they reported separate adjusted ORs for medical and surgical patients,11,14 for non-neutropenic and neutropenic sepsis patients,34 according to IH duration (one, two and three days),30 and according to the country of origin (Australia/New Zealand and UK) and infection diagnosis (four groups in total).35 In the funnel plot (Fig. 2), study distribution was relatively symmetrical on both sides of the mean, thus concerns for publication bias

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Table 1 Characteristics and quality appraisal of reviewed studies. Author

Study design/country

Study population

Hypothermia definition, incidence/Tc thermometry method

Outcome definition

NOSa /RFBb

Abelha et al.22

Prospective, single-center/Portugal

5/6

Retrospective, multi-center/The Netherlands

28-day mortality

7/3

Bush et al.24

Prospective, single-center/USA

Tc < 35 ◦ C on ICU admission, 57.8%/tympanic membrane (thermometer) Tc < 35 ◦ C on ICU admission, 37.1%/nasopharynx, rectum (thermistor) Tc < 34.5 ◦ C on ICU admission, 25.2%/pulmonary artery (thermistor)

Hospital mortality

Balvers et al.23

185 surgical pts (elective/emergency non-cardiac surgery), mean age ± SD 66.0 ± 12.6y, 60.5% males 953 trauma pts, median age (IQR) 45 (29–64)y, 79.0% males

Hospital mortality

6/3

Inaba et al.25

Prospective, single-center/USA

Tc < 35 ◦ C on ICU admission, 15.1% (Tc < 33 ◦ C, 4.9%)/not defined

Hospital mortality

7/4

Insler et al.26

Retrospective, single-center/USA

Hospital mortality

7/4

Karalapillai et al.12

Retrospective, single-center/Australia

Hospital mortality

6/5

Kongsayreepong et al.27

Prospective, single-center/Thailand

184 surgical pts (elective/emergency non-cardiac surgery), mean age ± SD 58.1 ± 18.5y, 56.0% males

ICU mortality

5/6

Konstantinidis et al.28

Retrospective, single-center/USA

Hospital mortality

7/5

Laupland et al.11

Retrospective, multi-center/France

1281 pts with traumatic brain injury, mean age ± SD 38.1 ± 21.2y, 79.2% males 10,962 medical/surgical pts (75% medical), median age (IQR) 63 (49–76)y, 61% males

Tc < 36 ◦ C on ICU admission, 28.0% (Tc < 35 ◦ C, 3.3%)/urinary bladder (thermistor) Tc < 36 ◦ C within 24 h of ICU admission, 35% (Tc < 35 ◦ C, 5.8%)/tympanic membrane (thermometer) Tc < 36 ◦ C on ICU admission, 57.1% (Tc < 35.5 ◦ C, 41.3%; Tc < 35 ◦ C, 28.3%)/tympanic membrane (thermometer) Tc < 35 ◦ C on ICU admission, 10.9%/not defined

ICU mortality

8/2

Lee et al.29

Prospective, multi-center/Japan, Korea

1425 medical/surgical pts without neurological injuries, median age (IQR) 66 (54–74)y, 62.7% males

28-day mortality

8/0

Netzer et al.30

Prospective, multi-center/US

450 pts with acute lung injury (for 3 days after its onset), median age (IQR) 51 (41–62)y, 56.0% males

Hospital mortality

6/1

Niven et al.14

Retrospective, multi-center/Canada

15,291 medical/surgical pts (61% medical), mean age ± SD 57 ± 19y, 57.9% males

ICU mortality

7/2

Peres Bota et al.31

Prospective, single-center/Belgium

493 medical/surgical pts (55.6% medical), mean age ± SD 59 ± 17y, 63.3% males

Tc < 36 ◦ C on ICU admission, 18.3% (moderate hypothermia: 32 ◦ C < Tc < 35, 6.7%; severe hypothermia: Tc < 32 ◦ C, 0.7%)/not defined Tc < 36.5 ◦ C during ICU stay, 0.4%/pulmonary artery, urinary bladder (thermistor); tympanic membrane, axilla (thermometer) Tc < 36 ◦ C during ICU stay, 46.4%/rectum, urinary bladder (thermistor); tympanic membrane, axilla, oral cavity (thermometer) Tc < 36 ◦ C within 24 h of ICU admission, 23.0% (moderate hypothermia: 32 ◦ C < Tc < 35 ◦ C, 5.7%; severe hypothermia: Tc < 32 ◦ C, 0.7%)/tympanic membrane, temporal artery (thermometer) Tc < 36 ◦ C during ICU stay, 9.1%/pulmonary artery, rectum (thermistor)

