Induced Mild Hypothermia for Ischemic Stroke Patients

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1 Med. J. Cairo Univ., Vol. 82, No. 2, December: , Induced Mild Hyothermia for Ischemic Stroke Patients AHMED E.S. ELNAHRAWY, M.Sc.; MERVAT M. KHALEF, M.D.; HASSAN S. EFFAT, M.D. and ADEL ALSISI, M.D. The Deartment of Critical Care Medicine, Faculty of Medicine, Cairo University Abstract Background and Introduction: Theraeutic hyothermia is an established neurorotective intervention in ost-cardiac arrest atients. In our study we investigated the theraeutic of mild induced hyothermia in ischemic stroke atients and its effect on mortality and degrees of disability. Methods: A total of 40 atients admitted to the ICU with ischemic stroke were included in a rosective, randomized, double centre study, and were randomly assigned to grou A (30 atients) as the study grou and grou B (10 atients) as the control grou. Grou A atients were subjected to induction of mild hyothermia (34-35 degrees Celsius) for a 24 hour eriod, lus the conventional stroke theray. On the other hand, grou B atients received the conventional stroke theray alone. Hyothermia was achieved by IV acetaminohen, external cooling methods, and IV cold saline infusion. All atients were subjected to a through hysical examination, GCS and SOFA score calculations uon admission and daily thereafter. Brain CT scan imaging was erformed uon admission, 48 hours and 5 days after admission. Clinical outcome (conscious level, motor function, brain edema, duration of ICU stay, mortality) was recroded for all atients, as well as the develoment of any comlication. Results: In the study grou A, 63.3% of atients have shown markedly resolved brain edema, versus only 20% of atients in the control grou B (-: 0.028). The median length of ICU say (days) in grou A was 6 days, versus 8.5 days in grou B ( ). The GCS (cognitive functions) correlated strongly in an inversely roortional relationshi to the mean SOFA score (r= 0.89). Mortality in grou A was 30% versus 40% mortality in grou B, (-= 0.719). In grou A, 23.3% of atients were discharged with marked disability versus 30% of atients in grou B ( ). In grou A, 53.3% of atients have develoed infectious comlications versus 50% of atients in grou B ( - 1). Conclusion: Mild induced hyothermia is a romising neurorotective intervention that is chea, readily available and almost devoid of serious comlications. It decreases the length of ICU stay and effectively controls cytotoxic brain edema associated with large infarctions. Desite the lack of a statistically significant effect on the final outcome, there is a trend for a better outcome in atients treated with hyothermia which calls for further studies on larger numbers of atients. Corresondence to: Dr. Hassan S. Effat H.Effat@Hotmail.com Key Words: Stroke Induced mild hyothermia. Introduction ACCORDING to the World Health Organization (WHO) in its June 2011 review, cerebrovascular stroke is the fourth leading cause of death in the low income countries, and the second leading cause of death in the middle to high income countries. It is also one of the leading causes of disability and hosital admissions worldwide [1]. Due to the facts mentioned above, cerebrovascular stroke has received much attention, with many research studies conducted worldwide trying to develo more effective reventive and theraeutic aroaches, aiming to decrease the rates of mortality, and disability caused by this disease, as well as decreasing the devastating economic effect of stroke on the workforce and healthcare exenses [ 2 ]. One of the recent theraeutic aroaches that is being investigated nowadays is the alication of induced hyothermia in the treatment of cerebrovascular stroke victims. The studies conducted on animal models have been very encouraging, and the fact that inducing hyothermia is a very simle intervention that is almost free of any cost, and can be erformed in almost every hosital worldwide without the need for exensive equiment or exertise, makes it a very aealing theraeutic intervention once rovem efficient [2]. The theraeutic goal in ischemic stroke is reserving as much as ossible of the oligemic areas in the ischemic enumbra, and this theraeutic goal is achieved by 2 methods: 1- Restoration of blood flow (Recanalization strategies). 2- Minimising the severity of ischemic injury (neurorotective measures). 179

