**10. Complications of hypothermia**

60 Therapeutic Hypothermia in Brain Injury

**Table 1.** Main studies of the use of hypothermia in the treatment of acute stroke.

Schwab (59)

Single center,

nonrandomized,

open label.

(1998)

Schwab (58)

Single center,

nonrandomized,

open label.

(1998)

**MCA Stroke** 

(61)

(2002)

Els (62)

Single center,

12 NA Surface and

endovascular

48 h Intubated Fentanyl and

midazolam.

Kollmar (70) (2010) Single center, nonrandomized, open label. 12 12 h Endovascular 10 d Intubated Sufentanyl, midazolam, meperidine and cisatracurium 35°C NA Pneumonia 100% Thromb 33% Bradycardia 25% Hypothermia decreased perihematomal edema.

Temp = temperature; thromb = thrombocytopenia; CMRO2 = Cerebral metabolic rate of oxigen; CBF = cerebral blood flow; tPA = tissue plasminogen activator; ICP = intracranial pressure; MCA = middle

cerebral artery; NA = not available; h = hour, d = day; min = minutes.

randomized,

open label.

(2006)

**Hemorrhag**

**ic Stroke** 

open label.

Georgiadis

Single center,

19 24 h Surface and

endovascular

nonrandomized,

**Authors Study Number of Patients Time from Stroke Cooling Technique Cooling Time Patient Anti-shivering Target Temp Time to Target Temp Complications Comment** 

25 14±7 h Surface 48-72 h Intubated Fentanyl, propofol

50 22±9 h Surface 48-72 h Intubated Fentanyl, midazolam

or propofol and

33°C 22 ± 3.5 -

Thromb 70%

Bradycardia 62%

Pneumonia 48%

33°C 4 ± 1 h Pneumonia 78%

Arrythmia 42%

Bradycardia 58%

Thromb 37%

Hypokalemia 26%

11 h

atracurium.

48-72 h Intubated Fentanyl, midazolam

and atracurium.

and atracurium.

33°C 14±4 h Pneumonia 10%

Hypothermia effective in the

treatment of increased ICP after

MCA infarction.

Fast rewarming was associated

with rebound increased ICP.

Hypothermia was compared with

hemicraniectomy in the treatment

of large MCA strokes. The

hypothermia group had higher

mortality due to increased ICP

during rewarming.

hemicraniectomy.

35°C 2 ± 1 h Bradycardia 8% Hypothermia was used with

Arrythmia 60%

Induced therapeutic hypothermia is an intensive care procedure that has to be performed under continuous monitoring. Since most patients who are cooled are critically ill, they may be more prone to develop complications. These complications appear to be associated with de degree of hypothermia, with the risk of side effects being correlated with prolonged hypothermia and lower temperatures. In general, hypothermia is well tolerated, but complications may include: 1) cardiac: arrhythmias, bradycardia, reduced ventricular contractility, and hypotension; 2) immunologic: immunosuppression; 3) hematologic: thrombocytopenia and mild coagulopathy; and 4) metabolic: shivering, hyperglycemia, hypokalemia, ileus, and cold-induced diuresis. The most common complication in reported studies is pneumonia, followed by asymptomatic bradycardia, cardiac arrhythmias and thrombocytopenia (table).[14]

Pneumonia appears to occur more frequently in intubated patients who undergo cooling. Endovascular cooling with use of warm blankets to reduce shivering and prevent intubation is an alternative to surface cooling and may reduce the rate of pneumonia.

The most dangerous phase of induced hypothermia is the rewarming period. Particular care is required in stroke patients with intracranial mass effect and elevated ICP. Overly rapid rewarming can lead to a systemic inflammatory response syndrome; with systemic vasodilatation, hypotension, and reflex ICP elevation.[14] As a general rule, hypothermia patients with increased ICP should undergo active controlled rewarming (or "decooling") at a rate of 0.1°C per hour. Faster rates of 0.25°C to 0.33°C per hour can be tolerated in patients without ICP issues.[72-74] This high ICP rebound has especially been observed in patients with malignant MCA infarctions.[75]

One common complication of hypothermia that usually is overlooked is sedation. It has been demonstrated that patients who undergo hypothermia are more likely to receive sedation than those who are not treated with hypothermia.[76] Sedation in hypothermia patients may linger longer in the system, confounding neurological examination and prognostication.[77] This becomes a relevant issue in stroke patients who require daily neurological assessments.

