**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.

Hypothermia for Intracerebral Hemorrhage, Subarachnoid Hemorrhage & Spinal Cord Injury 71

**3. Therapeutic hypothermia for intracerebral hemmorhage** 

improve these injurious processes, but not outcomes (27-33).

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

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).

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

**4. Therapeutic Hypothermia for Subarachnoid Hemorrhage** 

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 33C 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 lifethreatening 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**

70 Therapeutic Hypothermia in Brain Injury

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

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 33C 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 lifethreatening 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

of local cooling, lead to the general abandonment of the idea.

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).

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).

Hypothermia for Intracerebral Hemorrhage, Subarachnoid Hemorrhage & Spinal Cord Injury 73

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

[1] Polderman, Kees H. Mechanisms of action, physiological effects, and complications of

[2] Bernard, SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, Smith,K. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced

[3] The Hypothermia After Cardiac Arrest Study Group. Mild Therapeutic Hypothermia to Improve the Neurologic Outcome after Cardiac Arrest. NEJM 346(8): 549-556. [4] Kelly DL Jr, Lassiter KR, Calogero JA, et al. Effects of local hypothermia and tissue oxygenation studies in experimental paraplegia. J Neurosurg 1970;33:554-563. [5] Demian YK, White RJ, Yashon D, et al. Anaesthesia for laminectomy and localized cord cooling in acute cervical spine injury. Report of three cases. Br J Anaesth 1971;43:973-9. [6] Bricolo A, Ore GD, Da Pian R, et al. Local cooling in spinal cord injury. Surg Neurol

[7] Hansebout RR, Kuchner EF. Effects of local hypothermia and of steroids upon recovery from experimental spinal cord compression injury. Surg Neurol 1975;4:531-536. [8] Kuchner EF, Hansebout RR. Combined steroid and hypothermia treatment of

[9] Dietrich, DW. Therapeutic hypothermia for spinal cord injury. Crit Care Med 2009;

[10] Dietrich DW, Levi AD, Wang M, Green B. Hypothermic treatment for acute spinal cord

[11] Cappuccino A, Bisson LJ, Carpenter B, et al. The use of systemic hypothermia for the treatment of an acute spinal cord injury in a professional football player. Spine (Phil Pa

[12] Levi AD, Green BA, Wang M, et al. Clinical Application of Modest Hypothermia after

[13] Levi AD, Casella G, Green BA, et al. Clinical outcomes using modest intravascular hypothermia after acute cervical spinal cord injury. Neurosurgery 2010; 66:670-77.

in improving outcomes for these potentially devastating conditions.

*Department of Critical Care Medicine, Mercy Hospital, St. Louis, USA* 

hypothermia. NEJM 346, 557-563.

hypothermia. Critical Care Medicine. 37(7):S186-S202, July 2009.

experimental spinal cord injury. Surg Neurol 1976;6L371-376.

injury. Neurotherapeutics 2011(8):229-239.

Spinal Cord Injury. J Neurotrauma 2009; 26:407-415.

1976). 2010 Jan 15;35(2):E57-62.

**Author details** 

David E. Tannehill

**6. References** 

1976;6:101-106.

37(Suppl.):S238-242.

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 "lastresort 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.

#### **Author details**

72 Therapeutic Hypothermia in Brain Injury

bad outcomes (45).

**5. Conclusion** 

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

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-

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

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

resort option", but side effects are common and potentially severe.

clear, but should be kept in mind when using this therapeutic approach (55).

David E. Tannehill *Department of Critical Care Medicine, Mercy Hospital, St. Louis, USA* 

#### **6. References**


[14] National Spinal Cord Injury Statistical Center. Spinal Cord Injury Facts and Figures at a Glance. Birmingham, Alabama: National Spinal Cord Injury Statistical Center, University of Alabama, 2010.

Hypothermia for Intracerebral Hemorrhage, Subarachnoid Hemorrhage & Spinal Cord Injury 75

[31] MacLellan, CL, Davies LM, Fingas, MS, et al. The influence of hypothermia on outcome

[32] Wagner, KR, Beiler, S, Beiler, C, et al. Delayed profound local brain hypothermia markedly reduces interleukin-1 beta gene expression and vasogenic edema development in a porcine model of intracerebral hemorrhage. Acta Neurochir.

