Curr Neurol Neurosci Rep (2014) 14:453 DOI 10.1007/s11910-014-0453-9

CRITICAL CARE (SA MAYER, SECTION EDITOR)

The Use of Targeted Temperature Management for Elevated Intracranial Pressure Jesse J. Corry

Published online: 17 April 2014 # Springer Science+Business Media New York 2014

Save for out-of-hospital ventricular fibrillation/pulseless ventricular tachycardia cardiac arrest, hypothermia use has inconsistent findings in many of the common neurocritical care populations of subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), ischemic stroke, and traumatic brain injury (TBI) [1–6]. Even with out-of-hospital ventricular fibrillation/ pulseless ventricular tachycardia cardiac arrest, the “degree” to which hypothermia should be titrated remains in question [7•].

As understanding of how best to cool patients to improve outcomes evolves, so does the practice’s sobriquet, increasingly known as targeted temperature management (TTM) [8••]. As contentious as TTM practices are, so is the best management of intracranial hypertension. Recent studies in TBI suggest care focused on maintaining intracerebral pressure (ICP) of 20 mmHg or less is not superior to a protocolized examination and neuroimaging-guided therapy [9••]. ICP targets in other diseases are often based on this literature [10]. Further, variability exists in the cause of ICP, and its treatment among intensivists [11]. The common medical therapies, mannitol and hypertonic saline, are limited by potential rebound cerebral edema, deleterious effects on renal function, and potentially greater risk of infection [12–15]. And, despite its increased use, hypertonic saline has not demonstrated any outcome benefit despite ICP reductions [15, 16]. Because of the heterogeneous reporting of ICP and inconclusive outcome data among studies, a recent consensus review by five international critical care societies ruled the evidence for ICP control by TTM, as it pertains to outcome, is insufficient for an affirmative recommendation at this time [8••]. When abstracting the results of large, multicenter trials to the bedside, clinicians must be mindful that evidence-based medicine rests on the assumption that valuable data can be derived from heterogeneous studies with uncounted-for variables merely by size [17]. Could the imprudent application of TTM to all studied patients with a diagnosis have obscured its beneficial effect? If data suggest hypothermia effectively reduces ICP, then one must ask, “for whom should TTM be used to reduce ICP?”

This article is part of the Topical Collection on Critical Care

Traumatic Brain Injury

J. J. Corry (*) Department of Neurology, Marshfield Clinic, 1000 N. Oak Ave., Marshfield, WI 54449-5777, USA e-mail: [email protected]

Elevated ICP is a marker for poor outcome in brain injury [18–24]. The greater the percentage of time with ICP over 15– 20 mmHg, particularly over 25 mmHg, the worse the outcome

Abstract The use of hypothermia for treatment of intracranial hypertension is controversial, despite no other medical therapy demonstrating consistent improvements in morbidity or mortality. Much of this may be the result of negative results from randomized controlled trials. However, the patients selected for these trials may have obscured the results in the populations most likely to benefit. Further, brain injury does not behave uniformly, not even within a diagnosis. Therefore, therapies may have more benefit in some diseases, less in others. This review focuses on the effect on outcome of intracranial hypertension in common disease processes in the neurocritical care unit, and identifies who is most likely to benefit from the use of hypothermia. Keywords Targeted temperature management . Hypothermia . Normothermia . Intracranial hypertension . Intracerebral pressure . Brain injury