2 180 Induced Mild Hyothermia for Ischemic Stroke Patients Induced mild hyothermia belongs to the neurorotective measures category, aiming at minimizing the severity of the ischemic injury and thus reserving more of the ischemic enumbra. Though the exact mechanism by which hyothermia exerts its theraeutic effect is not accurately understood, the following modes of action were suggested by laboratory and animal studies: - Reducing cerebral metabolism (glucose and oxygen consumtion). - Suresion of the inflammatory resonse. - Inhibition of cytoskeletal breakdown. - Attenuation of cerebrosinal fluid (CSF) latelet activating factor. - Decreasing intracellular Calcium rise. - Restoration of normal atterns of intracellular signaling and gene exression [3]. So in summary, hyothermia lowers the metabolic rate of brain cells, limits edema formation, suresses the inflammatory resonse, maintain integrity of the blood brain barrier, and normalize intra cellular signaling atterns, and thus interruts the rocess of necrosis and aotosis, and hels to reserve the viability of ischemic brain cells which is the ultimate target of ischemic cerebraovscualr stroke theray [4]. It is imortant to mention that most of the hazardous adverse effects of hyothermia were associated with moderate to extreme levels of hyothermia within the temerature range of degrees for rolonged eriods of time (between 48 hours u to 5 days), but with mild levels of hyothermia within the temerature range of degrees Celsius, most of these comlications were not encountered, and this newly adoted temerature range was found to be generally safe, but in site of the safety of the very mild level of hyothermia, the ossible comlications associated with hyothermia are worth mentioning, to be closely watched during the eriod of theraeutic hyothermia (for any reason), and to exclude the atients who are at a high risk of develoing any serious comlication due to co-existing morbidities [5]. Aim of this study: Our aim in this study is to evaluate the effect of induced mild hyothermia (in ischemic stroke atient oulation) on: - Mortality. - Disability. - Length of ICU stay. Patients and Methods Forty atients admitted to the intensive care unit (ICU) with the diagnosis of ischemic cerebrovascular stroke during the eriod between January 2013 and u till January 2014, were enrolled into a rosective randomized controlled trial. Patients who fulfilled inclusion criteria were randomly assigned into 2 grous: I- The study grou (A): 30 atients who received the conventional stroke theray + induced hyothermia (34-35 degrees Celsius). II- The control grou (B): 10 atients who received the conventional stroke theray alone. Inclusion criteria: - Patients of all ages, sexes, ethnic grous diagnosed with ischemic cerebrovascular stroke. - Disturbed level of consciousness with Glasgow Coma Scale (GCS) < Onset of symtoms < 12 hours and >3 hours. Exclusion criteria: - Onset of symtoms >12 hours or <3 hours. - GCS >11. - Patients with hemorrhagic stroke confirmed by CT. - Presence of other neurological co-morbidities (brain tumor, eilesy). - Significant hyothyroidism. - Significant hyokalemia. - Presence of heart block, heart failure, or any serious arrhythmia. Following ICU admission all atients were subjected to: I- Full general examination. II- Full neurological examination with assessment of motor & sensory deficits, motor ower grading, conscious level Glasgow Coma Scare (GCS) this is a 15 oint scoring system used in assessment of conscious level, and quantifying the degree and severity of imaired conscious level. It consists of a total of 15 atients, with 4 oints to the eye oening arameter, 5 oints to the verbal comonent, and 6 oints to the motor resonse. The best score is 15 and the worst is 3 [11], and daily thereafter. III- Investigations: Routine investigations: Comlete blood count, Coagulation rofile, Renal function tests, liver function tests, Arterial blood gases, (ABGs), serum electrolytes, Creatine hoshokinase (CPK), Electrocardiogram (ECG), Chest X-ray.