[33] Fingas, M, Penner, M, Silasi, G, et al. Treatment of intracerebral hemorrhage in rats with 12h, 3 days and 6 days of selective brain hypothermia. Exp Neurol. 2009;219:156-162. [34] Feng, H, Shi, D, Wang, D, et al. Effect of local mild hypothermia on treatment of acute intracerebral hemorrhage, a clinical study. Zhounghua Yi Xue Za Zhi 2002;(82):1622-

[35] Staykov D, Wagner I, Volbers B, et al. Mild Prolonged Hypothermia for Large

[36] Kollmar R, Juettler E, Huttner H, et al. Cooling in intracerebral hemorrhage (CINCH) trial: protocol of a randomized German-Austrian clinical trial. Int J Stroke.

[37] Badjiatia N. Hyperthermia and fever control in brain injury. Crit Care Med.

[38] Scaravelli V, Tinchero G, Citerio G, et al. Fever Management in SAH. Neurocrit Care.

[39] O'Grady NP, Barie PS, Bartlett JG, et al. Guidelines for evaluation of new fever in critically ill adult patients: 2008 update from the American college of critical care medicine and the infectious disease society of America. Crit Care Med. 2008;36:1330-49. [40] Diringer MN, Reaven NL, Funk SE, et al. Elevated body temperature independently contributes to increased length of stay in neurologic intensive care unit patients. Crit

[41] Wartenberg KE, Schmidt JM, Claassen J, et al. Impact of medical complications on

[42] Oliveira-Filho J, Ezzeddine MA, Segal AZ. Fever in subarachnoid hemorrhage:

[43] Ginsberg MD, Busto R. combating hyperthermia in acute stroke: a significant clinical

[44] Rossi S, Zanier ER, Mauri I, et al. Brain temperature, body core temperature, and intracranial pressure in acute cerebral damage. J Neurol Neurosurg Psychiatry.

[45] Todd MM, Hindman BJ, Clarke WR, et al. Perioperative fever and outcome in surgical patients with aneursymal subarachnoid hemorrhage. Neurosurgery. 2009; May;

[46] Oddo M, Frangos S, Milby A, et al. Induced normothermia attenuates cerebral metabolic distress in patients with aneurismal subarachnoid hemorrhage and refractory

outcoe after subarachnoid hemorrhage. Crit Care Med 2006;34:617-23.

relationship to vasospasm and outcome. Neurology. 2001;56:1299-304.

Intracerebral Hemorrhage. Neurocrit Care. Published online August 3, 2012.

after intracerebral hemorrhage in rats. Stroke. 2006;37:1266-1270.

2006;Suppl (96):177-182.

2012;Feb;7(2):168-172.

Care Med. 2004;32:1489-95.

concern. Stroke. 1998;29:529-34.

fever. Stroke. 2009;40:1913-6.

2009;37:S250-7.

2011;15:287-294.

2001;71:448-54.

64(5):897-908.

1624.


[31] MacLellan, CL, Davies LM, Fingas, MS, et al. The influence of hypothermia on outcome after intracerebral hemorrhage in rats. Stroke. 2006;37:1266-1270.

74 Therapeutic Hypothermia in Brain Injury

2006;66(8):1182-1186.

37.

25;66(8):1175-81.

Nov;33(11):2636-41.

2008;17:187-195.

2006;26:1031-1042.

University of Alabama, 2010.