Introduction

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[18, 20, 21, 25]. TBI patients not requiring interventions have a better prognosis than patients requiring therapy for elevated ICP [19]. Although no adequately powered prospective, multicenter, randomized controlled trial currently demonstrates monitoring ICP improves outcome, numerous smaller and retrospective studies demonstrate improved outcomes with ICP reductions [26–29]. Thus, monitoring ICP remains a level II recommendation in patients with a Glasgow Coma Scale (GCS) score of 3 8 and an abnormal CT scan, and a level III recommendation for patients with a GCS scan of 3–8 and a normal CT scan, and who are over 40 years of age, demonstrating motor posturing, or have a systolic blood pressure of 90 mmHg or less [30, 31]. Does TTM Lower ICP? Overwhelming evidence demonstrates TTM lowers ICP [4, 25, 26, 28, 29, 32–37]. However, early hypothermia versus normothermia has demonstrated no therapeutic benefit on mortality or morbidity [4, 5, 7•, 25, 38]. Thus, a physician’s reluctance to use a therapy to improve ICP that in the end may not improve outcome is understandable. Yet, this literature is heterogeneous, with dissimilar inclusion criteria, neurosurgical treatments, and cooling techniques, and antecedent use of sedation and osmotic therapy [39••]. In trials where patients were cooled to 33–35 °C because of elevated ICP, hypothermia reduced ICP by 15–35 % [32, 34, 35]. And, a recent meta-analysis of the efficacy of various ICP control methods found that for an average ICP reduction of 10 mmHg, hypothermia was more effective than hyperventilation, mannitol, and barbiturates, but less effective than hypertonic saline, CSF drainage, and decompressive craniectomy at reducing ICP [40]. The peaking of ICP after TBI is variable, with elevations starting shortly after injury and peaking within 4 days [41–44]. Prospective, observational studies in TBI demonstrate three phases of ICP elevation: early (days 1–2), intermediate (days 3–5), and late (after day 5) [42], with 20–30 % of patients displaying a delayed peak after day 5 [41, 42]. Although much literature focuses on delivering hypothermia in the first 8 h from injury, hypothermia may still effectively lower ICP when initiated from 12 h to 10 days from injury [35, 45]. However, much of the published literature would not apply to this late population. Also, studies comparing normothermia with hypothermia for treatment of TBI have noted patients with intermediate and late elevations required the greatest number of therapeutic interventions [46]. Refractory ICP Brain injury is not a homogeneous disease process; responses differ depending on the mechanism of injury [29, 47–53]. Further, patient populations within a diagnosis of “TBI” or

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“stroke” will have different responses to a therapy. This is particularly true for TBI [54, 55]. The pattern of injury on CT often predicts response to hypothermia [56]. Differences in the use of osmotic therapy, patient admission GCS score and Marshall grade, hypothermia protocol and delivery, timing and reason for cooling, and use of barbiturates are a few factors contributing to the lack of uniformity of TTM studies in TBI [39••, 57]. Therefore, for whom should this therapy be used, patients with elevated ICP, or only those refractory to more conservative measures? In trials where ICP was controlled with use of sedation, neuromuscular blockade, or osmotic therapy, TTM was not associated with improved morbidity or mortality, and may have a detrimental effect [4, 5, 37, 38, 58]. In some of these studies without refractory ICP, TTM produced a marginal effect on ICP, or elevations in ICP [4, 5, 25, 38]. Perhaps the risk of TTM obscures the benefit of TTM in this group. A meta-analysis of randomized controlled trials of TTM in TBI attempted to ascertain if the refractory ICP subgroup demonstrated more benefit [57]. Although data interpretation is clouded by heterogeneity, it does suggest prolonged hypothermia for patients with ICP refractory to Brain Trauma Foundation first-tier therapy (i.e., head of bed at 30°, CSF drainage, sedation, paralysis) may be of benefit. Shiozaki et al. [26] evaluated the efficacy of hypothermia (34 °C) versus normothermia (37 °C) in patients with ICP greater than 20 mmHg refractory to hyperventilation and barbiturates. No mannitol or steroids were used. Three of 17 patients in the normothermia group and eight of 16 patients in the hypothermia group survived. The hypothermia group had a mean ICP reduction of 10.4 mmHg. Patients who did not respond died within 48 h. A study by Sahuquillo et al. [35] in patients with ICP greater than 20 mmHg refractory to treatment with sedation and osmotic therapy reported an ICP of less than 20 mmHg in 15 of 23 patients at 24 h from reaching a goal temperature of 32.5 °C, and in 19 of 23 patients at 48 h. They also reported nine patients with good to moderate disability at 6 months. Polderman et al. [59] reported observations in patients treated with hypothermia for refractory ICP despite sedation, paralytics, mannitol, and barbiturates to a burstsuppression pattern on electroencephalography. Patients for whom barbiturates controlled ICP acted as controls. Hypothermia resulted in ICP reductions to below 20 mmHg in 62 of 64 patients within 4 h of initiation. The group prehypothermia ICP was 37±20 mmHg; improving to 14±8 mmHg with hypothermia. The absolute risk reduction of mortality between the hypothermia and barbiturate groups was 10 %; this was statistically significant, driven largely by improved survival of patients in the hypothermia group with an admission GCS score of 5–6. However, a “ceiling” to the efficacy of hypothermia may exist. Shiozaki et al. [54] reported that above 40 mmHg, hypothermia efficacy becomes markedly reduced. Hypothermia can effectively lower ICP in patients refractory