3 Ahmed E.S. Elnahrawy, et al. 181 Investigations related to the study: Brain CT scan imaging uon admission, with serial followu studies comuted tomograhy scan (CT). IV- Sequential organ Failure assessment Score (SOFA) the SOFA score is a scoring system to determine the extent of a atient s organ function or rate of failure. The score is based on six different arameters, each assessing the function of a major body system, resiratory, cardiovascular, renal, heatic, neurological, and coagulation [12]. Score evaluation uon admission, and daily thereafter. V- Conventional stroke theray (antilatelet, statins, low dose Angiotensin Converting Enzyme (ACE-inhibitors), blood glucose and blood ressure control according to current guidelines, suortive care including roer nutrition, rohylaxis against stress ulcers, ressure ulcers, Dee Venous Thrombosis (DVT), care for the comatosed): Patients of the study grou were additionally subjected to induction of mild hyothermia (34-35 degrees Celsius) immediately after admission and for a 24 hours eriod, after which assive rewarming was allowed. Patients of the study grou received 2 doses of IV meeridine 25mgs + oral busirone 5 mgs as an anti-shivering recaution uon induction of hyothermia and after 12 hours. Rectal temerature was recorded on an hourly basis for 24 hours. Induction and maintenance of hyothermia: - Acetaminohen 1gm/6 hours I.V. - Cold fomentations alied to the forehead + ice acks intermittently alied to the groin and axilla. - Cold saline gastric lavage/6 hours. - Infusion of minimal amounts of cold saline (200cc) when needed to reach target temerature. Grou B (the control grou): Exactly like atients of grou A, atients of grou B (the control grou) had daily assessments of their general condition, neurological status, and serial evaluations of their SOFA score during their ICU stay until discharge, death or u to a total of 21 days. Patients of this grou received the same conventional stroke theray and care as Grou A atients. Statistical methods: Data were statistically described in terms of mean±standard deviation (+SD), median, minimum, maximum, frequencies (number of cases) and relative frequencies (ercentages) when aroriate. Comarison of quantitative variables between the study grous was done using Mann Whitney U test for indeendent samles. For comaring categorical data, Chi square (X 2 ) test was erformed. Exact test was used instead when the exected frequency is less than 5. Correlation between various variables was done using Searman rank correlation equation. A robability (-) less than 0.05 was considered statistically significant. All statistical calculations were done using SPSS (statistical Package for the Social Science; SPSS Inc. Chicago, IL, USA) version 16 for Microsoft Windows. Results I- Demograhic and baseline clinical data uon ICU admission: 1- The mean age (years) ±SD in the study grou (30 atients) were ±7.96 and it was 68.5±5.7 in the control grou 910 atients). The mean age in both grous was comarable with a - of Table (1). Table (1): Grous mean age. Age Range (years) Mean±SD grou A (n=30) ±7.96 grou B (n=10) ± The gender distribution in the study grou was 19 males and 11 females, while it was 6 males and 4 females in the control grou. Table (2): Gender distribution. Gender Male Female grou A (n=30) 19 (63.3%) 11 (36.7%) grou B (n=10) 6 (60%) 4 (40%) 1.00 The gender distribution in the study and the control grous was almost identical with a robability of 1 Table (2). 2- Diagnosis uon ICU admission: The anatomical locations of infarctions in the study and the control grous were almost identical with a robability of Table (3).

