InTechOpen uses cookies to offer you the best online experience. By continuing to use our site, you agree to our Privacy Policy.

Neuroscience » "Therapeutic Hypothermia in Brain Injury", book edited by Farid Sadaka, ISBN 978-953-51-0960-0, Published: January 30, 2013 under CC BY 3.0 license. © The Author(s).

Chapter 5

Hypothermia for Intracerebral Hemorrhage, Subarachnoid Hemorrhage & Spinal Cord Injury

By David E. Tannehill
DOI: 10.5772/54925

Article top

Hypothermia for Intracerebral Hemorrhage, Subarachnoid Hemorrhage & Spinal Cord Injury

David E. Tannehill

1. Introduction

As described previously in this book, hypothermia likely has many positive effects on injured brain and spinal cord to limit the damage caused by secondary injury. This secondary injury has multiple mechanisms, including inflammation, excitotoxicity, calcium homeostasis, blood brain barrier damage, release of toxic intermediates including free radicals, as well as cell necrosis & apoptosis (1). Hypothermia has been shown to be an effective treatment for comatose survivors of out of hospital cardiac arrest to both improve mortality and neurologic outcomes (2, 3). Much less is known about the role of hypothermia for treating patients that have suffered an intracerebral or subarachnoid hemorrhage. Experience and literature on the subject is quite limited. The same is true for hypothermia in the treatment of acute spinal cord injury. In fact, data on this topic is even more limited.

However, in the coming years it is likely that we will see more research on this important topic. The technology available to clinicians for achieving the treatment goals of this strategy has rapidly expanded in the past decade. Additionally, its ease of use and increasing familiarity amongst clinicians and intensive care unit staff will only help in growing the field. The basic science background, while not extensive, is at least encouraging and it is expanding. The clinical use, or at least consideration of this therapy is slowly beginning to expand as well. Options for medical therapy to improve outcomes in ICH, SAH & SCI are limited. Hopefully this continued work will improve upon that. This chapter will explore what has been published on these topics to this point.

2. Therapeutic hypothermia for acute spinal cord injury

In the 1960’s and 1970’s, multiple investigators published data examining the possibility of employing hypothermic therapy to improve outcomes in acute spinal cord injury. At that time, most of the studies focused on local cooling via the administration of cold saline to the spinal cord during decompressive laminectomy and durotomy (4-6). However, these studies were not rigorous randomized controlled trials and were fraught with multiple confounders, such as the concomitant administration of corticosteroids and the potential effects of surgery itself (7,8). This, combined with the technical difficulty and invasive nature of local cooling, lead to the general abandonment of the idea.

As technology improved and our understanding of the possible beneficial effects of systemic hypothermia grew, so did interest in applying this strategy to the acute spinal cord injury patient (9,10). Multiple animal studies have suggested a positive effect of either locally or systemically applied therapeutic hypothermia (9). However, clinical experience in the modern era is minimal. In 2010, there was a high-profile case of an NFL football player suspected to have a spinal cord injury who was treated with systemic hypothermia (11). This case garnered the attention of the mass media in addition to the medical community. However, it is important to recognize that it is impossible to discern if this patient’s excellent outcome can be in any way attributed to therapeutic hypothermia. That case does add to the literature describing the safe use of targeted temperature therapy in acute spinal cord injury. The largest and most often quoted case series for therapeutic hypothermia in this patient population is a retrospective review described by Levi et al in 2009 (12). This group describes their institutional experience with therapeutic hypothermia in 14 adult patients with acute, complete cervical spinal cord injury who presented to their institution over a two year period. Only complete cervical spinal cord injury patients with a GCS 15 were considered for their hypothermia treatment protocol. An intravascular cooling device was used to achieve and maintain a core body temperature of 33ºC over a 48 hour period. Corticosteroids were not used. All patients underwent surgical intervention. Patients were then rewarmed over a 24-32hr period. This group of patients averaged 39.4 years old from a range of 16-62years. Induction of hypothermia began within 9.17+/-2.24hr and time to target temperature was 2.72+/-0.42hr. They documented a strong correlation between temperature and heart rate. Additionally, in one patient, CSF temperature was measured and found to closely approximate core temperature. Importantly, none of the 14 patients suffered a life-threatening adverse event attributable to therapeutic hypothermia. The adverse events described were primarily respiratory and closely approximated the type and rate of adverse events experienced in an historical control cohort. In a follow-up manuscript, Levi et al describe the clinical outcomes of this patient cohort (13). All 14 patients were American Spinal Injury Association and International Medical Society of Paraplegia Impairment Scale (AIS) A on admission. 8/14 patients remained so, but 3 improved to B, 2 to C and one patient had dramatic improvement to AIS D. Importantly, none of the patients worsened. A control group of patients only had 3/14 patients improve AIS grade compared with the six in the hypothermia group, a non-statistically significant difference. While the low number of patients, strict inclusion criteria, observational nature of study and use of an historical control may temper enthusiasm for these results, they are nonetheless intriguing and provide an excellent basis for developing future studies.