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to first-line therapies; however, this efficacy has limits, and is best seen in patients with ICP below 40 mmHg at induction. Neurosurgical and CT Findings The CT pattern of injury may predict development of elevated ICP [5, 54]. This could be related to differences in pathophysiologic behavior of focal and diffuse injury [5, 55]. Surgically removed hematomas typically demonstrate a higher frequency of early ICP elevations [5, 54, 60]. Focal cerebral contusions often develop ICP elevations later [54]. A retrospective study by Shiozaki et al. [56] correlated CT findings with effective ICP control, hypothermia use, and clinical outcome. They noted patients with focal contusions or surgically evacuated lesions treated with hypothermia have a better response in terms of ICP than patients with more diffuse injury. Patients with diffuse swelling, characterized by cisternal effacement and/or obliteration of the third ventricle, have little reduction in ICP and mortality with hypothermia. No patient with a midline shift greater than 13 mm achieved ICP control [56]. Since the publications of this observation, subsequent studies have also supported the notion that surgically evacuated hematomas may have a beneficial response to hypothermia [5, 29, 33, 34, 45, 61••]. Focal injury and extracerebral hematomas, often surgically amenable, and a midline shift of less than 12 mm may respond best to hypothermia [56]. Smrcka et al. [29] reported patients with focal cerebral contusions demonstrated a significant reduction in ICP with hypothermia to 35 °C compared with normothermia (37 °C). However, ICP was not necessarily refractory in this cohort. Patients receiving hypothermia to 33–35 °C in combination with surgical evacuation of intracranial hematomas or decompression for contusions demonstrated a 10–16 % reduction in ICP compared with noncooled controls at the same time interval from injury [33, 34]. Recently, a meta-analysis of the National Acute Brain Injury Study: Hypothermia I and National Acute Brain Injury Study: Hypothermia II data suggests that patients with surgically evacuatable lesions reaching 35 °C by the time of surgery, and maintained near 33 °C for 48 h after, may be a TBI group in which hypothermia may be effective [61••]. These data suggest surgically evacuated subdural hematomas and epidural hematomas with a midline shift of less than 13 mm and focal cerebral contusions, often if decompressed, are more responsive to hypothermia for ICP reduction. A target temperature of 34 °C may be all that is required; however, diffuse lesions rarely respond to hypothermia. GCS Score Hypothermia appears ineffective in those patients with a GCS score of 3 4 [36, 45, 56, 59]. The National Acute Brain Injury Study: Hypothermia I and National Acute Brain Injury Study:

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Hypothermia II trials excluded patients with a GCS score of 3 and nonreactive pupils, and no significant differences were reported in patients in the hypothermia groups with a GCS score of 3–4 or 5–8 [4, 5]. But, several studies have reported patients with a GCS score of 5–7 obtaining the greatest benefit from hypothermia [36, 59].

