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(Stroke. 2001;32:1847.)
© 2001 American Heart Association, Inc.

Original Contributions

Cooling for Acute Ischemic Brain Damage (COOL AID)

An Open Pilot Study of Induced Hypothermia in Acute Ischemic Stroke

Derk W. Krieger, MD; Michael A. De Georgia, MD; Alex Abou-Chebl, MD; John C. Andrefsky, MD; Cathy A. Sila, MD; Irene L. Katzan, MD; Marc R. Mayberg, MD Anthony J. Furlan, MD

From the Cerebrovascular Center, The Cleveland Clinic Foundation, Cleveland, Ohio.

Correspondence to Derk W. Krieger, MD, Section of Stroke and Neurological Critical Care, Department of Neurology, Desk S-91, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195. E-mail krieged{at}ccf.org

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Background and Purpose—— Hypothermia is effective in improving outcome in experimental models of brain infarction. We studied the feasibility and safety of hypothermia in patients with acute ischemic stroke treated with thrombolysis.

Methods—— An open study design was used. All patients presented with major ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score >15) within 6 hours of onset. After informed consent, patients with a persistent NIHSS score of >8 were treated with hypothermia to 32±1°C for 12 to 72 hours depending on vessel patency. All patients were monitored in the neurocritical care unit for complications. A modified Rankin Scale was measured at 90 days and compared with concurrent controls.

Results—— Ten patients with a mean age of 71.1±14.3 years and an NIHSS score of 19.8±3.3 were treated with hypothermia. Nine patients served as concurrent controls. The mean time from symptom onset to thrombolysis was 3.1±1.4 hours and from symptom onset to initiation of hypothermia was 6.2±1.3 hours. The mean duration of hypothermia was 47.4±20.4 hours. Target temperature was achieved in 3.5±1.5 hours. Noncritical complications in hypothermia patients included bradycardia (n=5), ventricular ectopy (n=3), hypotension (n=3), melena (n=2), fever after rewarming (n=3), and infections (n=4). Four patients with chronic atrial fibrillation developed rapid ventricular rate, which was noncritical in 2 and critical in 2 patients. Three patients had myocardial infarctions without sequelae. There were 3 deaths in patients undergoing hypothermia. The mean modified Rankin Scale score at 3 months in hypothermia patients was 3.1±2.3.

Conclusion—— Induced hypothermia appears feasible and safe in patients with acute ischemic stroke even after thrombolysis. Refinements of the cooling process, optimal target temperature, duration of therapy, and, most important, clinical efficacy, require further study.

Key Words: hypothermia • ischemia • neuroprotection • stroke

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
Severe stroke leading to functional dependency constitutes 10% to 15% of all acute stroke admissions. Among other factors, stroke severity has the biggest impact on long-term outcomes.¹ Thrombolytic therapy has improved outcome for many patients with acute ischemic strokes, but the great majority of patients who present with severe anterior circulation territory ischemic strokes (those with initial the National Institutes of Health Stroke Scale [NIHSS] scores of >15) continue to have poor outcomes.^2–5 One reason for the poor outcomes is that patients with severe strokes simply have irreversibly damaged brain tissue at the time they present and do not benefit from the restoration of blood flow. Another reason is that reperfusion injury may paradoxically antagonize the benefit of early blood flow restoration and cause further tissue damage. There is overwhelming experimental and clinical data to support the use of hypothermia in limiting ischemic brain damage.⁶ Several animal stroke models have shown hypothermia to decrease the final infarct volume and to extend the duration the brain can withstand ischemia before permanent damage occurs ("therapeutic window").^7–11 There also is experimental evidence that moderate hypothermia suppresses the postischemic generation of oxygen free radicals and inflammatory responses known to play a role in "reperfusion injury."^12,13 Induced moderate hypothermia is therefore a logical approach to limit damage from ischemia and to reduce reperfusion injury in the setting of severe ischemic stroke.