ICU mortality

6/2

262 surgical pts (elective abdominal aortic aneurysm repair), age/gender data not provided 1252 surgical pts (laparotomy/thoracotomy due to trauma), mean age ± SD 32.0 ± 14.4y, 87.5% males 5701 surgical pts (coronary artery bypass grafting), mean age 64.3y, 76.8% males 5050 surgical pts (cardiac/general surgery), mean age 65y, 64.0% males

Please cite this article in press as: Kiekkas P, et al. Inadvertent hypothermia and mortality in critically ill adults: Systematic review and meta-analysis. Aust Crit Care (2017), http://dx.doi.org/10.1016/j.aucc.2017.01.008

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Study design/country

Study population

Hypothermia definition, incidence/Tc thermometry method

Outcome definition

NOSa /RFBb

Rincon et al.32

Retrospective, multi-center/USA

Tc < 36 ◦ C within 24 h of ICU admission, 1.0%/not defined

Hospital mortality

6/4

Tiruvoipati et al.17

Retrospective, single-center/Australia

Not reported/not defined

Hospital mortality

5/5

Tridente et al.33

Prospective, multi-center/16 European countries

Not reported/not defined

ICU, hospital and 28-day mortality

8/2

Weinkove et al.34

Retrospective, multi-center/Australia, New Zealand Retrospective, multi-center/Australia, New Zealand, UK

13,587 pts with neurological injuries, mean age ± SD 61 ± 15y, 56.0% males 175 septic pts; for those >65y median age (IQR) 76 (71–79)y, 61.1% males; for those <65y median age (IQR) 56 (46–60)y, 40.3% males 977 pts with faecal peritonitis, median age (IQR) 69.2 (58.3–77.1)y, 54.3% males 118,067 pts, mean age ± SD 58.9 ± 15.8y, 55.3% males 636,051 pts, mean age ± SD 60.6 ± 18.8y, 56.9% males

Tc < 36.5 ◦ C within 24 h of ICU admission, not reported/not defined Tc < 36.0 ◦ C within 24 h of ICU admission, 1.6% in infection group, 2.8% in non-infection group/not defined

Hospital mortality

7/2

Hospital mortality

8/2

Young et al.35

ICU, Intensive Care Unit; pts, patients; Tc , core temperature; y, years; SD, standard deviation; IQR, interquartile range; NOS, Newcastle–Ottawa Scale; RFB, risk for bias. a Score ranging from 0 to 9, the higher the score the higher the methodological quality. b Score ranging from 0 to 7, the higher the score the higher the risk for bias.

were not raised. No significant small-study effects were indicated by the Egger’s test (two-tailed p = 0.859). Among studies that defined IH as Tc < 36.0 ◦ C, the I2 statistic was 92.15% (Q test = 152.83, p < 0.001), indicating substantial heterogeneity. Pooled OR for mortality (by random effects model) was 2.09 (95% CI, 1.70–2.57), indicating that Tc < 36.0 ◦ C was associated with significantly higher adjusted mortality (Fig. 3a). Among studies that defined IH as Tc < 35.0 ◦ C, the I2 statistic was 5.12% (Q test = 2.11, p = 0.742), indicating low heterogeneity. Pooled OR for mortality (by fixed effects model) was 2.95 (95% CI, 2.17–4.00), indicating that Tc < 35.0 ◦ C was associated with significantly higher adjusted mortality (Fig. 3b). 5. Discussion This systematic review and meta-analysis synthesized the findings on the association between IH and mortality of critically ill adults. It is worth-noticing that all included studies had high methodological quality, with half of them being multi-center. In summary, in the majority of studies Tc below normal or lowest Tc was reported to be associated with significantly higher mortality, both unadjusted and adjusted for individual risk for death. Thus, qualitative and quantitative synthesis of the existing evidence strongly supported that IH predicts mortality of critically ill adults. Pooled estimates showed increased risk for mortality in hypothermic patients, by 2.093-fold for Tc < 36.0 ◦ C and by 2.945-fold for Tc < 35.0 ◦ C. Given this association between IH and mortality, the most critical question seems to be whether Tc below normal can be not only an indicator but a mediator of adverse outcome as well. To answer this, the standards for causal associations in epidemiology need to be considered. These include strong associations independent from bias or confounding, consistent across studies, specific to the exposure and biologically plausible, which demonstrate an increasing outcome risk for higher levels of exposure (dose-response effect).36,37 IH or lowest Tc were independently associated with higher mortality in thirteen out of sixteen studies, in which adjustment for patient clinical severity and other possible confounding factors was conducted with multi-