Temperature Goals of TTM Increased brain temperature and ICP do appear to correlate [62–64], and an association between low brain temperature and high ICP is found. TBI patients with brain temperature spontaneously below 36 °C and/or rectal temperature 0.4 °C or higher than brain temperature have poor outcomes [65]. And, brain temperature often falls below core temperature in brain death [66]. Therefore, instances where brain temperature is less than core temperature, or the difference becomes increasingly variable, may suggest a loss of autoregulation. Yet, no direct correlation between brain temperature and ICP can be made. If direct correlations between temperature and ICP cannot be consistently made, what should the temperature target be? The cardiothoracic surgical literature has demonstrated temperature is not a reliable marker for brain metabolism [67, 68]. Would titration of temperature on the basis of ICP be an effective method? A study of six TBI patients found this feasible [69]. EUROTHERM3235 will hopefully address both these issues [70]. Work has demonstrated in patients with refractory ICP that a temperature of 31 °C offers no benefit over 34–35 °C [54]. Tokutomi et al. [71] reviewed 31 patients with a GCS score of 3–5 cooled to 33 °C. Twenty-three had an evacuated lesion. The greatest ICP reductions occurred with a brain temperature of 36.9 °C or lower, decreasing further with a brain temperature of 35.9 °C or lower. Below a brain temperature of 35 °C, no further reductions were seen. Additionally, the frequency of ICP readings greater than 20 mmHg dropped dramatically below 35.9 °C from approximately 40 % to 20 %. This correlated with a reduced frequency of jugular venous oxygen saturation readings below 55 %. Oxygen consumption decreased significantly until 35 °C. Later this group reported clinical findings in changing their hypothermia target from 33 to 35 °C [72]. This resulted in no loss of efficacy for ICP reduction, and showed significant trends toward lower pulmonary embolism, deep venous thrombosis, and pneumonia, plus lower mortality. This target of 35 °C prior to surgical intervention was also a noted target in the post hoc analysis of the National Acute Brain Injury Study: Hypothermia I and National Acute Brain Injury Study: Hypothermia II data [61••]. The data from the TBI population suggest a brain temperature of 35 °C, or a rectal temperature of 34.5 °C, would be the best target.

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Timing, Duration, and Efficacy of Therapy The literature suggests hypothermia for 48 h is relatively safe, and the increased rates of infection commonly reported do not affect outcome [5, 33, 34, 40, 73, 74]. However, during rewarming, ICP may rebound, often exceeding that of normothermia control populations [25, 27, 38, 46, 75]. Hypothermia for less than 48 h does not prevent the development of “rebound” ICP. On rewarming, the rate should be 0.1–0.25 °C/h [26, 28, 59, 76]. Some authors have reported if ICP exceeds 20 mmHg with rewarming, the patient should be re-cooled until the ICP is again below 20 mmHg [59]. Approximately 25 % of TBI patients will have late ICP peaks [41, 42], and often ICP will remain elevated for more than 48 h. If hypothermia use should parallel intracranial hypertension, much of the current literature does not offer logistical guidance. A longer duration of cooling, 5 days or more, may mitigate this rebound [27, 28]. A technique commonly reported in the TBI literature is to begin rewarming only after the ICP has remained at or below 15–20 mmHg for at least 12–24 h [28, 32, 35, 59]. This technique, and in fact hypothermia for more than 72 h, does not result in an increased incidence of complications, such as electrolyte and/or acid–base imbalance, infections, cardiovascular dysfunction, or deep venous thrombosis–pulmonary embolism, and mitigates rebound ICP [28, 29, 32, 45, 59]. This suggests for TBI, hypothermia can be delivered for more than 48 h without a substantial increase in the relative risk of death [32–34, 69, 77]. Markers of vasoreactivity may help identify patients at risk of rebound ICP, allowing clinicians to augment therapy. Transcranial Doppler studies evaluated mean flow velocity of the middle cerebral artery (FVMCA) and internal carotid artery (FVICA) during cooling and rewarming in TBI patients [78]. Patients with rebound ICP demonstrated near doubling of the FVMCA, and eventual velocity over 100 cm/s, as the patient temperature reached 34–36 °C. This change was not noted in patients in whom rebound ICP did not occur. The ICP elevation tended to lag behind the flow velocity changes, suggesting a window for intervention. The increases in FVMCA with rewarming portend the development of hyperemia, with increased cerebral blood flow and subsequent ICP [76, 78]. TBI patients cooled to 33–35 °C because of ICP below 20 mmHg may develop a temperature-dependent loss of autoregulation on rewarming [76]. Cerebrovascular pressure reactivity index (PRx) was not impaired with a rewarming rate of 0.2 °C/h to a target of 37 °C. However, PRx demonstrated impairment as temperatures rose above 37.8 °C, suggesting impaired autoregulation. This group later reported TBI patients cooled to 35 °C did not demonstrate this change in PRx [76]. Thus, hypothermia may adversely affect cerebrovascular reactivity in some patients, requiring strict