This pilot study explores the feasibility and safety of adjunct moderate hypothermia (target temperature 32°C) in patients with ischemic strokes who show no or minimal clinical improvement even after undergoing thrombolysis. Moderate hypothermia was achieved using surface cooling and maintained from 12 to 72 hours depending on when the target vessel recanalized as assessed with angiography or transcranial Doppler (TCD) sonography.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
General Protocol
The study protocol was approved by The Cleveland Clinic Foundation Institutional Review Board. Informed consent was obtained from all patients or a designated surrogate before thrombolytic therapy. From October 1999 to September 2000, all patients with acute ischemic strokes were screened for eligibility. Patients were eligible if they met all of the following inclusion criteria: (1) age of >18 years, (2) middle cerebral artery (MCA) territory ischemic stroke, (3) NIHSS score of >15 at baseline, (4) eligible for intravenous thrombolysis or intra-arterial thrombolysis/thrombectomy, (5) significant neurological deficit after thrombolytic therapy/thrombectomy (NIHSS score of >8), and (6) the initiation of moderate hypothermia within 5 hours of symptom onset (for patients treated with intravenous thrombolysis) or 8 hours after symptom onset (for patients treated with intra-arterial thrombolysis).

Patients were ineligible if they met any of the following exclusion criteria: (1) sepsis (defined as bacteremia and clinical septic syndrome within 72 hours), (2) platelet count of <75,000/mm³, (3) coagulopathy (INR >1.3, partial thromboplastin time >1.5x control, hypofibrinogenemia), (4) hemodynamically significant cardiac dysrhythmias or QTc interval >450 milliseconds, (5) preexisting illness that limits life expectancy to <6 months after stroke event, or (6) preexisting neurological disability with modified Rankin Scale (mRS) score of >2.

Eligible patients screened during the study period who were not enrolled served as concurrent controls. A total of 19 patients were eligible for the study, of whom 10 were treated with moderate hypothermia (Table 1).

View this table: [in this window] [in a new window]   Table 1. Basic Characteristics, Vascular Pathology, and Stroke Severity in Hypothermia Patients and Nonhypothermia Patients

Monitoring Protocol
Patients undergoing endovascular therapy had a pretreatment and a posttreatment angiogram. Flow was assessed using the Thrombolysis In Myocardial Infarction (TIMI) flow grading system.¹⁴ Those undergoing intravenous thrombolysis had at least a posttreatment TCD sonography examination. Flow in these patients was assessed using the Thrombolysis In Brain Infarction (TIBI) flow grading system. The TIBI grades are based on identification of abnormal residual flow signals in the affected artery corresponding to a completely or partially occluded vessel (TIMI 0 to 2 grades equivalent) or low resistance signals (TIMI 3 equivalent) suggesting reperfusion.¹⁵ Serial TCD sonography studies were performed at least daily.

Hypothermia Protocol
After initial assessment in the emergency department, patients were treated with intravenous recombinant tissue plasminogen activator or transferred to the angiography suite for intra-arterial therapy. All patients were then admitted to the neurological critical care unit. All patients were treated according to a standardized medical protocol. Patients undergoing hypothermia were treated according to a standardized hypothermia protocol. Invasive monitoring requirements included arterial line and central venous catheterization for the hypothermia group. To prevent shivering, all patients undergoing hypothermia were endotracheally intubated, sedated, and pharmacologically paralyzed. Assisted mode of ventilation with pressure support was used. The sedation protocol included intravenous propofol infusion begun at 5 µg · kg^-1 · min^-1. The infusion rate was increased by 5- to 10-µg · kg^-1 · min^-1 increments every 10 to 20 minutes until the desired level of sedation was achieved. In all patients, the muscle relaxant atracurium was administered as a 0.4-mg/kg bolus followed by an infusion of 5 µg · kg^-1 · min^-1 with titration of the dose to achieve suppression of shivering.