As mentioned previously, medical therapies for acute spinal cord injury are extremely limited. However, with future study, perhaps therapeutic hypothermia’s role in treating the 11,000-12,000 spinal cord injury patients per year in the United States can further be defined (14).

3. Therapeutic hypothermia for intracerebral hemmorhage

Intracerebral hemorrhage (ICH) accounts for approximately 10% of all cerebral vascular accidents in the United States and carries a mortality rate of up to 50% (15,16). Options for medical therapy are extremely limited and are primarily focused on supportive therapy (17). Mayer et al investigated the potential use of rFVIIa for improving outcome and established that this therapy may in fact improve hematoma volume, but its impact on outcomes was limited (18). Hematoma volume & growth does correlate with various outcome measures (19-21), but so does perihemorrhagic edema (22-25). ICH is associated with secondary injury characteristics that are similar to ischemia and ischemia-reperfusion, including blood-brain barrier disruption, inflammation and edema. The edema progresses through three phases related initially to hydrostatic forces & clot retraction, then activation of the coagulation cascade and thrombin formation and later, via RBC lysis and hemoglobin-induced neuronal toxicity (26). This edema – termed perihemorrhagic edema – has been associated with poor outcomes (22, 23, 25). Data from animal models of ICH suggest that hypothermia can improve these injurious processes, but not outcomes (27-33).

There is a suggestion that the application of therapeutic hypothermia may be beneficial in preventing the progression of periphemorrhagic edema and improving outcomes in patients who suffer intracranial hemorrhage (34). In a pilot study by Kollmar et al, hypothermia was determined to be safe as well as potentially provide a positive effect on ICH perihemorrhagic edema (25). This was a comparison of 12 patients w/ supratentorial ICH >25mL in volume cooled with an intravascular cooling device to 33 degrees C with 12 historical controls. Amongst the control cohort, there were more patients with uncontrolled intracranial hypertension, perihemorrhagic edema progression and death. In a followup study by the same group, Staykov et al described similar findings with 25 patients with large ICH as compared with an historical control group (35). Again, perihemorrhagic edema remained mostly unchanged in the hypothermia group, but steadily increased in the historical control group, with a statistically significant difference in perihemorrhagic edema volume. This difference was also associated with a suggestion of mortality difference, but with such a small sample size it was not statistically significant. The mortality rate was 8.3% in the hypothermia cohort, 16.7% in the control group at 3 months and 28% vs 44% at one year. There is a prospective, multicenter, randomized controlled phase II trial currently underway to more formally evaluate this question using a similar protocol (36).

4. Therapeutic Hypothermia for Subarachnoid Hemorrhage

As in all neurocritical care related illnesses, fever control may be important for minimizing secondary injury (37). In subarachnoid hemorrhage, this is particularly true. As many as 72% of all SAH patients may experience fever (38). Infection should always be ruled out and treated aggressively (39); however, the fever needs to be controlled whether it is secondary to infection or not. Fever in SAH is strongly linked to poor outcome and increased length of stay (40), as well as vasospasm (41, 42), ischemic injury (43), cerebral edema and worsened intracranial hypertension (44). Even a single episode of fever has been associated with poorer outcomes. However, one can only definitively say that fever is associated with worsened outcomes, it may not be causative. In other words, it may simply be a marker of bad outcomes (45).