4 182 Induced Mild Hyothermia for Ischemic Stroke Patients Table (3): Anatomical distribution. Anatomical grou A grou B distribution (n=30) (n=10) Cerebral 21 (70%) 6 (20%) Brainstem 6 (60%) 3 (30%) 0.98 Thalamic 3 (10%) 1 (10%) Infarction sizes within the study and control grous: Table (4): Infarction size. Infarction grou A grou B size (n=30) (n=10) Large sized 13 (43.3%) 3 (30%) Medium sized 17 (56.7%) 7 (70%) 0.71 Infarction sizes in both grous were comarable with a - of Table (4). 3- Onset of symtoms: The mean onset of symtoms (hours) ±SD in the study grou was 7.67 ±2.02, while it was 7.4± 1.51 in the control grou. It is obvious that the mean onset of symtoms ±SD in both grous was so close, with a robability of The severity of illness: The severity of critical illness uon admission was assessed in both study and control grous using the SOFA scoring system, with further daily assessment of the SOFA score Table (5). The degree of conscious level affection was also estimated uon admission in both grous using the Glasgow coma scale scoring system Table (6). Table (5): SOFA Score (severity of illness). Parameter Initial SOFA Highest SOFA Mean SOFA ± ± ±4.53 Table (6): Admission GCS. Parameter Range Mean±SD Range Mean±SD Range Mean±SD ± ± ± Range Mean±SD GCS ± ± (admission) II- Assessment of the outcome: 1- Duration of ICU stay: There was a statistically significant difference in the duration of ICU stay between the study grou treated with induced hyothermia beside the conventional stroke theray, and the control grou treated with the conventional theray alone. The mean duration of ICU stay (days) in the study and the control grous were 6 ±2.92 and 8.9±3.14 resectively, with a robability of 0.006, which shows a statistically significant difference Fig. (1) =0.006 Patients treated hyothermia ICU stay (days) Fig. (1): ICU stay (days) of atients and controls. 2- Imrovement in motor & sensory functions: Though there is a difference in the collective ercentages of atients who showed any degree of imrovement in motor and sensory functions between the 2 grous, and though the difference is in favor of the study grou atients, Table (7), the difference was not statistically significant. Table (7): Motor and sensory functions. Motor & sensory No imrovement Mild to moderate imrovement Marked imrovement grou A (n=30) 9 (30%) 7 (23.4%) 14 (46.7%) Contro grou B (n=10) 4 (40%) 3 (30%) 3 (30%) Imrovement in conscious level (GCS uon discharge/re death): The Glasgow coma scale was assessed daily in atients of both grous, to asses the imrovement in conscious level. The final GCS recorded at the day of discharge or death was used to comare the degree of imrovement in the conscious level between both the study and the control grous.

5 Ahmed E. S. Elnahrawy, et al. 183 There was a slight and non significant difference between both grous regarding the final GCS, with the mean final GCS, with the mean final GCS+SD in the study and the control grous, ±5.35 and 10.20±5.79 resectively Table (8). Table (8): Discharge GCS. Parameter Range Mean±SD Patients treated hyothermia =0.028 Resolved brain edema Range Mean±SD No change GCS ± ± (admission) 4- CT Brain changes: There was a statistically significant difference in the number of atients whom showed markedly resolved brain edema in their follow-u CT studies between the study and the control grous. The atients in the study grou treated with hyothermia beside the conventional theray have shown resolved brain edema in 63.3% of the cases versus only 20% of the cases in the control grou treated with the conventional theray alone. This difference shows a statistical significance, with a - of 0.028, and verifies the role of induced hyothermia in brain edema Fig. (2). Fig. (2): Follow-u CT results for atients and controls. 5- Final outcome (mortality & disability): Concerning the final outcome, atients of both grous were classified into three categories: a- Healthy survivors: Patients discharge with no or minimal disability. b- Unhealthy survivors: Patients discharge with marked disability (Cognitive or motor). c- Non survivors Table (9). Table (9): Final outcome. Final outcome Healthy survivors Unhealthy survivors Non survivors grou grou A (n=30) 14 (46.7%) 7 (23.3%) 9 (30%) Healthy survivors Unhealthy survivors Non survivors grou B (n=10) 3 (30%) 3 (30%) 4 (40%) grou 0.72 Though there was a trend towards a better outcome with decreased mortality and a decreased degree of disability in the atients of the study grou versus the atients of the control grou, the differences were not statistically significant with a - of Out of the 30 atients of the study grou, 14 atients were discharged normally, 7 atients discharged with marked disability and 9 atients died. While in the