variate regression. These associations were remarkably consistent across studies, despite heterogeneity attributed to differences in hypothermia definitions (different Tc thresholds and different time points/periods for considering IH), Tc thermometry methods, ICU patient groups included, and follow-up period for mortality. At the same time, studies that explored different Tc thresholds or IH duration reported that mortality increased with decreasing Tc (that is, with increasing IH severity) and increasing IH duration among patients. Detrimental consequences of IH provide plausible mechanisms that explain its possible negative contribution to survival of ICU patients, who can be unable to compensate for even mild physiological disorders due to their high clinical severity. IH has been documented to suppress stress response, immune and hematopoietic system, cardiorespiratory, renal, and hepatic function, which are generally compromised in the critically ill.28,38 Different mechanisms may account for the increased risk for death due to IH among diverse patient groups. Among septic patients, central nervous system dysfunction, increased serum bilirubin concentration, prolonged prothrombin times, and failure to recover from shock were more common in hypothermic patients.16 Likewise, in postoperative patients, IH predisposes to increased risk for surgical infections, cardiac events and adverse effects related to allogeneic blood transfusion, which have all been followed by high attributable mortality.4,39–41 In severe trauma patients, IH, along with acidosis and coagulopathy, constitutes the lethal triad that worsens their prognosis; in this group, Tc below normal induces arrhythmias and contributes to coagulopathy and pneumonia.42 Finally, in medical ICU patients, severe IH increases the risk for ICU-acquired bloodstream infection and pneumonia, due to the suppression of the immune function.13 It is worth-noticing that only three out of eighteen included studies reported non-significant associations between IH and unadjusted mortality. Two of these studies were single-center, relatively underpowered compared to the majority of included studies (including only 185 and 184 patients respectively) and limited to surgical ICU patients.22,27 This patient group has been reported to have significantly lower clinical severity (according to Acute Physiology and Chronic Health Evaluation II score) and ICU mor-

Please cite this article in press as: Kiekkas P, et al. Inadvertent hypothermia and mortality in critically ill adults: Systematic review and meta-analysis. Aust Crit Care (2017), http://dx.doi.org/10.1016/j.aucc.2017.01.008

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Table 2 Findings of reviewed studies. Author

Unadjusted mortality (univariate associations)

Adjusted mortality (multivariate associations)

Abelha et al.22

No significant difference in hospital mortality between hypothermic (Tc < 35 ◦ C) and normothermic pts: 18.7% vs 11.5%, OR 1.76, 95% CI 0.76–4.11, p = 0.190 Hypothermic pts (Tc < 35 ◦ C) had higher 28-day mortality than normothermic ones: 28.5% vs 9.5%, p < 0.001 Hypothermic pts (Tc < 34.5 ◦ C) had higher hospital mortality than normothermic ones: 12.1% vs 1.5%, p < 0.01

Not reported

Balvers et al.23 Bush et al.24

Inaba et al.25

Hypothermic pts (Tc < 35 ◦ C) had higher hospital mortality than normothermic ones: 35.1% vs 7.7%, OR 6.45, 95%CI 4.44–9.39, p < 0.001 Pts with Tc < 33 ◦ C had higher hospital mortality than those with Tc > 33 ◦ C: 55.0% vs 10.4%, OR 10.53, 95%CI 5.50–20.17, p < 0.001

Insler et al.26

Hypothermic pts (Tc < 36 ◦ C) had higher hospital mortality than non-hypothermic ones, p = 0.02 (percentages or ORs not reported) Hypothermic pts (Tc < 36 ◦ C) had higher hospital mortality than normothermic ones: 8.9% vs 5.6%, p < 0.001

Karalapillai et al.12

Hypothermia was independently associated with higher 28-day mortality: OR 2.82, 95% CI 1.83–4.35, p < 0.001 Hypothermia was independently associated with multiple organ dysfunction (p = 0.030), which was independently associated with higher hospital mortality (p = 0.003) Hypothermia was independently associated with higher hospital mortality: OR 3.15, 95% CI 1.88–5.27, p < 0.001