Whether fever is simply a marker for bad outcomes or something more, there is a suggestion that controlling fever may actually be neuroprotective. Oddo et al demonstrated that induced normothermia in 18 SAH patients resulted in a lower lactate-pyruvate ratio, fewer metabolic crises and lower ICP (46). But what about therapeutic hypothermia as a primary treatment modality – not just for fever control? Mild hypothermia has been shown to decrease cytotoxic edema, lactate accumulation and improve the metabolic stress response to SAH in rats (47). It has also been shown to lower ICP and improve outcomes in rats, including decreased neurologic deficits (48). In a dog model of SAH, therapeutic hypothermia decreased cerebral vasospasm, possibly by decreasing the rise in endothelin-1 and lessening the decrease of NO in CSF and the blood (49). In patients with SAH treated with therapeutic hypothermia, Kawamura used PET scans to demonstrate that hypothermia did decrease cerebral blood flow and oxygen metabolic rate (50). Seule et al. treated 100 patients with SAH who developed intracranial hypertension, symptomatic cerebral vasospasm or both, with mild therapeutic hypothermia (51). The majority of these patients had poor-grade SAH. 90 patients were evaluated at follow-up, 32 (35.6%) had survived with good neurologic outcome (Glasgow Outcome Scale 4 or 5) and 43 (47.8%) died. Side effects were common, including electrolyte disorders, pneumonia, thrombocytopenia and septic shock. From this study, the authors conclude that therapeutic hypothermia is a viable “last-resort option”, but side effects are common and potentially severe.

One of those common side effects of this therapy, shivering, can be detrimental to patients. Similar to any condition for which therapeutic hypothermia is employed, shivering should be avoided if possible and treated aggressively if present. Shivering has been associated with higher oxygen consumption, reduced PbtO2, higher ICP and lower CPP and higher resting energy expenditure (52-54). A substudy of the Intraoperative Hypothermia Aneurysm Surgery Trial revealed that bradycardia, a common and expected side effect of hypothermia, was associated with a higher 3-month mortality rate after SAH. “Relative tachycardia” and nonspecific ST-T wave changes, also common with hypothermia therapy, were also associated with a mortality difference. The implications of these findings are not clear, but should be kept in mind when using this therapeutic approach (55).

5. Conclusion

Therapeutic hypothermia has already been shown to have a positive impact on survival and neurologic outcome for survivors of out-of-hospital cardiac arrest (2, 3). That benefit likely is related to hypothermia’s impact on the multiple mechanisms of secondary brain injury. There is certainly potential for therapeutic hypothermia to reduce the secondary injury that results from brain and spinal cord injury as well. Many animal studies, but to this point only limited clinical studies, have suggested such an effect in treating patients that have suffered spinal cord injury, intracerebral hemorrhage or subarachnoid hemorrhage. Fortunately, the technology available to help us achieve and maintain the goals of targeted temperature management has made it easier to do so. The availability of that technology and increasing familiarity with its use will only serve to help investigators understand the potential impact of this therapy in brain and spinal cord injury. Medical therapy for these conditions is limited. Hopefully, future studies will clarify the potential role of therapeutic hypothermia in improving outcomes for these potentially devastating conditions.