control grou (10 atients), 3 atients were discharge normally, 3 atients were discharged with disability and 4 atients died. Though there was a trend towards a better outcome with decreased mortality and a decreased degree of disability in the atients of the study grou versus the atients of the control grou, the differences were not statistically significant with a - of Fig. (3). Final outcome Fig. (3): Final outcome III- Develoment of comlications: In out study we did not find any tendency towards develoing infectious comlications in atients treated with induced mild hyothermia, and the rate of infectious comlications were almost identical in both grous, with 53.3% of the atients in the study grou develoed infectious comlications versus 50% of the atients in the control

6 184 Induced Mild Hyothermia for Ischemic Stroke Patients grou, and the robability was 1. Though there is a theoretical risk of develoment of thrombocytoenia (with increased bleeding tendency) and cardiac arrhythmias with hyothermia, none of these comlications were observed during our study Table (10). Table (10): Infectious comlications. Parameter Present Count Infect. No Comlication Yes IV- Correlative results: 1- Correlation between the SOFA score and the final outcome: The SOFA score was found to be the most imortant redictor of the final outcome in atients of both grous either on mortality or the degree of disability. The mean SOFA score showed a very strong ositive relationshi with mortality with a correlation coefficient of about 0.9. It did also show a very significant negative relationshi with the cognitive functions uon discharge. The lower the SOFA score was, the better the GCS was uon discharge (r= 0.894). 2- Other correlations: The age of the atients showed a weak negative correlation with the final conscious level ( r= 0.448). The onset of symtoms (6-12 hours) did not show any significant correlation with the final outcome in both the study and the control grous. Discussion Cerebrovascular stroke is a universal roblem leading to high mortality and high degrees of disability worldwide, and certainly adding a lot to the healthcare budget and that necessitates a lot of research to investigate new ossible interventions and theraies to address this worldwide roblem [1]. The main goal of theray in acute ischemic stroke is to reserve the oligemic neurons in the ischemic enumbra. Over the years, many harmacological neurorotective agents, as well as other neuro-rotective interventions have been investigated, but none has roved efficient u to date. % Count % Recently interest in one of the effective neurorotective strategies that has roved efficient in other conditions like cardiac arrest and near drowning, that intervention is induced hyothermia has gained a lot of attention in acute ischemic stroke [3]. The objectives of our study were to investigate the efficiency of mild induced hyothermia as a neuro-rotective intervention in ischemic stroke atients by identifying the overall effect of its alication on mortality, degrees of disability, as well as its effect on the duration of ICU stay. Moreover, we studied the effect of this intervention on cytotoxic brain edema, as well as the rate of develoment of infectious comlications associated with its alications. In our study, the age and sex of atients in both the study and control grous were comarative with -s of and 1 resectively. The resent study has not shown a statistically significant correlation between the age/gender of atients and the final outcome. The age of the atients in both grous did not show a solid correlation with the CGS/motor function uon discharge (disability) with a - of and a correlation coefficient of A study conducted by Stehen Bagg, MD, and Alicia Paris, MD, at Queen s University showed only that the effect of age on the final outcome after adjustment of other factors was only 1.3% which coincides with our study findings [6]. The effect of age on survival/mortality in our study in both grous was almost negligible when excluding the effect of other co-morbidities with a - of almost 1. A study conducted by L.P. Kammersgaard et al at Hvidovre University Hosital, Coenhagen, Denmark concluded that very old age (above 85) was a remarkable redictor of mortality and outcome with a - of [7]. The difference between Kammersgaard et al., and our study s conclusions can be attributed to the fact that the mean age in our study oulation was 67.47±7.96, and that their study had only found age to be a redictor of final outcome in the very old age range (above 85 years) [7]. In our study, the more rominent redictor was the resence of co-morbidities exressed in terms of the mean SOFA score. The mean SOFA score was a strong redictor of final outcome in our study. There was a directly roortional, statistically significant relationshi between the mean SOFA score and the rates of mortality with a - of zero and a correlation coefficient of 0.9. There was