For the induction of moderate hypothermia, the patient was positioned on a cooling blanket (Aquamatic K-Thermia EC600). For initial cooling, the blanket was set on automatic mode at 4.0°C. Ice water and whole body alcohol rubs were performed concurrently. After the core temperature reached 34°C as determined by thermistor Foley catheter (Mon-A-Therm; Mallinckrodt Medical), the patient was sandwiched between 2 cooling blankets, and blanket water temperature was maintained at 32°C. Core temperature was continuously monitored and recorded every 30 minutes. The time when the core target temperature of 32°C was achieved served as the reference for the determination of rewarming. Blanket temperature was adjusted to maintain the core temperature at 32°C. The cooling period was limited to 12 hours in patients who had TIMI 3 or TIMI 3–equivalent flows in both of their middle cerebral arteries before the induction of hypothermia. In the remaining patients, rewarming was initiated 12 hours after a repeat TCD sonography examination showed TIMI 3–equivalent flow in the MCA. Repeat TCD studies were performed at 12- to 24-hour intervals. The maximal hypothermia duration was 72 hours.

All patients underwent a CT scan at 24 hours to rule out hemorrhagic transformation. Controlled rewarming at a rate of no faster than 0.25° to 0.5°C/h was initiated by turning off the cooling blanket and covering patients with cloth blankets. All patients underwent a CT scan at 7 to 10 days for assessment of infarct volume.

Data Collection and Definitions
All examinations were performed in open fashion by a critical care stroke neurologist. Clinical data included (1) stroke severity at baseline and after thrombolysis/thrombectomy (NIHSS score), (2) functional outcome at 3 months (mRS score), and (3) length of intensive care unit and hospital stay. Radiological data that were collected included visual assessment of early infarct signs on the initial CT scan and volumetric infarct analysis on the 7- to 10-day CT scan. At The Cleveland Clinic Foundation, a Computer Assisted Volumetric Analysis (CAVA) software program was developed to measure infarct volumes in ischemic strokes.¹⁶ The follow-up CT scans were also assessed for hemorrhagic transformation and parenchymal hemorrhages using generally accepted guidelines.¹⁷ Physiological data that were collected included (1) heart rate and blood pressure and (2) temperature (every 30 minutes in hypothermia patients, every 4 to 24 hours in control subjects). Time-line data that were collected included (1) time of stroke onset, (2) time of thrombolysis or endovascular procedure, (3) time of hypothermia initiation, (4) time of target temperature, (5) time of rewarming, and (6) time of normothermia. Laboratory data that were collected included measures of hemoglobin, hematocrit, leukocyte count, platelet count, sodium, potassium, magnesium, creatinine, glucose, albumin, creatine kinase, AST, LDH, lactate, amylase, lipase, prothrombin time, activated partial thromboplastin time, fibrinogen, and arterial blood gas. In addition, urinalysis and chest radiography were performed. Complications were assessed regarding severity using a comprehensive list of prespecified neurological, cardiovascular, respiratory, digestive, endocrine, urogenital, and miscellaneous complications adapted from the National Acute Brain Injury Study.¹⁸ The following severity grades were applied: 1 to indicate none; 2, noncritical complication; and 3, critical complication. Some complications could be coded only as critical, such as ventricular fibrillation, cardiac arrest, multiorgan failure, sepsis, and transtentorial herniation. Complication data were monitored on a prespecified data form and collected by one of the authors (A.A.-C.).

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
Technical Feasibility
Hypothermia was successfully initiated in all 10 patients at a mean of 6.2±1.3 hours after stroke onset (Table 2). Time to reach core target temperature of 32°C averaged 3.5±1.5 hours (range 2 to 6.5 hours). Hypothermia at 32±1°C was maintained for a mean of 22.8±8 hours (range 11 to 41 hours). For 9 of the 10 patients, the target temperature was overshot (the lowest temperature reached was 28.4°C). Rewarming of patients to 37°C required 22.6±15.6 hours (range 6.5 to 49.8 hours) as a result of the slow rewarming process at a mean of 0.21°C/h. The total duration of hypothermia (body temperature <36°C) averaged 47.4±20.4 hours (range 23.5 to 96 hours). Figure 1 shows the average temperature over time for the hypothermia patients.