[14] National Spinal Cord Injury Statistical Center. Spinal Cord Injury Facts and Figures at a Glance. Birmingham, Alabama: National Spinal Cord Injury Statistical Center,

[17] Broderick J, Connolly S, Feldmann E, et al. Guidelines 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

[18] Mayer SA, Brun NC, Begtrup K, et al. Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med. 2008 May 15;358(20):2127-

[19] Brott T, Broderick J, Kothari R, et al. Early hemorrhage growth in patients with

[20] Davis SM, Broderick J, Hennerici M, et al. Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage. Neurology. 2006 Apr

[21] Hemphill JC, Bonovich DC, Besmertis L, et al. The ICH score: a simple, reliable grading

[22] Zazulia AR, Diringer MN, Derdeyn CP, et al. Progression of mass effect after

[23] Fernandes HM, Siddique S, Banister K, et al. Continuous monitoring of ICP and CPP following ICH and its relationship to clinical, radiological and surgical parameters. Acta

[24] Gebel JM, Jauch EC, Brott TG, et al. Relative edema volume is a predictor of outcome in patients with hyperacute spontaneous intracerebral hemorrhage. Stroke. 2002

[25] Kollmar R, Staykov D, Dorfler A, et al. Hypothermia reduces perihemorrhagic edema

[26] Xi, G, Keep, RF, Hoff, JT. Mechanisms of brain injury after intracerebral haemorrhage.

[27] Kawai, N, Kawanishi, M, Okauchi, M, et al. Effects of hypothermia on thrombin-

[28] Fingas, M, Clark, DL, Colbourne, F. The effecs of selective brain hypothermia on

[29] Kawanishi, M, Kawai, N, Nakamura, T, et al. Effect of delayed mild brain hypothermia on edema formation after intracerebral hemorrhage in rats. J Stroke Cerebrovasc Dis.

[30] MacLellan, CL, Auriat, AM, McGie, SC, et al. Gauging recovery after hemorrhagic stroke in rats: implications for cytoprotection studies. J Cereb Blood Flow Metab.

[15] Gebel, JM, Broderick JP. Intracerebral hemorrhage. Neurol Clin 2000; 18(2):419-438. [16] Flaherty ML, et al. Long-term mortality after intracerebral hemorrhage. Neurology

Interdisciplinary Working Group. Stroke 2007;38(6):2001-2023.

intracerebral hemorrhage. Stroke. 1997 Jan;28(1):1-5.

intracerebral hemorrhage. Stroke 1999;30:1167-1173.

Neurochir Suppl 2000;76:463-66.

Lancet Neurol. 2006;5:53-63.

scale for intracerebral hemorrhage. Stroke. 2001;32:891-897.

after intracerebral hemorrhage. Stroke 2010;41:1684-1689.

induced brain edema formation. Brain Res. 2001;895:50-58.

intracerebral hemorrhage in rats. Exp. Neurol 2007;208:277-284.

	- [47] Schubert et al. Hypothermia reduces cytotoxic edema and metabolic alterations during the acute phase of massive SAH: a diffusion weighted imaging and spectroscopy study in rats. J Neurotrauma 2008;Jul;25(7):841-52.

**Section 4** 

**Therapeutic Hypothermia- Traumatic Brain** 

**Injury/Intracranial Hypertension** 


**Therapeutic Hypothermia- Traumatic Brain Injury/Intracranial Hypertension** 

76 Therapeutic Hypothermia in Brain Injury

2011;Sep;61(1):137-43.

2000;142(10):1117-21.

in rats. J Neurotrauma 2008;Jul;25(7):841-52.

vasospasm. Neurosurgery 2009;Jan;64(1):86-92.

injury. Neurocrit Care. 2008;9:37-44.

surgery trial. Stroke. 2009;Feb;40(2):412-8.

intracerebral hemorrhage. Stroke. 2011;42:2625-9.

Neurocrit Care. 2009;12:10-6.

2008;Dec 39(12):3242-7.

2009;373:1632-44.

Am. 2002;13:371-83.

106.

hemorrhage in rats. Neurosurgery. 2009;Aug;65(2):352-9.

[47] Schubert et al. Hypothermia reduces cytotoxic edema and metabolic alterations during the acute phase of massive SAH: a diffusion weighted imaging and spectroscopy study

[48] Torok E, Klopotowksi M, Trabold R, et al. Mild hypothermia (33 degrees C) reduces intracranial hypertension and improves functional outcome after subarachnoid

[49] Wang Zp, Chen 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.