7 Ahmed E.S. Elnahrawy, et al. 185 also an inversely roortional, statistically significant relationshi between the mean SOFA score and the final GCS (cognitive functions) with a - of zero and r- of 0.8. We concluded from this data that age alone is not a strong redictor of final outcome, and that the general condition and the resence of co-morbidities are more accurate redictors of the final outcome. Our study demonstrated almost no difference in the rate of infection with the use of induced hyothermia in the temerature range of degrees Celsius, as in the resent trial 53.3% of the atients in the hyothermia grou have had infectious comlications during the course of their ICU stay, mostly in the form of chest infections that resonded well to antibiotic theray, while only 50% of the atients in the control grou have had infectious comlications, with a - of 1. In the year 2000 [8], Kammersgaard et al., conducted a feasibility and safety study for mild hyothermia (35.5 degrees) for stroke atients. The authors concluded that using mild induced hyothermia in stroke atients was not associated with oor outcome, death or increased risk of infections [8], results that coincide with our own study s findings [8]. Zweifler et al., [9] conducted a trial on healthy volunteers to study the effect of mild hyothermia (34-35 degrees) using external cooling methods, and have demonstrated that there was no increased risk of infections in that temerature range [9], which coincides with our study findings. In our study, shivering was totally suressed by a combination of low dose meeridine and oral busirone, and did not ose any technical roblem, a finding that coincides with that Zweifler et al., demonstrated in their study when they suressed shivering totally at the same temerature range with meiridine and acetaminohen [9]. In our study, we did not record thrombocytoenia, increased bleeding tendency, or arrhythmias in any case treated by mild hyothermia. In the Schwab et al., study that alied moderate hyothermia (<33 degrees), 70% of the atients have suffered thrombocytoenia and 62% have suffered bradycardia [5]. Zweifler et al., study of mild hyothermia on healthy volunteers has not shown thrombocytoenia or arrhythmias to be an encountered side effect associated with mild degrees of hyothermia [9], which coincides with our own study results. In our study, the mortality in the atients of the study grou treated with mild hyothermia was 30%, and 23.3% of the atients of the same grou were discharged with marked disability. In atients of the control grou, the mortality rate was 40% and 30% of the atients were discharged with marked disability. The ercentages show a trend for a better outcome for atients treated with mild hyothermia, but the difference was not statistically significant with a - of Other clinical trials conducted on humans investigating hyothermia for stroke atients have not found a statistically significant difference in mortality rates, a conclusion suorted and documented in the review and meta analysis for human trials on hyothermia for stroke conducted by Shaheen E. Lakhan and Fabricio Pamlona from the deartment of Biosciences, in the Global Neuroscience Initiative Foundation in Los Angeles, which demonstrated that though there was a trend for a better outcome with hyothermia but there is no statistically significant difference u to date [3]. In our study there was a statistically significant difference in the duration of ICU stay between the study grou and the control grou. The mean duration of ICU stay (days) in the study and the control grous were 6 ±2.92 and 8.9±3.14 resectively, with a - of 0.006, which shows a statistically significant difference. The duration of ICU stay as one of the final outcome arameters was not assessed in any of the reviously ublished studies, but it did show a strong statistically significant difference between both grous in our study. In our study, the follow-u CT scan images have shown a markedly resolved brain edema in 63.3% of the atietns of the study grou treated by hyothermia, versus 20% only of the atients in the control grou with a - of In Schwab et al., study, intracranial ressure was well controlled and cytotoxic brain edema associated with large infarctions was markedly decreased [5], a finding that coincides with our study results, though in Schwab et al., study, rebound increased in ICP was noticed during the hase of assive re-warming [5], which was not noticed in our study, ossibly due to lower range of hyothermia that was used in Schwab et al., trial [5].