View this table: [in this window] [in a new window]   Table 2. Feasibility of Surface-Induced Moderate Hypothermia in Acute Ischemic Stroke Patients in Comparison to Nonhypothermia Patients

View larger version (41K): [in this window] [in a new window]   Figure 1. Representation of bladder temperatures obtained during initiation, maintenance, and termination of moderate hypothermia.

Safety
Hypothermia was well tolerated by most patients. Table 3 lists all of the complications encountered by both hypothermia and nonhypothermia patients. Except for sinus bradycardia, there were no significant differences in minor or critical complication rates. Bradycardia was temporary and asymptomatic in most cases; patient 7 required a prophylactic transvenous pacemaker for a heart rate of <40 bpm associated with hypotension. All other complications associated with hypothermia therapy did not result in any significant complications. Of all laboratory measures (see Patients and Methods), only pH, PCO₂, and potassium concentrations were significantly altered by hypothermia, and all quickly corrected without sequelae on return to normothermia.

View this table: [in this window] [in a new window]   Table 3. Safety of Surface-Induced Moderate Hypothermia in Acute Ischemic Stroke Patients and Nonhypothermia Patients

There were 3 deaths in the hypothermia group. Patients 7 and 8 died within the first week of admission. Patient 7 had a carotid terminus thrombus and a large infarct (entire MCA and posterior cerebral artery territories) associated with a type 1 aortic dissection on transesophageal echocardiography. The dissection was deemed inoperable by the cardiothoracic surgery consultant. The patient developed severe metabolic acidosis, presumed to be secondary to tissue hypoperfusion as a result of the dissection, and per his family’s request, supportive care was withdrawn on return to normothermia. Patient 8 developed a large parenchymal hematoma with uncal herniation. The hematoma may have occurred at the time of hypothermia induction when the patient had a hypertensive spike and bradycardia. The patient underwent a hemicraniectomy but developed disseminated intravascular coagulation and a subdural fluid collection. Patient 10 was discharged from the hospital to a nursing home with an mRS score of 5 but died unexpectedly 2 weeks later. The exact cause of death was unknown but was presumed to be a pulmonary embolism.

Outcomes
In the hypothermia group, 8 of 10 patients had TIMI 0 or TIMI 0–equivalent flow in the M1 segment of the MCA on the initial vascular imaging study (angiography or TCD). The remaining 2 patients had TIMI 2 and TIMI 3–equivalent flows. Among the nonhypothermia patients, all 9 had TIMI 0–equivalent flow initially. Eight of 10 patients (80%) in the hypothermia group and 5 of 9 (56%) in the nonhypothermia group achieved partial or complete recanalization of the MCA after thrombolysis. Treatment of the hypothermia and nonhypothermia patients is summarized in Table 2.

Baseline characteristics of the hypothermia and nonhypothermia patients are shown in Table 1. Clinical and CT outcomes are summarized in Tables 2 and 4. Infarct patterns in patients who underwent hypothermia therapy and those who did not are shown in Figure 2. The mean mRS score was 3.1±2.3 and 4.2±1.6 in the hypothermia and nonhypothermia patients, respectively (not statistically different). Mortality rates were also comparable between the 2 groups at 3 months; 3 of 10 (30%) hypothermia patients died compared with 2 of 9 (22.2%) nonhypothermia patients.

View larger version (55K): [in this window] [in a new window]   Figure 2. Representation of infarct pattern on 7- to 10-day CT or MRI in hypothermia patients (A) and nonhypothermia patients (B).