#### **11. Conclusion and recommendations**

Despite the many potential neuroprotective effects of hypothermia seen in animal stroke models and the benefit of hypothermia observed in humans following cardiac arrest, there is

still no solid evidence demonstrating improved outcomes in stroke patients. In addition, a systematic review found no definitive evidence that either physical or chemical cooling interventions improve outcomes after acute ischemic stroke.[78] The total number of participants included in the studies reviewed in this chapter is far to small and the interventions too heterogeneous for definitive conclusions (table). Moreover, all studies were designed to test safety and feasibility, and allowed rather long time periods between stroke onset and start of cooling, which may lower the likelihood of observing a treatment effect.

Therapeutic Hypothermia in Acute Stroke 63

**Author details** 

**12. References** 

Jan;24(1):35-41.

Engl J Med. 2002 Feb 21;346(8):557-63.

Invest. 2000 Sep;106(6):723-31.

Edgar A. Samaniego

*Baptist Neuroscience Center, Baptist Cardiac and Vascular Institute, Miami, Florida, USA* 

[1] Adams HP, Jr., Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993

[2] O'Collins VE, Macleod MR, Donnan GA, Horky LL, van der Worp BH, Howells DW. 1,026 experimental treatments in acute stroke. Ann Neurol. 2006 Mar;59(3):467-77. [3] Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N

[4] Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD, Ferriero DM, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy:

[5] Kollmar R, Staykov D, Dörer A, Schellinger PD, Schwab S, Bardutzky Jr. Hypothermia Reduces Perihemorrhagic Edema After Intracerebral Hemorrhage. Stroke.

[6] Hammer MD, Krieger DW. Hypothermia for acute ischemic stroke: not just another

[7] Lee JM, Grabb MC, Zipfel GJ, Choi DW. Brain tissue responses to ischemia. J Clin

[8] Nishijima MK, Koehler RC, Hurn PD, Eleff SM, Norris S, Jacobus WE, et al. Postischemic recovery rate of cerebral ATP, phosphocreatine, pH, and evoked

[9] Kintner D, Costello DJ, Levin AB, Gilboe DD. Brain metabolism after 30 minutes of hypoxic or anoxic perfusion or ischemia. Am J Physiol. 1980 Dec;239(6):E501-9. [10] Busch E, Kruger K, Allegrini PR, Kerskens CM, Gyngell ML, Hoehn-Berlage M, et al. Reperfusion after thrombolytic therapy of embolic stroke in the rat: magnetic resonance

[11] Yenari MA, Colbourne F, Hemmen TM, Han HS, Krieger D. Therapeutic hypothermia

[12] Berger C, Schabitz WR, Georgiadis D, Steiner T, Aschoff A, Schwab S. Effects of hypothermia on excitatory amino acids and metabolism in stroke patients: a

[13] Globus MY, Alonso O, Dietrich WD, Busto R, Ginsberg MD. Glutamate release and free radical production following brain injury: effects of posttraumatic hypothermia. J

and biochemical imaging. J Cereb Blood Flow Metab. 1998 Apr;18(4):407-18.

multicentre randomised trial. Lancet. 2005 Feb 19-25;365(9460):663-70.

[10.1161/STROKEAHA.110.587758]. 2010;41(8):1684-9.

potentials. Am J Physiol. 1989 Dec;257(6 Pt 2):H1860-70.

in stroke. Stroke Res Treat. 2011;2011:157969.

Neurochem. 1995 Oct;65(4):1704-11.

microdialysis study. Stroke. 2002 Feb;33(2):519-24.

neuroprotectant. Neurologist. 2003 Nov;9(6):280-9.

Stroke studies have used surface and endovascular cooling systems for induction and maintenance of hypothermia (table). Goal temperatures usually range from 33° to 35°C. IV infusion of ice-cold saline [25 mL/kg body weight) has been shown to induce hypothermia rapidly and may be used as an initial cooling method in stroke patients who are initially assessed in the field.[53]

Pharmacologic agents like meperidine and buspirone, and concurrent skin warming inhibit shivering and allow patients to tolerate treatment with less sedation. Moreover, these antishivering protocols have allowed the induction and maintenance of mild and moderate hypothermia in awake patients.[47] Recent studies have demonstrated that endovascular cooling is more accurate in keeping patients in the target temperature range than surface cooling with ice bags and cooling blankets.[79, 80] Endovascular cooling also allows for concurrent use of surface warming to reduce shivering. However, endovascular cooling implies accessing the femoral vein to place the cooling catheter, increasing the risk of procedural complications and infection. In general, each center should choose the cooling method that is more familiar to the personnel and easier to implement.

