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A systematic review of the effects of body temperature on outcome after adult traumatic brain injury.

ABSTRACT

Objective: This systematic review describes effects of body temperature alterations defined as fever, controlled normothermia, and spontaneous or induced hypothermia on outcome after traumatic brain injury (TBI) in adults. Data Sources: A search was conducted using PubMed, Cochrane Library database, Cumulative Index to Nursing and Allied Health Literature, EMBASE, and ISI Web of Science in July 2013 with no back date restriction except for induced hypothermia (2009). Study Selection: Of 1366 titles identified, 712 were reviewed. Sixteen articles met inclusion criteria: randomized controlled trials in hypothermia since 2009 (last Cochrane review) or cohort studies of temperature in TBI, measure core and/or brain temperature, neurologic outcome reporting, primarily adult patients, and English language publications. Exclusion criteria were as follows: most patients with non-TBI diagnosis, primarily pediatric patients, case reports, or laboratory/animal studies. Data Synthesis: Most studies found that fever avoidance resulted in positive outcomes including decreased length of stay in the intensive care unit; mortality; and incidence of hypertension, elevated intracranial pressure, and tachycardia. Hypothermia on admission correlated with poor outcomes. Controlled normothermia improved surrogate outcomes. Prophylactic induced hypothermia is not supported by the available evidence from randomized controlled trial. Conclusion: Setting a goal of normothermia, avoiding fever, and aggressively treating fever may be most important after TBI. Further research is needed to characterize the magnitude and duration of temperature alteration after TBI, determine if temperature alteration influences or predicts neurologic outcome, determine if rate of temperature change influences or predicts neurologic outcome, and compare controlled normothermia versus standard practice or hypothermia.

Keywords: body temperature, body temperature changes, brain injuries, craniocerebral trauma, emergency treatment, fever, hypothermia, normothermia, outcome

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Traumatic brain injury (TBI) is a leading cause of death and disability, contributing to one third of all injury-related deaths in the United States (Faul, Xu, Wald, & Coronado, 2010). The annual economic burden of TBI in the United States has been estimated to be $4.5 billion in direct expenses for hospital care, extended care, and other medical services (Barker-Collo & Feigin, 2009). An additional $20.6 billion in injury-related disability and loss of work and $12.7 billion in lost income from premature death are attributed to TBI in the United States (Barker-Collo & Feigin, 2009). Poor outcomes from the primary injury and preventable secondary brain injuries result in significant costs to individuals, families, and society. Published guidelines provide limited evidence to guide interventions intended to reduce secondary insult. One of the more widely studied strategies has been targeted temperature management (TTM), which involves the identification of the desired patient temperature with interventions or treatments provided to achieve goals. TTM may occur in the form of fever reduction, controlled normothermia (NT), or induced hypothermia (FIT). Prior studies and reviews have focused on these individual forms of TTM, but none have looked at this body of literature and synthesized the findings regarding the broader range of temperature and outcome in TBI. Disparate findings regarding the effect of temperature alterations have resulted in a lack of clear and robust evidence to guide temperature management in TBI.

Fever

Fever, generally defined as elevation of core body temperature above normal body temperature (37[degrees]C), has been identified as a mechanism of secondary insult that can exacerbate primary TBI through multiple cellular mechanisms (Childs et al., 2006; Thompson, Pinto-Martin, & Bullock, 2003). Healthy human brains tolerate increases in metabolism because of fever; however, the injured brain does not. Fever exposure has resulted in an increase in ischemic injury and infarct in injured brain, but the same fever exposure in non-injured brain did not result in such findings or show any impact on the integrity of neuronal tissue (Dietrich, 1992). A central reason for this damage may be related to a 7%-13% increase in cerebral metabolism for each increase of 1 [degrees]C in core body temperature (Thompson et al., 2003; Wong, 2000). To make matters worse, the threshold for ischemia in the injured brain is lower than that of the normal brain, widening the mismatch between cerebral blood flow and metabolic demand (Schroder, Muizelaar, Kuta, & Choi, 1996). Thus, mechanisms to minimize cerebral metabolic demand have been extensively studied with the goal of avoiding or minimizing the extent of secondary insult. Cerebral insults beyond the primary injury have been associated with longer intensive care unit (ICU) and hospital stays as well as reduced survival and quality of life after injury (Jones et al, 1994; Stocchetti et al., 2002).

Controlled NT

Controlled NT is a form of TTM. The Guidelines for the Management of Severe Traumatic Brain Injury suggest NT for patients with TBI (Bratton et al., 2007). Aberrance of temperature from normal range (fever or HT) is associated with more deaths and poorer neurologic outcomes (Childs et al., 2006; Sacho, Vail, Rainey, King, & Childs, 2010).

HT on Admission

HT on admission has been found to correlate with poor outcomes in both general trauma literature (Jeremitsky, Omert, Dunham, Protetch, & Rodriguez, 2003; Steinemann, Shackford, & Davis, 1990) and specifically in TBI (Jurkovich, Greiser, Luterman, & Curreri, 1987). This may be related to the established association between HT, coagulopathy, and acidosis. Poor outcomes associated with HT might simply reflect a higher severity of brain tissue injury (e.g., more extensive injury to the hypothalamus) or more severe blood loss related to systemic injuries.

Induced HT

Interest in the effect of temperature on outcome in TBI led to randomized controlled trials (RCTs) testing HT in TBI. Prophylactic induced mild-to-moderate HT (32[degrees]C-35[degrees]C) has been studied extensively in ischemic neurologic injury and has been found to be neuroprotective via decrease in excitatory amino acid release, metabolism suppression, and other actions (Adelson, 2009; Adelson et al., 2005; Bayir et al., 2009; Clifton, 1995b; Fox et al., 2010; Jiang, 2009; Shann, 2003). Multiple pilot studies of HT in TBI have resulted in improved outcomes and decreased mortality (Clifton, 1995a; Marion et al., 1997; Shiozaki et al., 1993). Several single-center trials have shown that moderate HT compared with NT led to improvement in survival and outcome (Clifton et al., 1993; Inamasu et al., 2006; Jiang, Yu, & Zhu, 2000). Contrary to those promising pilot results (Clifton et al., 1993), large multicenter clinical trials (Clifton et al., 2001, 2011) failed to show improvement in TBI outcomes with induced HT. Whereas a pilot study in ischemic stroke (Krieger et al., 2001) and an RCT in hypoxic ischemic encephalopathy in newborns (Shankaran et al., 2005) have found benefit from induced moderate HT (Krieger et al., 2001; Shankaran et al., 2005), studies investigating HT in TBI have not consistently shown improved patient outcomes, identified an ideal duration of treatment, or established an optimal body temperature goal. Recent investigation of 33[degrees]C versus 36[degrees]C in cardiac arrest patients has shown no difference in neurologic outcome or mortality between groups (Nielsen et al., 2013).