Hypothermia was independently associated with higher hospital mortality: OR 1.69, 95% CI 1.10–2.59, p = 0.02 Lowest Tc (within 24 h of ICU admission) was independently associated with higher hospital mortality: per 1 ◦ C decrease, OR 1.83, 95% CI 1.28–2.60, p < 0.001

Pts with Tc < 35 ◦ C had higher hospital mortality than those with Tc > 35 ◦ C: 14.7% vs 6.3%, p < 0.001 Hospital mortality per 1 ◦ C decrease of Tc : OR 1.54, 95% CI 1.35–1.75, p < 0.001 Kongsayreepong et al.27

No significant difference in ICU mortality between hypothermic (Tc < 36 ◦ C) and normothermic pts: OR 2.09, 95% CI 0.54–8.14, p = 0.279 No significant difference in ICU mortality between pts with Tc < 35.5 ◦ C and those with with Tc > 35.5 ◦ C: OR 1.77, 95% CI 0.52–6.01, p = 0.358 No significant difference in ICU mortality between pts with Tc < 35 ◦ C and those with Tc > 35 ◦ C: OR 2.23, 95% CI 0.65–7.67, p = 0.191

Not reported

Konstantinidis et al.28

Hypothermic pts (Tc < 35 ◦ C) had higher hospital mortality than normothermic ones: 70.0% vs 21.6%, OR 8.5, 95% CI 5.8–12.5, p < 0.001 Pts with 33 ◦ C < Tc < 35 ◦ C had higher hospital mortality than normothermic ones: 67.5% vs 21.6%, p < 0.05 Pts with Tc < 33 ◦ Cad higher hospital mortality than those with 33 ◦ C < Tc < 35 ◦ C: 75.0% vs 67.5%, p < 0.05

Hypothermia was independently associated with higher hospital mortality: OR 2.9, 95% CI 1.3–6.7, p = 0.013

Laupland et al.11

Hypothermic pts (Tc < 36 ◦ C) had higher ICU mortality than normothermic ones: 13.5% vs 10.0%, p < 0.01

In medical pts, mild (Tc < 36 ◦ C), moderate (32 ◦ C < Tc < 35 ◦ C) and severe hypothermia (Tc < 32 ◦ C) were independently associated with higher ICU mortality: OR 1.28, 95% CI 1.01–1.63, p = 0.04, OR 2.25, 95% CI 1.68–3.02, p < 0.001, and OR 3.49, 95% CI 1.87–6.53, p < 0.001 respectively In surgical pts, mild (Tc < 36 ◦ C), moderate (Tc < 35 ◦ C) and severe hypothermia (Tc < 32 ◦ C) were not independently associated with higher ICU mortality: OR 1.06, 95% CI 0.73–1.56, p = 0.75, OR 1.36, 95% CI 0.88–2.11, p = 0.17, and OR 1.84, 95% CI 0.28–12.20, p = 0.53 respectively

Pts with Tc < 35 ◦ C had higher ICU mortality than those with Tc > 35 ◦ C: 22.5% (percentage for those with Tc > 35 ◦ C not reported), p < 0.001

Pts with Tc < 32 ◦ C had higher ICU mortality than those with Tc < 32 ◦ C: 37.9% (percentage for those with Tc > 32 ◦ C not reported), p < 0.001 Lee et al.29

No significant difference in 28-day mortality between hypothermic (Tc < 36.5 ◦ C) and normothermic pts: Sepsis group: OR 3.08, 95% CI 0.41–23.10, p = 0.57 Non-sepsis group: comparisons not applicable (28-day mortality 0% in pts with Tc < 36.5 ◦ C)

Hypothermia was not associated with 28-day mortality (OR not applicable)

Netzer et al.30

Hypothermic pts (Tc < 36 ◦ C) had higher hospital mortality than normothermic ones: 59.9% vs 38.9%, p < 0.001

Hypothermia duration of >2 days was independently associated with higher hospital mortality: One day with hypothermia: OR 1.29, 95% CI 0.87–1.92, p = 0.20 Two days with hypothermia: OR 1.69, 95% CI 1.13–2.52, p = 0.01 Three days with hypothermia: OR 1.68, 95% CI 1.06–2.66, p = 0.03

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Unadjusted mortality (univariate associations)

Adjusted mortality (multivariate associations)

Niven et al.