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normothermia, in the 37 °C range, to prevent further brain injury as a result of impaired autoregulation.

Intracerebral Hemorrhage Data demonstrating a clear relationship between ICP and outcome in ICH are conspicuously absent. Known factors contributing to poor outcome in ICH are hemorrhage size, rebleeding and expansion, hydrocephalus, intraventricular hemorrhage, and perihemorrhagic edema (PHE) resulting in increased volume and ICP [79–86]. Although CSF draining in ICH with intraventricular hemorrhage and hydrocephalus does improve ICP, the level of consciousness, ventricular size, the need for intubation, and mortality do not necessarily improve [85, 87]. Prior work has demonstrated regional pressure gradient differences in patients with expanding ICH resulting in elevated ICP in the region of the ICH, but not more distant [88]. A single-center study investigating outcome and ICH noted neurologic deterioration in 46.3 % of patients at a mean of 2.73±2.9 days after ICH [83]. Early in the course of ICH, short-term mortality may be most affected by PHE increases that contribute to elevated ICP [82, 83, 89••, 90]. Elevated initial, maximum, and mean ICP all significantly correlated to neurologic deterioration. Death by the third day following ICH is significantly associated with maximum ICP [89••]. Hemorrhages of more than 30 mL cause greater blood–brain barrier permeability than smaller bleeds [91]. PHE volumes demonstrate their fastest growth in the first 48 h, and peak by 1.5–2 weeks [89••, 92•, 93]. Similarly to TBI, although ICPs below 20 mmHg correlate with worse outcome, and removal of hematoma typically reduces ICP [83], surgical therapy has not demonstrated superiority over medical management in ICH [86, 94]. Some evidence does suggest hypothermia to 35 °C may be sufficient to reduce PHE and normalize ICP [95, 96••]. Patients with supratentorial hemorrhages of more than 25 mL were cooled for 7–10 days and compared with matched controls from a database. PHE was measured on CT. The hypothermia group failed to demonstrate ICP elevations, whereas 44 % of controls demonstrated ICP elevations [95]. Whereas the mean ICH volume was similar between the hypothermia and control groups, in the hypothermia group, edema volume remained stable. The uncooled cohort demonstrated significant increases in PHE in terms of both absolute and relative volume, with a near doubling of the ratio of the initial hemorrhage volume to the absolute PHE volume [95, 96••]. No significant differences in side effects were noted. With rewarming, the hypothermia group was warmed at 0.5 °C/ 24 h without any development of rebound edema [96••]. Hopefully, the recently completed Cooling in Intracerebral Hemorrhage (CINCH) trial, investigating the 30-day mortality and effect on ICH and PHE volumes with hypothermia, will

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clarify the role of hypothermia in ICH (Current Controlled Trials ISRCTN28699995; http://controlled-trials.com). Other trials could better quantify the role of hypothermia in ICH. A phase I trial is looking at the safety and tolerability of the Excel Cryo Cooling System, as well as its effect on brain oxygenation and ICP (ClinicalTrials.gov identifier NCT01933230). A phase II study is investigating a hypothermia protocol to mitigate hematoma and PHE growth (ClinicalTrials.gov identifier NCT01866384). Hypothermia remains a tool in the armamentarium of the intensivist to reduce cerebral edema, but with an unclear effect on outcome. The current data suggest supratentorial hemorrhages, particularly lobar, and of more than 25 mL, may be responsive to an early course of 35 °C for 7–10 days.