A 2009 Cochrane review (Sydenham, Roberts, & Alderson, 2009) included RCTs of HT versus control in patients with blunt TBI. Exclusion of low-quality studies defined as non-RCTs, lacking good allocation concealment, high risk of bias, or unclear methods resulted in no significant differences in survival, neurologic outcome, or incidence of pneumonia between the HT groups versus control patients (Sydenham et al., 2009). Sadaka and Veremakis (2012) conducted a systematic review of induced HT (32[degrees]C-34[degrees]C) specific to management of elevated intracranial pressure (ICP; >20 mm Hg) in severe TBI (GCS [less than or equal to] 8). The review included 13 RCTs and five observational studies and concluded that induced HT should be included as an option to control ICP. Fox and colleagues (2010) performed a systematic review of induced HT in TBI, dividing studies into two categories: those with cooling protocols for a short, predetermined period (e.g., 24-48 hours) and those that cool for >48 hours and/or terminate based on normalization of ICR The review supported the use of early prophylactic induced mild-tomoderate HT in patients with severe TBI with a goal-directed cooling protocol in which cooling was maintained for [greater than or equal to] 72 hours and/or until normalization of ICP for at least 24 hours was achieved (see Supplementary Table 1, available as Supplemental Digital Content 1 at http://links.lww .com/JNN/A34).

Purpose

Despite lack of consistent robust evidence, TTM has been a fundamental element of patient care after TBI. The diverse approaches to temperature management after TBI and lack of well-controlled clinical trials of interventions have hindered the development of evidenced-based treatment guidelines. Prior publications have reviewed fever in TBI or in general neurocritical care or induced HT in TBI or a variety of populations. The purpose of this systematic review of the literature is to describe the effects of body temperature alterations defined as fever, controlled NT, HT on admission, or spontaneous or induced HT on outcome after TBI in adults.

Methods

A search was conducted using PubMed, the Cochrane Library database, Cumulative Index to Nursing and Allied Health Literature, EMBASE, and ISI Web of Science. The search was conducted in July 2013 with no back date restriction except for induced HT RCTs (2009 back date, date of last Cochrane review). Of 1366 titles identified, 712 were reviewed (see Figure 1). Sixteen articles met the following criteria: (a) either RCTs in HT made available since 2009 or cohort studies of temperature ("naturally occurring temperature," fever, NT, HT on admission, or induced HT) in TBI; (b) measure of core and/or brain temperature (BT); (c) reports of neurologic outcome measures or, for the only NT study, outcome surrogate (e.g., intracranial hypertension burden); (d) primarily adult patients; and (e) English language publications. Exclusion criteria were most patients with non-TBI diagnosis, primarily pediatric patients, case reports, or laboratory/animal studies.

Results

Cohort Characteristics

Patients were primarily adults with blunt-force moderate or severe TBI. Some observational cohorts included lower severity of injury. Consistent with epidemiologic reporting of TBI (Faul et al., 2010), men were more prevalent in studies, with some studies including a disproportionate number of men. Because of the heterogeneity of studies reviewed, a brief summary of each study is provided (see Tables 1-4). Although methodologically diverse, the studies included reflect the most rigorous and recent studies considering the spectrum of temperature variations after TBI.

Quality of Studies

Volume of Studies to Review

According to criteria for Cochrane review (RCT of HT to a maximum of 35[degrees]C for [greater than or equal to] 12 consecutive hours vs. control in patients with any closed TBI requiring hospitalization), lower quality studies (poor or unclear allocation concealment) of HT were excluded. In addition, studies in which surrogate measures of outcome were used (measures other than Glasgow Outcome Scale [GOS] or extended GOS) were excluded. Surrogate measures may not consistently correlate with neurologic outcome, so this would also likely confound recommendations. The exception from this is the singular controlled NT study (Puccio et al., 2009) that used surrogate measures of outcome that was selected for inclusion because it is the only study of controlled NT in TBI.

Measurement Issues

Studies used a variety of temperature sources (bladder, brain, arterial, axillary, rectal). This is one limitation of studies using existing data. Childs et al. convened a consensus group regarding temperature and TBI and advised that BT should be used because this is the organ of interest (2010). However, studies using BT monitoring to guide management have a significant delay in temperature measurement and interventions. Childs et al.'s initial BT measurement occurred 4-41 hours after admission with a mean delay of 10.5 hours. Sacho et al.'s initial BT measurement occurred 6-32 hours after admission with a mean time of 11 hours (Childs et al, 2006; Sacho et al, 2010).

Although Puccio and colleagues considered secondary insult burden by identifying the percentage of time outside a nonnal threshold (intracranial hypertension burden [percent of time, in minutes, for ICP measurements >25 mm Hg calculated for the initial 5 days of the monitoring period]), they did not account for the degree (or extent) of difference between the measured temperature value and the threshold temperature value. There may be some effect related to the magnitude of the difference between those two values. This is the same limitation in studies that used mean temperature values or stratified patients according to temperature groups (NT, mild fever, or high fever), consequently limiting statistical power and internal validity of the findings.