Hypothermic pts (Tc < 36 C) had higher ICU mortality than normothermic ones: 31% vs 18%, p < 0.01

In medical pts, mild (Tc < 36 ◦ C), moderate (32 ◦ C < Tc < 35 ◦ C) and severe hypothermia (Tc < 32 ◦ C) were independently associated with higher ICU mortality: OR 1.59, 95% CI 1.21–2.09, p = 0.001, OR 4.21, 95% CI 2.96–5.98, p < 0.001, and OR 3.96, 95% CI 1.42–11.07, p = 0.009 respectively In surgical pts, mild (Tc < 36 ◦ C), moderate (Tc < 35 ◦ C) and severe hypothermia (Tc < 32 ◦ C) were independently associated with higher ICU mortality: OR 1.72, 95% CI 1.14–2.60, p = 0.01, OR 5.98, 95% CI 3.88–9.24, p < 0.001, and OR 135.9, 95% CI 9.6–944.5, p < 0.001 respectively

Peres Bota et al.31

Hypothermia or fever were independently associated with higher ICU mortality: OR 3.07, 95% CI 1.65–5.74, p < 0.001 Hypothermia was independently associated with higher hospital mortality: OR 7.8, 95% CI 3.9–15.4, p < 0.001

Tiruvoipati et al.17

Hypothermic pts (Tc < 36 ◦ C) had higher ICU mortality than normothermic ones: 33.3% vs 10.3%, p < 0.01 Hypothermic pts (Tc < 36 ◦ C) had higher hospital mortality than normothermic ones: 78.0% vs 23.1%, OR 12.7, 95% CI 8.4–19.4, p < 0.001 Not reported

Tridente et al.33

Not reported

Weinkove et al.34

Not reported

Lowest Tc (within 24 h of ICU admission) was independently associated with higher ICU, hospital and 28-day mortality: per 1 ◦ C decrease, OR 0.83, 95% CI 0.73–0.94, p < 0.001; OR 0.88, 95% CI 0.78–0.99, p < 0.001; and OR 0.82, 95% CI 0.70–0.95, p < 0.001 respectively Hypothermia (Tc < 36.5 ◦ C) was independently associated with higher hospital mortality (compared to normothermic patients): In non-neutropenic sepsis pts: OR 1.5, 95% CI 1.4–1.6, p < 0.001 In neutropenic sepsis pts: OR 1.9, 95% CI 1.3–2.8, p < 0.001

Young et al.35

Hypothermic pts (Tc < 36 ◦ C) had higher hospital mortality than normothermic ones: Australia/New Zealand pts, infection group: OR 4.84, 95% CI 3.99–5.89; non-infection group: OR 6.72, 95% CI 6.24–7.24 UK pts, infection group: OR 3.99, 95% CI 3.54–4.48; non-infection group: OR 4.32, 95% CI 3.98–4.69

Hypothermia was independently associated with higher hospital mortality: Australia/New Zealand pts, infection group: OR 3.01, 95% CI 2.37–3.82; non-infection group: OR 3.60, 95% CI 3.26–3.98 UK pts, infection group: OR 3.04, 95% CI 2.67–3.46; non-infection group: OR 2.80, 95% CI 2.61–3.01

14

Rincon et al.32

◦

Lowest Tc (within 24 h of ICU admission) was independently associated with higher hospital mortality: In all pts, OR per 1 ◦ C decrease: 0.58, 95% CI 0.40–0.87, p = 0.008 In pts >65y, OR per 1 ◦ C decrease: 0.51, 95% CI 0.31–0.85, p = 0.01

ICU, Intensive Care Unit; pts, patients; Tc , core temperature; OR, odds ratio; CI, confidence interval.