Subarachnoid Hemorrhage Elevated ICP is common in poor-grade SAH patients, and is associated with poor outcome [97–99]. This is particularly foreboding if the ICP is refractory to medical management [100, 101]. Patients with ICP greater than 20 mmHg often demonstrate focal neurologic deficits and alterations in cerebral metabolism [i.e., elevated lactate to pyruvate ratio (LPR), increased glutamate concentration, increased glycerol concentration] consistent with metabolic stress [102]. Consensus on how best to manage ICP in SAH (i.e., targets, methods) is lacking [103–105]. Fascinatingly, evidence suggests use of barbiturate coma for ICP reduction does not mitigate many of the metabolic dysfunctions found with SAH, whereas decompressive craniectomy improved ICP and glycerol levels, but not LPR [102]. The volume of literature regarding hypothermia in SAH for ICP control is remarkably slight, with much focused on intraoperative uses; however, the intraoperative use of hypothermia has not demonstrated any clinically meaningful improvement in outcome [3]. The literature for hypothermia to control ICP in SAH is mixed. Inamasu et al. [106] have described how hypothermia controlled ICP refractory to mannitol in nine of 11 poor-grade SAH patients. However, none had a satisfactory outcome. Gasser et al. [107] reported on 21 patients cooled to 33– 34 °C with concomitant barbiturate coma titrated to an EEG burst-suppression pattern for elevated ICP defined as more than 15 mmHg despite use of mannitol, hypertonic saline, and mild hyperventilation. Cooling was maintained until the patient’s ICP was below 15 mmHg for more than 24 h. Cerebral perfusion pressure was maintained at 70 mmHg or higher. Nine patients were treated for less than 72 h, and 12 patients were treated for more than 72 h. Despite this combined approach, three of the nine patients treated for less than 72 h and seven of the 12 patients treated for more than 72 h developed ICP refractory to this therapy, and required decompressive craniectomy. This decreased efficacy of hypothermia

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to control ICP, or change outcomes in patients with SAH, mirrors the finding of less efficacy of hypothermia in patients with TBI demonstrating diffuse injury [56]. Of particular concern in SAH is the potential temperaturedependent loss of autoregulation [76, 78, 108]. Yanagawa et al. [109] reported on seven patients with traumatic SAH (Fisher grade 2), with a GCS score of 8 or lower and ICP persistently above 20 mmHg. Patients cooled to control ICP often demonstrated vasospasm on angiography, and cerebral infarcts on rewarming. Others have suggested hypothermia may be useful for treatment of severe vasospasm with progressive neurologic decline [110]. Seule et al. [111] reported their findings on the use of hypothermia for treatment of elevated ICP and delayed cerebral ischemia. Patients treated for refractory vasospasm/ delayed cerebral ischemia demonstrated the greatest significant outcome benefit at 1 year, with a GOS score of 4–5 in 57.1 % versus 25.0 % in the ICP treatment group and 57.1 % versus 26.5 % in the ICP and vasospasm group. Perhaps the greatest role of TTM is in the delivery of normothermia. Fever is known to worsen brain injury in SAH, and is associated with poor outcome [112, 113]. In a study by Oddo et al. [114], normothermia to a goal of 37 °C not only improved LPR during times of ICP below 20 mmHg, but also improved LPR when ICP was above 20 mmHg. Compared with fever, normothermia resulted in significantly fewer episodes of metabolic crisis (8 % vs 37 %), defined as an LPR greater than 40, and significantly lower ICP elevations (28±12 mmHg vs 32±11 mmHg).