Outcome Assessment

The outcome measure most commonly reported was the 5-point GOS score at 3 or 6 months. The one controlled NT study considered a surrogate measure (ICP burden) rather than neurologic outcome. Most studies collapsed the 5-point GOS ordinal scale into a binary variable of "favorable" (moderate disability, good recovery) versus "unfavorable" (death, vegetative state, severe disability) or "survival" versus "mortality" outcome (McHugh et al., 2007).

Findings

Naturally Occurring Temperature Whereas many studies focused on specific temperatures within a sample, a few observed "naturally occurring" patient temperatures, which include fever, NT, and HT during varying periods after injury (Childs et al., 2006; Elf et al., 2008; Jeremitsky et al., 2003; Sacho et al., 2010; Yamamoto et al., 2002). Childs et al. examined BT and outcomes in 36 patients with moderate-to-severe TBI (Childs et al., 2006) to explore the relationship between initial and 48-hour postinjury mean BT and 3-month mortality. Initial BT measured shortly after ICU admission did not predict outcome. Depending on which statistical model was used, patients with higher or lower mean BTs had an increased risk of death. Sacho et al. (2010) followed a cohort prospectively with the purpose of exploring the relationship between 5-day postinjuiy BT and 30-day mortality and 3-month dichotomized extended GOS (favorable/unfavorable neurologic outcome). Systemic cooling was provided in a tiered fashion for elevated ICP of >25 mm Hg accompanied by fever > 37.5[degrees]C or temperature > 39[degrees]C regardless of ICP. Antipyretic medications were provided as part of routine care. BT was independently predictive of 30-day mortality adjusting for some potential confounders. When pupillary reaction was added as a variable, the relationship between BT and outcome was no longer significant (Table 1).

Elf and colleagues (2008) identified 53 patients during the first 120 hours after TBI to describe the occurrence of spontaneous fever, HT, and temperature correlates with secondary insults. However, review of bladder temperature and other secondary insult variables revealed a nonsignificant trend toward better outcome for patients with normal temperature compared with those with aberrant temperatures (Table 1). Both Jeremitsky et al. (2003) and Yamamoto et al. (2002) sought to identify variables that might predict outcome in severe TBI. Jeremitsky et al. identified frequency of occurrence of secondary insults, including HT and fever. Hypotension, hypoglycemia, and HT were associated with an increased mortality rate. Yamamoto et al. looked at variables that were associated with good or poor outcomes in a sample of patients with HT compared with a sample of patients with NT who received barbiturates as a part of their therapy. Patients in the HT group fared better than the NT group.

Fever

When Li and Jiang stratified patient temperatures into groups, they found that increasing severity and duration of fever predicted poorer outcomes (Table 1). Normal temperature or low fever and shorter duration of exposure to elevated temperature were associated with more favorable outcomes (Li & Jiang, 2012). Those with severe TBI who had more high-fever days had higher mortality (Li & Jiang, 2012). Stocchetti et al. also found that the occurrence and duration of fever is significantly associated with severe TBI (Stocchetti et al., 2002). Most studies found that avoidance of fever is valuable, decreasing ICU length of stay, mortality, incidence of hypertension, high ICP, and tachycardia (Childs et al., 2006; Elf et al., 2008; Jeremitsky et al., 2003; Li & Jiang, 2012; Sacho et al., 2010; Stocchetti et al., 2002). However, these findings are not consistent across studies (Childs et al., 2006; Spiotta et al., 2008). One critical aspect to consider may be timing of fever. Geffroy et al. found that patients who have an early fever are more likely to have a poor outcome. Those with early fever are more likely to have a less favorable survival than those without early fever (Geffroy et al., 2004).

Controlled NT

Puccio et al. performed the only study of controlled NT using a cohort of 21 adult patients with severe TBI treated with routine care matched to 21 patients treated with induced NT via an intravascular cooling catheter (Puccio et al., 2009). ICP was measured via an external ventricular drain, and time duration for ICP > 25 mm Hg was calculated for the initial 72-hour monitoring period (ICP burden). Fever burden was defined as the percentage of time in which rectal temperature was >38[degrees]C in the first 72 hours. Induced NT via intravascular cooling catheter was effective in reducing both fever burden and intracranial hypertension burden (Table 2).

HT on Admission

Bukur et al. (2012) examined the relationship between admission HT and mortality in patients with moderate-to-severe TBI and found that admission HT was independently associated with increased mortality in moderate-to-severe TBI. Similarly, Konstantinidis et al. (2011) sought to identify the influence of admission HT on outcome in patients with isolated severe TBI. All trauma patients admitted to the surgical ICU (SICU) with isolated (no other significant injuries) severe TBI were classified as HT (temperature [less than or equal to] 35[degrees]C) or NT (temperature > 35[degrees]C) based on their first core temperature recorded after SICU admission. Patients who were HT on SICU admission were significantly less likely to survive.

Thompson and colleagues (2010) sought to determine the incidence and magnitude of HT in patients on emergency department (ED) admission and the effect of HT and rate of rewarming on patient outcomes in a secondary data analysis of patients admitted to a single level 1 trauma center after severe TBI. The authors found that HT on admission was correlated with worse outcomes (Table 3) and concluded this related to rapid rewarming (increase of 0.25[degrees]C/hour) of patients presenting with HT on admission.

Induced HT

Since the latest Cochrane review in 2009, two RCTs, one observational study comparing two TTM goals, and one secondary analysis of data from two RCTs have been published (Table 4). Zhao and colleagues (2011) studied the effect of 72 hours of mild HT (32.7[degrees]C) on glucose and lactate levels in patients randomized to HT or NT. HT was identified as an independent predictor for favorable outcome in patients with severe TBI.

Clifton and colleagues (2011) reported on the findings of the National Acute Brain Injury Study: Hypothermia (NABIS:H II), a multicenter RCT of severe TBI treated with NT or HT for 48 hours. The study was stopped for futility at interim analysis, failing to show that early induction of HT resulted in improved outcomes. Clifton suggested that elevated ICP in the HT treatment group may be related to rebound elevation in ICP during rewarming as well as ICP elevation related to mass lesions before evacuation. This led to a post hoc analysis of patients enrolled in both NABIS:H I and NABIS:H II to identify whether cooling before evacuation of traumatic intracranial hematomas protects the brain from reperfusion injury (Table 4). Clifton et al. (2012) proposed that induced HT in this population before or soon after craniotomy may be associated with improved outcomes.