View this table: [in this window] [in a new window]   Table 4. Preliminary Efficacy of Surface-Induced Moderate Hypothermia in Severe Ischemic Stroke Patients Showing Improvement in Mean mRS, Actual Values, Frequencies, and Dichotomized Outcome Variables

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
The results of the present study suggest that moderate hypothermia induced by surface cooling is technically feasible and safe for patients with acute ischemic strokes who are undergoing thrombolytic therapy. Limitations of this study, including small sample size, open design, and nonrandomized concurrent controls, preclude any conclusions about efficacy. However, all outcome trends favored hypothermia.

Induced moderate hypothermia with surface cooling requires general anesthesia to prevent shivering, which precludes clinical assessment. The mean time from stroke onset to induction of hypothermia slightly exceeded 6 hours. The time required to reach target temperature in this study is comparable to that in previous reports of the use of surface cooling for patients with acute brain injury (References ^{18 through 22} and R.A. Felberg, D.W. Krieger, R. Chuang, S. Hickenbottom, D. Persse, W.S. Burgin, and J.C. Grotta, unpublished data, 2000). Although we demonstrated that surface cooling is feasible at a tertiary referral center with dedicated stroke and neurological critical care services, the target temperature of 32°C was reached only at almost 10 hours after stroke onset. Endovascular cooling may be faster than with surface cooling.^23,24

For the majority of patients, the target temperature was overshot. Because the rewarming process was deliberately slow, the mean duration of hypothermia, defined as the time during which core temperature was <36°C, was 48.6 hours. This was shorter than that in other previous stroke studies.^19,25,26 The occurrence of fever after rewarming was similar for patients and concurrent control subjects. We believe that fever after the termination of active cooling was likely related to the underlying disease rather than a response to hypothermia, although it is possible that hypothermia-related procedures contributed to fever.

The results of the present study suggest that close monitoring with CT scanning, serial TCD examinations, and physiological and laboratory studies is feasible and makes moderate hypothermia a relatively safe procedure for patients with acute stroke. In all patients, hypothermia was induced only after techniques to restore blood flow failed to significantly improve the neurological deficit. We know of only 2 previous reports in humans on the combination of hypothermia and thrombolytic therapy. In these reports, 4 patients received intravenous thrombolysis followed by moderate hypothermia induced by surface cooling within 6 hours of stroke onset. Hypothermia duration varied from 3 to 5 days and was well tolerated.^25,26

In the present study, moderate hypothermia to a target temperature of 32±1°C was safely implemented in patients with acute ischemic stroke. Hypothermia-related coagulopathies or platelet dysfunction that caused hemorrhagic complications after thrombolysis was not observed. Sinus bradycardia was observed with hypothermia, but transient pacing was required in only 1 patient who had a stroke after open-heart surgery. Four patients with a history of chronic atrial fibrillation developed a rapid ventricular rate during hypothermia that required medical intervention. Noncritical hypotension was observed in hypothermia patients but could be effectively managed using volume expansion or vasopressors. Three patients in the hypothermia group had myocardial infarctions (MIs) on ECG and serial creatine kinase–troponin testing, but 2 nonhypothermia patients also had MIs. In the hypothermia group, 1 patient had an MI before the initiation of hypothermia, 1 patient had an MI during hypothermia, and 1 patient had an MI 24 hours after rewarming. None of the MIs were associated with cardiogenic shock. The frequency of myocardial ischemia in the present study was higher than previously reported and may be due to the patient selection criteria used in this study.²⁷

Other than hypocarbia and hypokalemia in hypothermia patients, there were no significant changes in any of the laboratory tests, including hematocrit, platelet counts, amylase, creatinine, and coagulation parameters. Overall, there were 9 critical complications noted in the hypothermia patients and 5 noted in the nonhypothermia patients, according to guidelines for the assessment of hypothermia-related complications applied by the National Acute Brain Injury Study group.¹⁸ All 9 critical complications in the hypothermia group occurred in 4 patients, and 7 of the 9 occurred in 2 very critically ill patients. Most of the critical complications occurred either after 24 hours of hypothermia or when the core temperature was below target temperature.