tality than medical ICU patients.43 Therefore, surgical patients are expected to be less susceptible to IH complications than other ICU patient groups, and the detection of significant IH-mortality associations would require large population enrolment. The third study was not limited to surgical patients and enrolled a much larger population (1,425 patients), but reported the lowest IH incidence among included studies (0.4%), which corresponded to only six patients.29 This surprisingly small number of hypothermic patients seems possible to have precluded the detection of significant hypothermia-mortality associations. An alternative explanation for the IH-mortality association is that high clinical severity of ICU patients could be the underlying cause of both increased mortality and failure to maintain normal Tc . Previous studies in septic patients have suggested that IH may have been the result of incubating infection, or that sepsis severity combined with subsequent aggressive fluid resuscitation can be important sources of both IH and adverse outcome; moreover, inability to mount febrile response or maintain normothermia could indicate metabolic exhaustion associated with poor prognosis.17,44,45 Likewise, in trauma patients, increased mortality of hypothermic ones can be primarily caused by high injury severity rather than by hypothermia per se.46 5.1. Implications for clinical practice and research The association of IH with worsened patient outcome poses an imperative need for Tc to be appropriately monitored in the

ICU, as the first step for preventing or early detecting IH. Medical and nursing personnel should be cautious in the selection of Tc measurement devices and sites, since there is evidence that some easy-to-use thermometry methods (such as temporal artery or tympanic membrane thermometry) are characterized by low sensitivity for detecting temperature disorders, and thus they often fail in effectively screening hospitalized patients for fever or IH.47,48 Considering that many patients arrive hypothermic in the ICU, effective prevention of this temperature disorder is obviously extended beyond critical care, especially in the operating room, the emergency department and medical/surgical wards. IH incidence in postoperative patients transferred to the ICU continues to be remarkably high, despite the development of clinical guidelines for preventing perioperative IH.49,50 With regard to trauma patients, return to normothermia can be particularly difficult, since they sometimes suffer from profound IH. In this case, IH treatment may require the use of more invasive, aggressive warming methods, such as extracorporeal rewarming.51 In both postoperative and trauma patients, other aspects of medical and nursing care are commonly prioritized instead of Tc management; however, in patients with critical illness, adverse consequences of IH should not be underestimated. In the absence of ICU-specific evidence-based guidelines for IH prevention, the recommendation of experts on perioperative IH that Tc of all patients should be maintained >36.0 ◦ C (unless therapeutic hypothermia is indicated) can be used for guiding therapeutic decisions in the critically ill.2,8 IH prevention should be

Please cite this article in press as: Kiekkas P, et al. Inadvertent hypothermia and mortality in critically ill adults: Systematic review and meta-analysis. Aust Crit Care (2017), http://dx.doi.org/10.1016/j.aucc.2017.01.008

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Fig. 3. Forest plots depicting adjusted odds ratios for mortality (with 95% confidence intervals) according to inadvertent hypothermia, (a) hypothermia defined as core temperature <36.0 ◦ C, (b) hypothermia defined as core temperature <35.0 ◦ C. pts, patients; CI, confidence interval.

based on appropriate Tc monitoring along with the identification of groups being at high risk for IH, such as trauma, postoperative and septic patients. In the absence of evidence-based guidelines for IH management in critically ill adults, the use of clinically sound management strategies, tailored to individual patient characteristics and institutional expertise and resources, has been suggested for maintaining normothermia.52 In this context, active external or internal rewarming methods generally need to be applied when Tc declines below normal, including combinations of forced-air warming or resistive heating, inhalation rewarming with humidified oxygen, along with intravenous infusion heating (especially when large amounts of fluids need to be administered). In addition, ICU personnel are strongly recommended to develop and implement normothermia care plans. Respective plans previously developed for perioperative care have been shown to result in significant decreases in IH incidence of surgical patients.53 A recommended issue for future research would be the evaluation of prewarming in critically ill adults being at high risk for IH. Proactive use of warming methods has been particularly effective for IH prevention in the perioperative setting, by decreasing the normal core-to-periphery temperature gradient.54 Randomized trials should be conducted to test the effectiveness of prewarming in decreasing IH incidence and duration in the ICU, along with its possible effects on mortality. Moreover, since IH-mortality association might be differentiated among diverse patient groups (with some of them being particularly vulnerable to even slight Tc decreases below normal), identification of patients who will bene-