Tokutomi et al. (2009) attempted to clarify whether cooling to 35[degrees]C has the same effect as 33[degrees]C in reducing elevated ICP and whether it is associated with fewer complications and improved outcomes in patients with severe TBI. There were no significant differences in ICP, cerebral perfusion pressure, or outcomes between groups. The authors concluded that cooling to 35[degrees]C is equally effective as 33[degrees]C.

Limitations

Temperature Measures

Investigators stratified patients by temperature ranges rather than considering temperature as a continuous variable. All studies quantified temperature by the number of days or fever incidence rather than the nuances of temperature during that 24-hour period such as amount of time temperature was elevated, severity of temperature measurement difference from identified normal range, or timing of a peak temperature. A few studies reported findings as "naturally occurring" temperatures, yet interventions modifying temperature were provided. Delayed temperature measurement from 6 to 24 hours after injury may have missed important early information (Childs et al., 2006; Sacho et al., 2010; Spiotta et al., 2008). Definitions of fever and treatment thresholds for elevated temperature vary in the literature and in practice. Details of fever dose and impact on outcome are not well described in the literature.

Warming Rates

Patients presenting with HT on admission may be passively or actively rewarmed. The rate of rewarming is not reported in most of the HT literature. Thompson et al, considered this issue in a post hoc analysis of patients with TBI presenting to the ED and noted that the rate of rewarming varies and is not well documented (Thompson et al., 2010). Patients who have been cooled for induced HT are also rewarmed at varying rates. In the Clifton RCTs, rewarming was done slowly. When rates have been reported, they vary among trials and may or may not have been adjusted according to ICP response. Prior RCT control groups were not purely control groups of usual care since patient management varied. In prior RCTs, there were also variations in "control" methods (e.g., patients who were hypothermic on admission, treatment thresholds for fever) making comparison among results challenging. Furthermore, the negative effect of active rewarming upon randomization to NT may have made NT patient outcomes worse than if they were passively or more slowly rewarmed. In the case of passive rewarming, spontaneous elevations of temperature may result in more rapid rewarming than controlled rewarming (Polderman & Herold, 2009).

Variables Influencing Temperature

Injury activates an immune response and incites varying degrees of cytokine and interleukin release with white blood cell activation resulting in temperature elevation. Injury to the hypothalamus can also cause impaired regulation of temperature. Blood products within the brain tissue and/or ventricular system can elicit temperature elevation. None of these variables (such as serum or cerebrospinal fluid cytokine levels, head computed tomography scan, or brain magnetic resonance imaging findings) were reported in the studies reviewed, with the exception of white blood cell values in one study (Geffroy et al., 2004). Barbiturate administration confounded results. Yamamoto et al. found that patients with HT who did not receive barbiturates had better survival than patients with NT who received barbiturates (Yamamoto et al., 2002). Elf et al. found that, excluding barbiturate-treated patients, those with HT and NT fared better than those with fever (Elf et al., 2008).

Conclusion

Studies investigating TTM in TBI suggest that mild HT (targeting either 33[degrees]C or 35[degrees]C) may benefit those patients who have elevated ICP; yet, with no statistically significant difference in 6-month GOS between those groups, the evidence is not compelling (Tokutomi et al., 2009). The Guidelines for the Management of Severe Traumatic Brain Injury (Bratton et al., 2007) suggest NT for patients with TBI. Although controlled NT improved surrogate outcome measures of ICP burden (Puccio et al., 2009) and was associated with a lower probability of death (Childs et al., 2006), its practice is lacking outcomes-based evidence. Maintenance of NT may be most important for physiologic homeostasis after TBI. Yet, identification of a temperature range that positively impacts patient outcomes has not been determined.

Timing, duration, and severity of fever exposure influence patient outcomes. However, many interventions to treat fever are not aggressive (Thompson, Kirkness, & Mitchell, 2007). Recent investigation of 33[degrees]C versus 36[degrees]C in cardiac arrest patients (Nielsen et al., 2013) supports the hypothesis that fever avoidance may be the highest yield intervention in TTM (Rittenberger & Callaway, 2013), but this is not translatable directly to TBI and requires further investigation in this population.

HT on admission correlated with poor outcomes. Advanced Trauma Life Support protocols do not clearly direct rates of rewarming patients with traumatic injuries. Aggressive practices of warming hypothermic patients to avoid the "lethal triad" of acidosis, HT, and coagulopathy (Burch et al., 1992) may be detrimental to those patients with TBI. The benefits associated with HT (lowered ICP) are negated when rewarming is done rapidly (Povlishock & Wei, 2009). The rate of temperature change, whether from HT to normal temperature or further toward fever, may be as important as the rate of cooling from fever toward NT or HT. Rate of change, or slope, of the patient temperature curve is not documented in the literature and may be important in both understanding the process after injury and identifying targets for treatment that may improve outcomes. Slow rewarming of hypothermic trauma patients in the ED with a goal of NT may be a safer approach for management of this patient population.

Current evidence-based TTM goals are poorly defined. Further research is needed to (a) characterize the magnitude and duration of temperature alteration after TBI, (b) determine if temperature alteration influences or predicts neurologic outcome, (c) determine if the rate of temperature change influences or predicts neurologic outcome, and (d) compare controlled NT versus standard practice or HT. Setting a goal of NT, avoiding fever, and aggressively treating fever if it occurs may help achieve the neuroprotective benefits of HT with lower risks.

Acknowledgment

Special thanks to Reference Librarian Brace Abbott for his assistance in identifying the literature in this review.

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Questions or comments about this article may be directed to Lori Kennedy Madden, PhD RN ACNP-BC CCRN CNRN, at lkmadden@ucdavis.edu. She is a Nurse Practitioner, Department of Neurological Surgery, University of California Davis, Sacramento, CA.

Holli A. DeVon, PhD RN FAHA FAAN, is an Associate Professor, Department of Biobehavioral Health Science, College of Nursing, University of Illinois at Chicago, Chicago, IL.