The relative safety of moderate hypothermia has also been demonstrated in other studies. The Pittsburgh group and, more recently, the National Acute Brain Injury Study reported on the safety and preliminary efficacy of moderate hypothermia (32° to 33°C) in patients with traumatic brain injury. There were no serious side effects associated with hypothermia, and no differences were noted in platelet counts, amylase, creatinine, or hematocrit.^18,22 Likewise, rates of intracranial hemorrhages in patients with head injury who were treated with hypothermia were not increased.²⁸ Similarly, 2 hypothermia in cardiac arrest studies reported no relevant complications associated with moderate hypothermia (^{Reference 20 and R.A. Felberg, D.W. Krieger, R. Chuang, S. Hickenbottom, D. Persse, W.S. Burgin, and J.C. Grotta, unpublished data, 2000}). In the setting of acute stroke, the Heidelberg group reported sinus bradycardia and cardiac arrhythmias (with prolongation of the PR and QT intervals) not associated with critical hypotension or requiring antiarrhythmic therapy in the majority of patients. Pneumonia occurred in 10 patients and may have been related to the longer duration of hypothermia used in their study. Similar to our results, no significant differences in laboratory test results were reported.¹⁹ The Copenhagen Stroke Study, which used mild hypothermia (mean of 35.5°C) for 6 hours, found a slight decrease in heart rate and systolic blood pressure but no adverse effect on short- or long-term outcome. Infectious complications occurred in 18% of the hypothermia patients and 13% of the control group (not significantly different).²⁹

The focus in the Heidelberg study was to study the effect of hypothermia on increased intracranial pressure in patients with massive hemispheric strokes.¹⁹ In contrast, the goal of the present study was to provide brain protection to patients at high risk for the development of large strokes by combining early recanalization strategies with hypothermia. The Copenhagen Stroke Study was based on the presumption that body temperature on admission is an independent predictor of stroke outcome up to 12 hours after onset. Their study population consisted of patients with only mild to moderate strokes who underwent only 6 hours of modest hypothermia (35° to 36°C). The final neurological impairment was slightly less in those patients who received hypothermia than in historic controls, whereas the mortality rate was almost half in patients treated with hypothermia. It is difficult to attribute the reduction in mortality rate to hypothermia, because neurological outcomes were only slightly better.²⁹

Regarding the optimal duration of hypothermia, several studies in animals have shown that although brief durations of preinsult hypothermia may be sufficient to protect against cerebral ischemia, longer durations of hypothermia are necessary when started in the postischemic period.^6,30–32 Although the restoration of blood flow is necessary for improvement, reperfusion injury in the postischemic period may, in theory, paradoxically antagonize the initial benefit from early recanalization.^13,33 Maximal reperfusion injury occurs on recanalization between 3 and 6 hours after onset.³⁴ In this pilot study, most patients were recanalized within 24 hours. Thus, because most patients present either late in the "intraischemic period" or in the "postischemic period," when they may be at risk for reperfusion injury, prolonged hypothermia is more likely to confer a benefit in the clinical setting than is brief hypothermia. Although hypothermia has been shown to be safe in several studies, the risk of complications increases when the duration is >24 hours. In a balance of risk and benefit, a duration of hypothermia that does not exceed 24 hours may be an initial reasonable choice. Based on the results of this pilot study and the available literature, a larger randomized, controlled trial of hypothermia in acute ischemic stroke is warranted.

	Acknowledgments

 
This work was supported by departmental and institutional funds of The Cleveland Clinic Foundation. The authors express their deep appreciation to the patients and their families as well as the residents and nursing staff who made this study possible. We would also like to express our thanks to Jeff Hammel for statistical advice, Joe Kanasz for help with medical illustrations, and Martha Tobin for editorial expertise.

Received January 11, 2001; revision received April 23, 2001; accepted May 25, 2001.

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