1 - PoldermanKees H. Mechanisms of action, physiological effects, and complications of hypothermia.Critical Care MedicineS186S202, July 2009
2 - S. A Bernard, T. W Gray, M. D Buist, B. M Jones, W Silvester, G Gutteridge, K Smith, Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia.NEJM 346557563
3 - The Hypothermia After Cardiac Arrest Study GroupMild Therapeutic Hypothermia to Improve the Neurologic Outcome after Cardiac Arrest. NEJM 3468549556
4 - Kelly DL JrLassiter KR, Calogero JA, et al. Effects of local hypothermia and tissue oxygenation studies in experimental paraplegia. J Neurosurg 197033554563
5 - Y. K Demian, R. J White, D Yashon, et alAnaesthesia for laminectomy and localized cord cooling in acute cervical spine injuryReport of three cases. Br J Anaesth 1971439739
6 - A Bricolo, G. D Ore, Da Pian R, et al. Local cooling in spinal cord injury.Surg Neurol 19766101106
7 - R. R Hansebout, E. F Kuchner, Effects of local hypothermia and of steroids upon recovery from experimental spinal cord compression injury.Surg Neurol 19754531536
8 - E. F Kuchner, R. R Hansebout, Combined steroid and hypothermia treatment of experimental spinal cord injury.Surg Neurol 1976L371376
9 - D. W Dietrich, Therapeutic hypothermia for spinal cord injury.Crit Care Med 2009Suppl.):S238242
10 - D. W Dietrich, A. D Levi, M Wang, B Green, Hypothermic treatment for acute spinal cord injury.Neurotherapeutics 201120118229239
11 - A Cappuccino, L. J Bisson, B Carpenter, et alThe use of systemic hypothermia for the treatment of an acute spinal cord injury in a professional football player. SpinePhil Pa 1976). 2010Jan 15;35(2):E5762
12 - A. D Levi, B. A Green, M Wang, et alClinical Application of Modest Hypothermia after Spinal Cord InjuryJ Neurotrauma 200926407415
13 - A. D Levi, G Casella, B. A Green, et alClinical outcomes using modest intravascular hypothermia after acute cervical spinal cord injury.Neurosurgery20106667077
14 - National Spinal Cord Injury Statistical CenterSpinal Cord Injury Facts and Figures at a Glance. Birmingham, Alabama: National Spinal Cord Injury Statistical Center, University of Alabama, 2010
15 - J. M Gebel, J. P Broderick, Intracerebral hemorrhage. Neurol Clin 2000182419438
16 - M. L Flaherty, et alLong-term mortality after intracerebral hemorrhage.Neurology200666811821186
17 - J Broderick, S Connolly, E Feldmann, et alGuidelines for the management of spontaneous intracerebral hemorrhage in adults: 2007 update: a guideline from the American Heart Association/American Stroke Association Stroke Council, High Blood Pressure Research Council, and the Quality of Care and Outcomes in Research Interdisciplinary Working Group.Stroke 200738620012023
18 - S. A Mayer, N. C Brun, K Begtrup, et alEfficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhageN Engl J Med. 2008May 15;35820212737
19 - T Brott, J Broderick, R Kothari, et alEarly hemorrhage growth in patients with intracerebral hemorrhageStroke1997Jan;28115
20 - S. M Davis, J Broderick, M Hennerici, et alHematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage.Neurology2006Apr 25;668117581
21 - JC Hemphill, , DC Bonovich, , L Besmertis, , et al. The ICH score: a simple, reliable grading scale for intracerebral hemorrhage. Stroke. 2001;32891897 .
22 - A. R Zazulia, M. N Diringer, C. P Derdeyn, et alProgression of mass effect after intracerebral hemorrhage.Stroke 19993011671173
23 - H. M Fernandes, S Siddique, K Banister, et alContinuous monitoring of ICP and CPP following ICH and its relationship to clinical, radiological and surgical parameters.Acta Neurochir Suppl 20007646366
24 - J. M Gebel, E. C Jauch, T. G Brott, et alRelative edema volume is a predictor of outcome in patients with hyperacute spontaneous intracerebral hemorrhage.Stroke. 2002Nov;3311263641
25 - R Kollmar, D Staykov, A Dorfler, et alHypothermia reduces perihemorrhagic edema after intracerebral hemorrhage.Stroke 20104116841689
26 - G Xi, R. F Keep, J. T Hoff, Mechanisms of brain injury after intracerebral haemorrhageLancet Neurol. 200655363
27 - N Kawai, M Kawanishi, M Okauchi, et alEffects of hypothermia on thrombin-induced brain edema formation.Brain Res. 20018955058
28 - M Fingas, D. L Clark, F Colbourne, The effecs of selective brain hypothermia on intracerebral hemorrhage in rats. Exp. Neurol 2007208277284
29 - M Kawanishi, N Kawai, T Nakamura, et alEffect of delayed mild brain hypothermia on edema formation after intracerebral hemorrhage in ratsJ Stroke Cerebrovasc Dis. 200817187195
30 - MacLellanCL, Auriat, AM, McGie, SC, et al. Gauging recovery after hemorrhagic stroke in rats: implications for cytoprotection studies.J Cereb Blood Flow Metab. 20062610311042
31 - MacLellanCL, Davies LM, Fingas, MS, et al. The influence of hypothermia on outcome after intracerebral hemorrhage in rats.Stroke. 20063712661270