Research reported in this publication was supported by the National Institute of Nursing Research of the National Institutes of Health (F31NR013813) and the Gordon and Betty Moore Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

The authors declare no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.jnnonline.com).

DOI: 10.1097/JNN.0000000000000142

TABLE 1. Naturally Occurring Temperature/Fever in TBI

Author        Study Design and Participants     Comparisons/Measures

Childs et    n = 36 (32 M/4 F)                 BT
al. (2006)   Median age = 31 (18-70) years     ICU admission temp
             Moderate and severe TBI           48-hour postinjury temp

Elf,         n = 53 (42 M/11 F; 79.2% M)       Bladder temp
Nilsson,     Mean age = 42.3 (16-75) years     Mean temp over
Ronne-       Severe TBI                        5 days postinjury: HT:
Engstrom,    Patients with [greater than or    temp < 36[degrees]C
Howells,     equal to] 54 hours of valid       (adjusted to 36.5
and Enblad   monitoring measures in the        [degrees]C for analysis
(2008)       first 120 hours post-TBI          between groups)
                                               NT: temp 36.5[degrees]
                                               C-38[degrees]C Fever:
                                               temp > 38[degrees]C
                                               ICP, CPP, SBP, MAP,
                                               and HR

Geffroy et   n= 101 (83 W18 F)                 Tympanic temp
al. (2004)   Median age = 33 (18-51) years     Early fever = temp >
             Severe TBI                        38.5[degrees]C during
             Early fever = 44 (42 M/2 F;       the first 2 days after
             82.2% M)                          admission
             No fever = 57 (41 M/16F)

Li and       n = 7145 (5427 M/1718 F; 76% M)   Axillary body temp
Jiang        Age = 1 -92 years                 Temp magnitudes
(2012)       (75.3% adult)                       NT (36.3[degrees]C-
             Mild TBI (4297)                       37.2[degrees]C)
             Moderate TBI (1222)                 MiF (37.3[degrees]C-
             Severe TBI (1626)                     38.0[degrees]C)
                                                 MoF (38.1[degrees]C-
                                                   39.0[degrees]C)
                                                 HF (>39.0[degrees]C)
                                               Duration: number of
                                               fever days (based on
                                               highest temp for 2
                                               consecutive hours in
                                               that day) for the first
                                               3 days after injury

Sacho et     n = 67 (52 M/15 F; 77.6% M)       BT 5 days after injury
al. (2010)   Median age = 32 years               Initial temp
             Severe TBI                          Mean 24-hour temp
             Admission to ICU                    Mean 48-hour temp
                                               Fever [greater than or
                                               equal to] 39[degrees]C
                                               BT
                                               Details of temp profile
                                               not reported

Stocchetti   n = 110 (93 M/1 7 F; 84.5% M)     Core body temp
et al.       Median age = 34 (14-83) years     Axillary temp >
(2002)       Mild-to-severe TBI (median        38.0[degrees]C or
             GCS = 7)                          core temp >
             Admission to ICU                  38.4[degrees]C
                                               in the first 7 days
                                               postinjury
                                               Classified as number
                                               of days at least one
                                               fever was detected

Yamamoto,    n = 84                            Identify factors
Mori, and    Severe TBI                        predictive of outcome
Maeda (2002) NT (total = 49; 1 7 [1 5 M/2 F]   to identify indications
             with barbiturate therapy had      for HT
             GOS assessed)                     Prediction modeling for
             Mild HT (total = 35; 22 [16       GOOD versus POOR
             M/6 F] with complete data)        outcome
                                               Mild HT ([BT =
                                               33[degrees]C-35
                                               [degrees]C] for 36-168
                                               hours) with rewarm
                                               rate [less than or
                                               equal to] 0.5[degrees]
                                               C/12 hours

Author           Outcomes                    Main Findings

Childs et    3-month             --Initial BT obtained between 4-41
al. (2006)   mortality           (median = 10.5) hours after
             3-month GOS         admission; range = 33.5[degrees]C-
                                 39.2[degrees]C (median =
                                 37.4[degrees]C)
                                 --No association between initial BT
                                 (mean = 10.5 hours) and risk of death
                                 (OR = 1.3, 95% CI [0.68, 2.5], p =
                                 .42)
                                 --Higher brain temp associated with
                                 lower mortality (OR = 0.31, 95% CI
                                 [0.09, 1.1 ], p = .06) for death per
                                 1[degrees]C drop in BT
                                 --With quadratic relationship, both
                                 high and low temp associated with
                                 increased risk of death (p = .06)

Elf,         6-month GOS         44 experienced fever (>38[degrees]C),
Nilsson,                         and 29 experienced HT (<36[degrees]C)
Ronne-                           Incidence of fever:
Howells,                           --Correlated with occurrence of HTN
and Enblad                           ([r.sup.2] = .640, p < .00001)
(2008)                               and high CPP ([r.sup.2] = .464, p
                                     < .01)
                                   --Not correlated with IICP or
                                     tachycardia
                                   --Higher in those with admission GCS
                                     motor score of 1-4 than GCS motor
                                     score of 5-6 (median: 22.2% vs.
                                     11.8%, p < .05)
                                   --Higher in men than women (median:
                                     18.6% vs. 5.3%, p < .05)
                                   --Higher (excluding those treated
                                     with barbiturates) in:
                                     * Patients [greater than or equal
                                       to] 40 years old (median: 22.8%
                                       vs. 6.1 %, p = .0015)
                                     * Patients with GCS motor score of
                                       1-4 (median: 28.8% vs. 8.6%, p =
                                       .039)
                                     * Male gender (median: 21.5% vs.
                                       5.3%, p = .040)
                                 Outcomes:
                                   --No significant difference for NT
                                     (p = .091) than fever or HT
                                     (favorable outcome: 64% vs. 29%
                                     and 33%, respectively).
                                   --Excluding those treated with
                                     barbiturates, 60% of HT and 63% of
                                     NT had a favorable outcome
                                     compared with 29% of febrile
                                     patients