Similar uncertainty exists on the optimal treatment duration. In animal models of focal cerebral ischemia, pathophysiological processes exert their deleterious effects over various time courses, extending from the rst hours to several days after vessel occlusion.[81] Such observations may imply that temperature lowering therapy should be more effective when used for prolonged time. On the other hand, longer treatment was not associated with improved outcomes in a meta-analysis of hypothermia in animal models of focal cerebral ischemia. Moreover, the risk of side effects such as infections may increase with longer cooling times.[39] In clinical trials of cardiac arrest, hypothermia was maintained for 12 or 24 hours.[3] Most recent studies of hypothermia in acute ischemic stroke aim for 12 – 24 hours of cooling (table).

For unknown reasons, patients with massive brain injuries may experience rebound intracranial hypertension when rapidly rewarmed after prolonged periods of mild to moderate hypothermia. Whether this occurs in experimental stroke models has not been widely studied. Previous stroke studies suggest that controlled rewarming seems to prevent rebound brain edema and is the standard protocol in most recent trials.[14] Trials using milder hypothermia [35°C) and slower rewarming periods have reported lower complication rates.[62] For practical purposes, a 24-hour cooling period followed by a >12 hour slow rewarming, such as 0.1° C/h is advised.[82]

#### **Author details**

62 Therapeutic Hypothermia in Brain Injury

assessed in the field.[53]

of cooling (table).

effect.

still no solid evidence demonstrating improved outcomes in stroke patients. In addition, a systematic review found no definitive evidence that either physical or chemical cooling interventions improve outcomes after acute ischemic stroke.[78] The total number of participants included in the studies reviewed in this chapter is far to small and the interventions too heterogeneous for definitive conclusions (table). Moreover, all studies were designed to test safety and feasibility, and allowed rather long time periods between stroke onset and start of cooling, which may lower the likelihood of observing a treatment

Stroke studies have used surface and endovascular cooling systems for induction and maintenance of hypothermia (table). Goal temperatures usually range from 33° to 35°C. IV infusion of ice-cold saline [25 mL/kg body weight) has been shown to induce hypothermia rapidly and may be used as an initial cooling method in stroke patients who are initially

Pharmacologic agents like meperidine and buspirone, and concurrent skin warming inhibit shivering and allow patients to tolerate treatment with less sedation. Moreover, these antishivering protocols have allowed the induction and maintenance of mild and moderate hypothermia in awake patients.[47] Recent studies have demonstrated that endovascular cooling is more accurate in keeping patients in the target temperature range than surface cooling with ice bags and cooling blankets.[79, 80] Endovascular cooling also allows for concurrent use of surface warming to reduce shivering. However, endovascular cooling implies accessing the femoral vein to place the cooling catheter, increasing the risk of procedural complications and infection. In general, each center should choose the cooling

Similar uncertainty exists on the optimal treatment duration. In animal models of focal cerebral ischemia, pathophysiological processes exert their deleterious effects over various time courses, extending from the rst hours to several days after vessel occlusion.[81] Such observations may imply that temperature lowering therapy should be more effective when used for prolonged time. On the other hand, longer treatment was not associated with improved outcomes in a meta-analysis of hypothermia in animal models of focal cerebral ischemia. Moreover, the risk of side effects such as infections may increase with longer cooling times.[39] In clinical trials of cardiac arrest, hypothermia was maintained for 12 or 24 hours.[3] Most recent studies of hypothermia in acute ischemic stroke aim for 12 – 24 hours

For unknown reasons, patients with massive brain injuries may experience rebound intracranial hypertension when rapidly rewarmed after prolonged periods of mild to moderate hypothermia. Whether this occurs in experimental stroke models has not been widely studied. Previous stroke studies suggest that controlled rewarming seems to prevent rebound brain edema and is the standard protocol in most recent trials.[14] Trials using milder hypothermia [35°C) and slower rewarming periods have reported lower complication rates.[62] For practical purposes, a 24-hour cooling period followed by a >12-

method that is more familiar to the personnel and easier to implement.

hour slow rewarming, such as 0.1° C/h is advised.[82]

Edgar A. Samaniego

*Baptist Neuroscience Center, Baptist Cardiac and Vascular Institute, Miami, Florida, USA* 

#### **12. References**


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**Chapter 5** 

© 2013 Tannehill, 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 Tannehill, 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.

**Hypothermia for Intracerebral Hemorrhage,** 

David E. Tannehill

**1. Introduction** 

http://dx.doi.org/10.5772/54925

Additional information is available at the end of the chapter

what has been published on these topics to this point.

**2. Therapeutic hypothermia for acute spinal cord injury** 

**Subarachnoid Hemorrhage & Spinal Cord Injury** 

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

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