fit most from aggressive IH treatment is suggested. In this context, the investigation of the impact of different methods and rates of rewarming on patient outcomes seems to be important. 5.2. Study limitations In the present systematic review, searches were conducted in only five information sources, and only full-text articles published in English-language journals were considered for inclusion. Therefore, other comprehensive and updated databases were not searched, and theses, conference abstracts and other-language articles were not covered. Second, although risk for bias of included studies was evaluated according to specific criteria, established tools for assessing risk for bias (such as The Cochrane Risk of Bias Tool) were not used. Third, the conduction of multivariate regression can limit but not eliminate the possibility of confounding effects, which means that adjustment for confounders might be incomplete in some studies. This meta-analysis was further subject to certain limitations. First, substantial heterogeneity was identified among studies that defined IH as Tc < 36.0 ◦ C. Second, four of these studies did not provide adjusted ORs for mortality for the entire ICU population, but only for separate patient groups; thus, for each of these studies, more than one OR was used in the quantitative synthesis. Third, subgroup analysis based on admission type of ICU patients (e.g. surgical vs. medical) could not be conducted, since the majority of studies did not provide separate adjusted ORs for mortality. Such

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an analysis could have provided information about possible modification of the IH-mortality association according to admission type. 6. Conclusions and recommendations Considering that IH is common among adults admitted to the ICU, this systematic review and meta-analysis summarized the evidence about its association with mortality, which is important for prognostic and therapeutic purposes. In the majority of studies, IH or lowest Tc during ICU stay was associated with significantly higher mortality. Although observational study design cannot establish causality, the present findings along with previously-documented severe complications of IH raise considerable possibility that this temperature disorder can contribute, at least to some extent, to increased mortality of the ICU population. In this context, appropriate prevention and treatment of IH is expected to minimize complications and therefore improve patient outcomes. Being at the front line of IH management, nursing personnel are called to be aware of the importance of appropriate Tc monitoring and of IH complications, participate in decision-making about the application of preventive measures for IH and evaluate the effectiveness of available warming strategies and methods. Funding None. Authors’ contributions PK and EK contributed to conception, design, manuscript writing, and critically revised this article. FF, VK and DA contributed to data extraction and analysis, and drafted this article. MI and NS contributed to article acquisition and screening for inclusion. All authors have approved this version and agree to be accountable for all aspects of work ensuring integrity and accuracy. References 1. Sessler DI. Perioperative heat balance. Anesthesiology 2000;92(2):578–96. 2. Sessler DI. Complications and treatment of mild hypothermia. Anesthesiology 2001;95(2):531–43. 3. Frank SM, Fleisher LA, Breslow MJ, Higgins MS, Olson KF, Kelly S, et al. Perioperative maintenance of normothermia reduces the incidence of morbid cardiac events. A randomized clinical trial. J Am Med Assoc 1997;277(14):1127–34. 4. Hart SR, Bordes B, Hart J, Corsino D, Harmon D. Unintended perioperative hypothermia. Ochsner J 2011;11:259–70. 5. Reynolds L, Beckmann J, Kurz A. Perioperative complications of hypothermia. Best practice and research. Clin Anaesthesiol 2008;22(4):645–57. 6. Winkler M, Akc¸a O, Birkenberg B, Hetz H, Scheck T, Arkilic¸ CF, et al. Aggressive warming reduces blood loss during hip arthroplasty. Anesth Analg 2000;91(4):978–84. 7. Kumar S, Wong PF, Melling AC, Leaper DJ. Effects of perioperative hypothermia and warming in surgical practice. Int Wound J 2005;2(3):193–204. 8. Kurz A, Sessler DI, Lenhardt RA. Perioperative normothermia to reduce the incidence of surgical-wound infection and shorten hospitalization. Study of Wound Infections and Temperature Group. N Engl J Med 1996;334(19):1209–15. 9. Lenhardt R, Marker E, Goll V, Tschernich H, Kurz A, Sessler DI, et al. Mild intraoperative hypothermia prolongs postanesthetic recovery. Anesthesiology 1997;87(6):1318–23. 10. Kushimoto S, Gando S, Saitoh D, Mayumi T, Ogura H, Fujishima S, et al. The impact of body temperature abnormalities on the disease severity and outcome in patients with severe sepsis: an analysis from a multicenter, prospective survey of severe sepsis. Crit Care 2013;17(6):R271. 11. Laupland KB, Zahar JR, Adrie C, Schwebel C, Goldgran-Toledano D, Azoulay E, et al. Determinants of temperature abnormalities and influence on outcome of critical illness. Crit Care Med 2012;40(1):145–51. 12. Karalapillai D, Story DA, Calzavacca P, Licari E, Liu YL, Hart GK. Inadvertent hypothermia and mortality in postoperative intensive care patients: retrospective audit of 5050 patients. Anaesthesia 2009;64(9):968–72.

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