Geffroy et   6-month COS         Predictors of early fever occurrence
al. (2004)                       (univariate analysis):
                                   --Male gender (p = .02)
                                   --WBC > 14.5 x [10.sup.9]/l on
                                     admission (p = .001)
                                   --Admission body temp > 36[degrees]C
                                     (p = .0004)
                                 Predictors of no occurrence of
                                 early fever:
                                   --Early occurrence of DI (p = .006)
                                   --Prophylactic acetaminophen use
                                     (p = .002)
                                 Strong predictors of early fever
                                 (multivariate analysis):
                                   --WBC >14.5 x [10.sup.9]/l on
                                     admission (OR = 7.1, 95% CI [2.4,
                                     20.5]; p = .0003)
                                   --Body temp on admission of
                                     >36[degrees]C (OR = 6.7, 95% CI
                                     [2.3, 20.1]; p = .0006)
                                 Those with early fever were:
                                   --Less likely to have good outcome
                                     (GOS = 5; p = .03)
                                   --More likely to have moderate or
                                     severe disability at 6-month GOS
                                     (GOS 3/4; p = .01)
                                   --No more likely to die or survive
                                     in a vegetative state (6-month
                                     GOS 1/2)

Li and       3-month mortality   Dichotomized GOS
(2012)       dichotomized GOS      --Differences between three groups
                                     (NT and MiF, MoF, HF; p < .001)
                                   --Significantly worse (p < .001) in
                                     the MoF and HF groups in
                                     comparison with the combined NT and
                                     MiF group
                                   --Percentage of unfavorable outcomes
                                     in patients with severe TBI
                                     increased with each HF day
                                     (p < .01)
                                 Mortality
                                   --Differences between three groups
                                     (NT and MiF; MoF, HF; p < .001)
                                   --NT and MiF severe TBI group
                                     significantly lower mortality than
                                     in the MoF group (p < .05) and HF
                                     group (p < .001)
                                   --Significantly higher in patients
                                     with severe TBI with 3 days of HF
                                     versus 1 or 2 days of HF (p < .05)

Sacho et     30-day mortality    --10%-20% lower probability of death
al. (2010)   Dichotomized        for patients with temp of
             3-month GOS-E       36.5[degrees]C-38[degrees]C
                                 --30-day mortality independently
                                 predicted by mean 24-hour brain temp
                                 (OR = 1.89, 95% CI [1.08, 3.33]; p =
                                 .03)
                                 --Increased odds of mortality
                                 associated with lower BT (OR = 0.47
                                 per 1[degrees]C change in BT)

Stocchetti   6-month GOS         --Longer ICU stay associated with
et al.       ICU length          occurrence of fever (p = .0001)
(2002)       of stay             --Presence of fever (OR = 4.686, 95%
             Elevated ICP        CI [1.754, 1 2.521]) and GCS [less
             and CPP             than or equal to] 8 (OR = 3.126, 95%
             Effects of          CI [1.063, 9.193]) independent
             antipyretic tx on   predictors of ICU LOS > 12 days
               --Temp            --MAP of 95.3 [+ or -] 8.2 mm Hg in
               --ICP             patients with fever versus 90.7 [+
               --CPP             or -] 11 mm Hg in those without (p =
                                 .0193)
                                 --Pharmacological tx resulted in
                                 temp reduction (mean reduction =
                                 0.58[degrees]C [+ or -]
                                 0.7[degrees]C)
                                 Severe TBI
                                   --Significantly associated with
                                     occurrence and duration of fever
                                     (p = .0092)
                                   --Associated with increased odds of
                                     unfavorable outcome (OR = 5.414,
                                     95% CI H .934, 15.155])

Yamamoto,    Dichotomized        HT
Mori, and    3-month GOS
Maeda (2002)   --GOOD:             --GOS significantly better than NT
               good                  with barbiturates (p < .05)
               recovery or         --Mortality significantly better
               moderate              than NT with barbiturates (18.2%
               disability            vs. 52.9%, p < .05)
               --POOR:             --GOOD: n = 9, 40.9%;
               severe                  POOR, n = 13, 59.1%
               disability,           * Age (9-46 years, mean =
               vegetative              30.2 years) significantly lower
               state, or death         than in POOR (17-62 years, mean
                                       = 45.2 years; p < .05)
                                   --Patients aged over 50 years
                                     had poor outcome
                                   --CPP significantly higher in GOOD
                                     (100.1 [+ or -] 12.2 vs. 74.8 [+ or
                                     -] 1 7.2) during HT (goal CPP >
                                     70 mm Hg)
                                   --All patients with HT with
                                     thrombocytopenia had poor outcome

Note. AIS-H = abbreviated injury score of the head region; CI =
confidence interval; CPP = cerebral perfusion pressure; DI =
diabetes insipidus; F = female; CCS = Glasgow Coma Scale; COS =
Glasgow Outcome Scale; GOS-E = extended Glasgow Outcome Scale; HF =
high fever; mild TBI = GCS of 13-15; HR = heart rate; HT =
hypothermia; HTN = hypertension; ICP = intracranial pressure; IICP
= increased intracranial pressure; LOS = length of stay; M = male;
MAP = mean arterial pressure; MiF = mild fever; moderate TBI = GCS
of 9-12; MoF = moderate fever; NT = normothermia; OR = odds ratio;
SBIF = secondary brain injury factors; SBP = systolic blood
pressure; severe TBI = GCS of 3-8; TBI = traumatic brain injury;
temp = temperature; tx = treatment; WBC = white blood cell count.