[50] Kawamura S, Suzuki A, Hadeishi H, et al. Cerebral blood flow and oxygen metabolism during mild hypothermia in patients with subarachnoid haemorrhage. Acta Neurochir.

[51] Seule MA, Muroi C, Mink S, et al. Therapeutic hypothermia in patients with aneurismal subarachonoid hemorrhage, refractory intracranial hypertension, or cerebral

[52] Hata JS, Shelsky CR, Hindman BJ, et al. A prospective, observational clinical trial of fever reduction to reuce systemic oxygen consumption in the setting of acute brain

[53] Oddo M, Frangos S, Maloney-Wilensky E, et al. Effect of shivering on brain tissue oxygenation during induced normothermia in patients with severe brain injury.

[54] Badjiatia N, Strongilis E, Gordon E, et al. Metabolic impact of shivering during therapeutic temperature modulation: the Bedside Shivering Assessment Scale. Stroke.

[55] Coghlan LA, Hindman BJ, Bayman EO, et al. Independent associations between electrocardiographic abnormalitieis and outcomes in patients with aneurismal subarachnoid hemorrhage: findings from the introperative hypothermia aneurysm

[56] Qureshi A, Mendelow AD, Hanley DF. Intracerebral haemorrhage. Lancet.

[57] Staykov, D, Wagner I, Volbers B, et al. Natural course of perihemorrhagic edema after

[58] Staykov D, Schwab S, Dorfler A, Kollmer R. Hypothermia Reduces Perihemorrhagic Edema After Intracerebral Hemorrhage: But Does it Influence Functional Outcome and Mortality? Therapeutic Hypothermia and Temperature Management. 2011;1:(2):105-

[59] Xi, G, Keep RF, Hoff, JT. Pathophysiology of brain edema formation. Neurosurg Clin N

**Chapter 6** 

© 2013 Sadaka et al., licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 Sadaka et al., licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**Therapeutic Hypothermia in** 

Additional information is available at the end of the chapter

Farid Sadaka, Christopher Veremakis, Rekha Lakshmanan and Ashok Palagiri

Traumatic brain injury (TBI) is a major source of death and severe disability worldwide. In the USA alone, this type of injury causes 290,000 hospital admissions, 51,000 deaths, and 80,000 permanently disabled survivors [1,2]. Intracranial hypertension develops commonly in acute brain injury related to trauma [3,4]. Raised Intracranial pressure (ICP) is an important predictor of mortality in patients with severe TBI, and aggressive treatment of elevated ICP has been shown to reduce mortality and improve outcome [4-11]. Guidelines for the Management of Severe TBI, published in the Journal of Neurotrauma in 2007 [12] make a Level II recommendation that ICP should be monitored in all salvageable patients with a severe TBI (Glasgow Coma Scale [GCS] score of 3–8 after resuscitation) and an abnormal computed tomography (CT) scan. ICP monitoring is also recommended in patients with severe TBI and a normal CT scan if two or more of the following features are noted at admission: age over 40 years, unilateral or bilateral motor posturing, or systolic blood pressure < 90 mm Hg (Level III recommendation). Furthermore, ICP should be maintained less than 20 mmHg and cerebral perfusion pressure (CPP) between 50 and 70

As in ischemia –reperfusion injuries, the acute post-injury period in TBI is characterized by several pathophysiologic processes that start in the minutes to hours following injury and may last for hours to days. These result in further neuronal injury and are termed the secondary injury. Cellular mechanisms of secondary injury include all of the following: apoptosis, mitochondrial dysfunction, excitotoxicity, disruption in ATP metabolism, disruption in calcium homeostasis, increase in inflammatory mediators and cells, free radical formation, DNA damage, blood-brain barrier disruption, brain glucose utilization disruption, microcirculatory dysfunction and microvascular thrombosis [13-50]. All of these processes are temperature dependent; they are all aggravated by fever and inhibited by

**Traumatic Brain Injury** 

http://dx.doi.org/10.5772/48818

**1. Introduction** 

mmHg (Level III).