32 - K. R Wagner, S Beiler, C Beiler, et alDelayed profound local brain hypothermia markedly reduces interleukin-1 beta gene expression and vasogenic edema development in a porcine model of intracerebral hemorrhage. Acta Neurochir. 2006Suppl (96):177-182.
33 - M Fingas, M Penner, G Silasi, et alTreatment of intracerebral hemorrhage in rats with 12h, 3 days and 6 days of selective brain hypothermia.Exp Neurol. 2009219156162
34 - H Feng, D Shi, D Wang, et alEffect of local mild hypothermia on treatment of acute intracerebral hemorrhage, a clinical study. Zhounghua Yi Xue Za Zhi 20021622 EOF4 EOF
35 - D Staykov, I Wagner, B Volbers, et alMild Prolonged Hypothermia for Large Intracerebral Hemorrhage. Neurocrit Care. Published online August 3, 2012
36 - R Kollmar, E Juettler, H Huttner, et alCooling in intracerebral hemorrhage (CINCH) trial: protocol of a randomized German-Austrian clinical trial.Int J Stroke. 2012Feb;72168172
37 - N Badjiatia, Hyperthermia and fever control in brain injury. Crit Care Med. 2009S2507
38 - V Scaravelli, G Tinchero, G Citerio, et alFever Management in SAH. Neurocrit Care. 201115287294
39 - O Grady, N. P Barie, P. S Bartlett, JG, et al. Guidelines for evaluation of new fever in critically ill adult patients: 2008update from the American college of critical care medicineand the infectious disease society of America.Crit Care Med. 2008;36133049
40 - M. N Diringer, N. L Reaven, S. E Funk, et alElevated body temperature independently contributes to increased length of stay in neurologic intensive care unit patients.Crit Care Med. 200432148995
41 - K. E Wartenberg, J. M Schmidt, J Claassen, et alImpact of medical complications on outcoe after subarachnoid hemorrhage. Crit Care Med 20063461723
42 - J Oliveira-filho, M. A Ezzeddine, A. Z Segal, Fever in subarachnoid hemorrhage: relationship to vasospasm and outcome.Neurology2001561299304
43 - M. D Ginsberg, R Busto, combating hyperthermia in acute stroke: a significant clinical concern.Stroke. 19982952934
44 - S Rossi, E. R Zanier, I Mauri, et alBrain temperature, body core temperature, and intracranial pressure in acute cerebral damageJ Neurol Neurosurg Psychiatry. 20017144854
45 - M. M Todd, B. J Hindman, W. R Clarke, et alPerioperative fever and outcome in surgical patients with aneursymal subarachnoid hemorrhage. Neurosurgery. 2009May;645897908
46 - M Oddo, S Frangos, A Milby, et alInduced normothermia attenuates cerebral metabolic distress in patients with aneurismal subarachnoid hemorrhage and refractory fever. Stroke. 20094019136
47 - Schubert et alHypothermia reduces cytotoxic edema and metabolic alterations during the acute phase of massive SAH: a diffusion weighted imaging and spectroscopy study in ratsJ Neurotrauma 2008Jul;25784152
48 - E Torok, M Klopotowksi, R Trabold, et alMild hypothermia (33 degrees C) reduces intracranial hypertension and improves functional outcome after subarachnoid hemorrhage in rats.Neurosurgery2009Aug;6523529
49 - Wang ZpChen HS, Wang FX. Influence of plasma and cerebrospinal fluid levels of ednothelin-1 and NO in reducing cerebral vasospasm after subarachnoid hemorrhage during treatment with mild hypothermia, in a dog model. Cell Biochem Biophys. 2011Sep;61113743
50 - S Kawamura, A Suzuki, H Hadeishi, et alCerebral blood flow and oxygen metabolism during mild hypothermia in patients with subarachnoid haemorrhage.Acta Neurochir. 200014210111721
51 - M. A Seule, C Muroi, S Mink, et alTherapeutic hypothermia in patients with aneurismal subarachonoid hemorrhage, refractory intracranial hypertension, or cerebral vasospasm. Neurosurgery 2009Jan;6418692
52 - J. S Hata, C. R Shelsky, B. J Hindman, et alA prospective, observational clinical trial of fever reduction to reuce systemic oxygen consumption in the setting of acute brain injury. Neurocrit Care. 200893744
53 - M Oddo, S Frangos, E Maloney-wilensky, et alEffect of shivering on brain tissue oxygenation during induced normothermia in patients with severe brain injury.Neurocrit Care. 200912106
54 - N Badjiatia, E Strongilis, E Gordon, et alMetabolic impact of shivering during therapeutic temperature modulation: the Bedside Shivering Assessment Scale. Stroke. 2008Dec 391232427
55 - L. A Coghlan, B. J Hindman, E. O Bayman, et alIndependent associations between electrocardiographic abnormalitieis and outcomes in patients with aneurismal subarachnoid hemorrhage: findings from the introperative hypothermia aneurysm surgery trial. Stroke. 2009Feb;4024128
56 - A Qureshi, A. D Mendelow, D. F Hanley, Intracerebral haemorrhage. Lancet. 2009373163244
57 - D Staykov, I Wagner, B Volbers, et alNatural course of perihemorrhagic edema after intracerebral hemorrhage.Stroke. 20114226259
58 - D Staykov, S Schwab, A Dorfler, R Kollmer, Hypothermia Reduces Perihemorrhagic Edema After Intracerebral Hemorrhage: But Does it Influence Functional Outcome and Mortality? Therapeutic Hypothermia and Temperature Management. 2011
59 - G Xi, R. F Keep, J. T Hoff, Pathophysiology of brain edema formationNeurosurg Clin N Am. 20021337183