TABLE 2. Normothermia in TBI

              Study Design and          Comparisons/Temperature
Author          Participants                    Measure

Puedo    n = 42 (36 M/6 F)            Rectal temp
et al.   --21 severe TBI              Induced NT (via
(2009)   induced NT group             intravascular cooling
         (18 M/3 F)                   catheter with rectal temp
         --21 matched cohort          set at 36[degrees]C-
         severe TBI traditional       36.5[degrees]C)
         treatment group (18 M/3 F)
                                      Traditional temp
         GCS median = 7 (3-8)         management (treatment for
         Mean age = 36.4              rectal temp > 38[degrees]C)
         (21.6-51.2) years
           --36.6 [+ or -] 15.2 NT
           --36.2 [+ or -] 14.9
             traditional treatment
             group

Author            Outcomes                   Main Findings

Puedo    Surrogate outcomes of:       NT:
et al.   ICP burden                     --Lower ICP burden
(2009)     --% time ICP > 25              (2.3% + 2.8%) versus
             mm Hg for the first          controls (9.4% [+ or -]
             72 hrs after ICU             11.4%;p= .03)
             admission                  --Lower fever burden
                                          versus controls (1.6%
         Fever burden                     vs.10.6%; p = .03)
           --% time rectal temp
             [greater than or equal
             to] 38[degrees]C for
             the first 72 hrs after
             ICU admission

Note. F = female; CCS = Glasgow Coma Scale; hrs = hours; ICP =
intracranial pressure; M = male; NT = normothermia; severe
TBI = GCS of 3-8; TBI = traumatic brain injury; temp = temperature.

TABLE 3. Hypothermia on Admission in TBI

                 Study Design and                Comparisons/
Author             Participants               Temperature Measure

Thompson,    n = 147                     Admission temp to ED (route
Kirkness,      --HT = 59 (46 M/13 F)     not specified)
and            --NT = 88 (67 M/21 F)     HT = temp < 35[degrees]C
Mitchell     Median age                  Rate of rewarming calculated
(2010)         --HT group: 34.9          by determining time to
                 [+ or -] 2.3 years      [greater than or equal to]
               --NT group: 37.5          36.5[degrees]C
                 [+ or -] 2.0 years      Rapid rewarm [greater than
             Severe TBI                  or equal to] 0.25[degrees]C/
                                         hour

Konstantin   n = 1403                    HT = first SICU measured core
idis et      Mean age = 38.1 [+ or -]    temp [less than or equal to]
al. (2011)   21.2 years                  35[degrees]C
             Severe TBI                  NT = first SICU measured core
             Admission to SICU           temp [greater than or equal
                                         to] 35[degrees]C
                                         Rewarming rate of HT not
                                         reported

Bukur et     n = 1834                    HT: [less than or equal to]
al. (201     Ages [greater than or       <35[degrees]C
2)           equal to] 14 years          NT: >35[degrees]C
             Severe TBI (AIS-H           Rewarming rate of HT not
             [greater than or equal      reported
             to] 3, all other < 3)

Jeremitsky   n = 81                      Retrospective review, 11
et al.       Adult                       SBIFs in the first 24 hours
(2003)       Severe TBI                  postinjury: hypotension,
             Transport time < 2 hours    hypoxia, hypercapnia,
             to level I trauma center    hypocapnia, HT, fever,
                                         metabolic acidosis, seizures,
                                         coagulopathy, hyperglycemia,
                                         and IICP SBIF was recorded
                                         during six periods: hours 1,
                                         2, 3, 4, 5-14, and 16-24
                                         Occurrence of each SBIF then
                                         correlated with outcome

Author          Outcomes                    Main Findings

Thompson,    Discharge and    HT on admission correlated with:
Kirkness,    6-month COS-E      --Longer LOS (r = .226, p = .006)
and                             --Worse neurological outcome at D/C
Mitchell                          (r = -.163, p = .049)
(2010)                          --Higher mortality up to 6 months
                                  postinjury (r = .202, p = .01 8)
                              Mortality at D/C based on rewarming
                              rates:
                                --[less than or equal to]0.25[degrees]
                                  C/hour (16.7%)
                                -->0.25[degrees]C/hour (23.4%)

Konstantin   In-hospital      HT on SICU admission
idis et      mortality SICU     --Incidence: 10.9% (n = 140)
al. (2011)   and hospital       --Significantly less likely to survive
             LOS                  (OR = 2.9, 95% CI [1.3, 6.7]; p <
                                  .013)
                              Independent risk factors of HT on
                              SICU admission:
                                --Penetrating MOI
                                --ISS [greater than or equal to] 25
                                --Exploratory laparotomy before SICU
                                  admission

Bukur et     Mortality        HT (n = 44)
al. (201     (time            NT (n = 1 790)
2)           frame not        Mortality for HT (25% vs. 7%)
             identified)      Admission HT independently associated
                              with increased mortality (AOR = 2.5,95%
                              CI [1.1, 6.3]; p = .04)

Jeremitsky   Mortality        Increased mortality rate associated with:
et al.                          --Hypotension (p = .001)
(2003)                          --Hyperglycemia (p = .032)
                                --HT (p = .002)
                              Mortality independently related to:
                                --Hypotension (p = .017)
                                --HT (p = .029)
                                --AIS-H (p = .024)
                              Survivors (mean = 34.0 years)
                              significantly younger than nonsurvivors
                              (mean = 44. 9 years; p = .03)

Note. AIS-H = abbreviated injury score of the head region; AOR =
adjusted odds ratio; CI = confidence interval; D/C = discharge; ED
= emergency department; F = female; GCS = Glasgow Coma Scale; GOS-E
= extended Glasgow Outcome Scale; HT = hypothermia; ISS = injury
severity score; LOS = length of stay; M = male; MOI = mechanism of
injury; NT = normothermia; OR = odds ratio/pts = patients; r=
Pearson product-moment correlation coefficient; SICU = surgical
ICU; TBI = traumatic brain injury; temp = temperature; tx =
treatment.