Stroke Space-occupying cerebral edema is main cause of death the first week after stroke [115]. Elevated ICP secondary to cerebral edema occurs in 23 % of patients younger than 60 years [116]. Similarly to data in ICH, cooling patients to 34.5 °C or below demonstrates reduced cerebral edema [117]. An ICP greater than 18 mmHg within the first 12 h of neurologic deterioration with concomitant stupor predicted death [118]. Regional pressure differences may play a role in early neurologic deterioration [88, 118]. Hacke et al. [119] reported death related to herniation peaked at day 4 in patients with complete middle cerebral artery stroke. With a midline shift of more than 10 mm, ICPs commonly exceeded 60 mmHg. The mean ICP was significantly greater in nonsurvivors, at 43 mmHg, than in survivors, at 28 mmHg. Perhaps mitigating cerebral edema with hypothermia can reduce ICP and improve survival. Faster rewarming potentiates rebound ICP elevations and increases mortality [120–122]. Schwab et al. [120] reported patients with large, middle cerebral artery strokes cooled to 33 °C had ICP averaging 20.9 ± 12.4 mmHg prior to

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hypothermia, 14.5±4 mmHg with initiation of hypothermia, and 13.4±8 mmHg at the goal temperature. However, after 24 h of passive rewarming, the ICP increased to 19±8 mmHg. In this group’s follow-up study, on rewarming to 36 °C, ICP had changed from an average of 12.4±5.3 mmHg at 33 °C to 23.4±8.7 mmHg [122]. With hypothermia, 74 % of patients were able to maintain a consistent ICP during the time at 33 °C. A nonsignificant finding was patients rewarmed over less than 16 h experienced larger ICP elevations. ICP from 33 to 36 °C increased by 26 % when patients were warmed for less than 16 h versus 15 % when they were warmed for more than 16 h [122]. This finding became statistically significant when looking only at nonsurvivors. Others have echoed that slowed, controlled rewarming correlates with better ICP control [123]. ICP may not be the sole issue in this disease. Patients treated with hemicraniectomy or hypothermia do not have great differences in ICP, or any significant increase in the number of episodes of more than 20 mmHg [124]. However, mortality is significantly less in patients treated with hemicraniectomy versus hypothermia, at 12 % versus 47 %. The combination of hemicraniectomy and hypothermia appears to improve patient outcome, on the basis of the National Institutes of Health Stroke Scale score, and is better than hemicraniectomy alone [125]. Although this finding just missed significance, the study was underpowered.

Conclusion In sum, the data suggest TTM is an effective, efficacious strategy for treatment of elevated ICP. However, the role of ICP in the outcome differs depending on the disease process. In TBI, the literature suggests this therapy may be most effective at lowering ICP and improving outcome in patients for whom prior first-line therapies were ineffective, whose admission GCS score was 5–8, whose ICP is below 40 mmHg, and who have an extracranial, and possibly focal, lesion amenable to surgery. Further, the target temperature should be a brain temperature of 34–36 °C. Of note, this is a population that is moderately different from those enrolled in recent trials. In ICH, SAH, and stroke, the data become less clear. Hypothermia may have a greater role in mitigating the effects of PHE and delayed cerebral ischemia. Further, other therapies (e.g., hemicraniectomy) may have a larger role in ICP reduction. The literature on all these disease states suggests two findings: First, that hypothermia may affect cerebral autoregulation with rewarming, necessitating strict normothermia on rewarming; Second, focal brain injury may respond better than more diffuse injury. Although hypothermia is theoretically attractive, a number of methodological questions exist, making hypothermia for treatment of elevated ICP in brain injury a reasonable option, although not the first.

Curr Neurol Neurosci Rep (2014) 14:453 Acknowledgments The author thanks Michele Salzman of Marshfield Clinic Research Foundation’s Office of Scientific Writing and Publication for assistance in the preparation of this review. Compliance with Ethics Guidelines Conflict of Interest Jesse J. Corry has received speakers bureau honorarium and paid travel accommodations from Zoll Circulation. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by the author.

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