TABLE 4. Induced Hypothermia in TBI Since 2009

Author       Study Design and             Interventions/Measures
              Participants

Clifton et   Initial n = 232            Bladder temp
al. (2011)   n = 97 ultimately          119 cooled to 35[degrees]C
             included in the entire     within
             study (no gender           2.6 [+ or -] 1.2 hours of
             reporting)                 injury
               --52 HT                    --52 cooled to 33[degrees]C
               --45 NT                      within 4.4 [+ or -] 1.5
             Age = 16-45 years              hours of injury (met
             (mean: 26 HT, 31 NT)           inclusion criteria after
             Severe TBI                     trauma assessment) for 48
                                            hours
                                          --Rewarm rate of
                                            0.5[degrees]C/2 hours
                                            regardless of ICP NT group
                                            temps > 38[degrees]C tx
                                            with acetaminophen and
                                            cooling blankets

Clifton et   NABIS:H I (392             Bladder temp
al. (2012)   patients), HT:             Cooling as noted for HT
             33[degrees]C x 48 hours    NT group temps >
             within 8.4 [+ or -] 3      38[degrees]C treated with
             after injury               acetaminophen and cooling
             NABIS:H II (97             blankets
             patients), HT:             Rewarming rate of HT:
             35[degrees]C x 48 hours    0.5[degrees]C/2 hours
             within 2.6 [+ or -] 1.2
             hours and 33[degrees]C
             within 4.4 [+ or -] 1.5
             hours after injury
             Subgroup analysis of
             those requiring surgery
             (craniotomy for hematoma
             evacuation)

Tokutomi     n = 61 (47 M/14 F; 77%     Rectal temp
et al.       M)                         Nonrandomized; tx goal changed
(2009)       --30 (21 M/9 F) cooled     from 33[degrees]C to
             to 35[degrees]C (11        35[degrees]C in January 2000;
             excluded from analysis)    matched cohorts
             --31 (19 M/12 F) cooled    All cooled to respective goal
             to 33[degrees]C (eight     temp after ICU admission and
             excluded from analysis)    then slowly rewarmed after 48-
             Age = 15-69 years          72 hours of HT If ICP < 20 mm
             --45 [+ or -] 19 years     Hg. If ICP remained >20 mm Hg
             in 35[degrees]C group      or rose during rewarming,
             --0 [+ or -] 18 years in   continued mild HT up to 48
             33[degrees]C group GCS     additional hours
             [less than or equal to]    Rewarm of HT reported as
             5 (range = 3-5, very       "slow," but rate not reported
             severe TBI)

Zhao,        n = 81 (59 M/22 F)         Core (rectal) temp
Zhang, and   --NT = 41 (30 M/11 F)      HT cooling blanket set to
Wang         --HT = 40 (29 M/11 F)Age   33[degrees]C for 72 hours,
(2011)       --NT median = 37.5 [+      spontaneous rewarming in room
             or -] 15.2 years           temp (rate not reported)
             --FIT median = 36.9 [+     NT maintained at 37[degrees]C
             or -] 14.8 years
             Severe TBI

Author            Outcomes                    Main Findings

Clifton et   6-month mortality     --Trial stopped before targeted
al. (2011)   Dichotomized          enrollment because of futility
             6-month GOS           (stopping rule at interim analysis
                                   if <20% chance of confirming
                                   primary hypothesis)
                                   --Unfavorable outcome in 31/52 HT
                                   and 25/45 NT (RR = 1.08, 95% Cl
                                   [0.76, 1.53]; p= .67)
                                   --Mortality in 12/52 HT and 8/45 NT
                                   (RR = 1.30, 95% CI [0.58, 2.89]; p=
                                   .52)

Clifton et   Dichotomized          Poor outcome (dichotomized GOS) in
al. (2012)   6-month GOS           NABIS:H II in 5/15 HT and in 9/13
                                   NT (RR = 0.44, 95% CI [0.22, 0.88];
                                   p = .02)
                                   In NABIS: H I, poor outcome in:
                                     --14/31 (45%) pts reaching
                                       35[degrees]C for [less than or
                                       equal to]1.5 hours of surgery
                                     --14 of 23 pts (61 %) reaching
                                       35[degrees]C for >1.5 hours of
                                       surgery
                                     --35/58 (60%) of NT (RR = 0.74,
                                       95% CI [0.49,1.13]; p = .16)
                                   Meta-analysis of pts achieving
                                   35[degrees]C for [less than or
                                   equal to]1.5 hours of surgery
                                   (n--46): significantly decreased
                                   rate of poor outcomes (41%) versus

                                   94 pts with HT who did not reach
                                   35[degrees]C for [less than or
                                   equal to]1.5 hours and pts with NT
                                   (62%, p = .009)

Tokutomi     6-month GOS           --Mean 24-hour (for 7 days
et al.       6-month mortality     postinjury) ICP < 20 mm Hg during
(2009)                             HT in both groups
                                   --No difference in incidence of
                                   IICP and low CPP between groups (p
                                   > .05)
                                   --No differences in 6-month GOS
                                   between groups
                                   --Mortality rate tended to be lower
                                   in 35[degrees]C group (27% vs. 48%,
                                   p= .0801)

Zhao,        Arterial glucose      --Insignificant difference in GOS
Zhang, and   Lactic acid           outcomes for HT versus NT unless
Wang         Dichotomized 3-       dichotomized into favorable/
(2011)       month GOS             unfavorable groups
             Favorable (good       --HT favorable outcome of 75.0%
             recovery/moderate     versus 51.2% NT favorable outcome
             disability)           (p = .038)
             Unfavorable           --HT independent predictor of
             (severe disability,   favorable outcome (RR = 4.9, 95% CI
             vegetative state,     [1.0, 15.6]; p< .05)
             death)

Note. AIS-H = abbreviated injury score of the head region; CI =
confidence interval; CPP = cerebral perfusion pressure; F = female;
CCS = Glasgow Coma Scale; GOS = Glasgow Outcome Scale; hrs = hours;
HT = hypothermia; ICH = intracerebral hematoma; ICP = intracranial
pressure; IICP = increased intracranial pressure; ICU = intensive
care unit; LOS = length of stay; M = male; MAP = mean arterial
pressure; NABIS:H = National Acute Brain Injury Study: Hypothermia;
NT = normothermia; pts = patients; RR = relative risk; severe TBI =
GCS of 3-8; TBI = traumatic brain injury; temp = temperature; tx =
treatment.
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Author:Madden, Lori Kennedy; DeVon, Holli A.
Publication:Journal of Neuroscience Nursing
Article Type:Report
Date:Aug 1, 2015
Words:9288
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