8 186 Induced Mild Hyothermia for Ischemic Stroke Patients In our study, the mean GCS+SD uon discharge for atients treated with hyothermia was ± 5.35, versus 10.20±5.79 in the control grou, with a - of There was no statistically significant difference in the degree of imrovement in motor functions between the control and the study grous, with a - of There was no imrovement in the motor functions with theraeutic hyothermia documented in any of the revious conducted trials [10]. Conclusion: Induced mild hyothermia is a very romising, neurorotective intervention. It is chea, easily alied, readily available and almost devoid of serious comlications. It is an effective, noninvasive measure that hels in controlling cytotoxic brain edema associated with moderate to large size brain infractions. It decreases the overall duration of ICU stay for stroke atients, and thus, hels in decreasing the healthcare exenses, and the economic burden for this atient oulation. Desite the lack of a statistically significant effect on the final outcome (mortality, degree of disability), there is an obvious trend for a better outcome in atients treated with mild hyothermia, which calls for further studies on larger number of atients. Recommendations: Based on the findings of the resent study, the authors of the study recommend the following: - Alying induced mild hyothermia (34-35 degrees Celsius) as a theraeutic intervention in selected cases of atients with moderate to large size brain infarctions associated with significant cytotoxic brain edema refractory to traditional theraies (in the absence of contraindications to hyothermia). - Conducting further, multicenter studies on larger number of atients, to further investigate the effect of induced mild hyothermia on the final outcome. References 1- WHO/mediacentre/factsheets/10leading causes of death June htt:/who.int/mediacentre/factsheets/fs310/ en/index1.html. 2- Theraeutic Hyothermia for Acute Ischemic Stroke: Ready to Start Large Randomized Trials? H Bart van der Wor, Malcolm R. Macleod, Rainer Kollmar J. Cereb Blood Flow Metab. June, 30 (6): , Alication of Mild Theraeutic Hyothermia on Stroke: A Systematic Review and Meta-Analysis. Shaheen E. Lakhan nad Fabricio Pamlona, Deartment of Biosciences, Global Neuroscience Initiative Foundation, Los Angeles, Panorama City, P.O. Box 4832 Ca 91412, USA, Stroke Research and Treatment Volume, Article ID , KRIEGER D.W. and YENARI M.A.: Theraeutic hyothermia for acute ischemic stroke: What do laboratory studies teach us? Stroke, 35: , SCHWAB S., GEORGIADIS D., et al.: Feasibility and safety of moderate hyothermia after massive hemisheric infarction. Stroke, 32: , STEPHEN BAGG, ALICIA PARIS POMBO and WILMA HOPMAN: Effect of age on functional outcomes after stroke rehabilitation. Stroke, 33: , LARS PETER KAMMERSGAARD, et al.: Short and long term rognosis for very old stroke atients. The Coenhagen stroke study. Age and Ageing, 33: , KAMMERSGAARD L.P., RASMUSSEN B.H., et al.: Feasibility and safety of inducing modest hyothermia in awake atients with acute stroke through surface cooling: A case control study: The Coenhagen stroke study. Stroke, 31: , ZWEIFLER R.M., MAHMOOD V.M., et al.: Induction and maintenance of mild hyothermia and surface cooling in non intubated subjects. J. Stroke Cerebrovasc. Dis., 12: , LYDEN P.D.1, ALLGREN R.L., et al.: Intravascular cooling in the treatment of stroke (ICTus): Early clinical exerience. J. Stroke Cerebovasc. Dis. May Jun., 14 (3): , JAN-ERIK STARMARK, M.D., DANIEL STALHAM- MAR, M.D., EDDY HOLMGREN M.D. and BJORN ROSANDER, B.Sc.: A comarison of the glasgow coma scale and the reaction level scale (BLS 85). Journal of Neurosurgery, November, Vol. 69, No. 5, Pages , ACHARYA S.P.1, PRADHAN B. and MARHATTA M.N.: Alication of the sequential organ failure assessment (SOFA) score in redicting outcome in ICU atients with SIRS. Kathmandu Univ. Med. J. (KUMJ). Oct. Dec., 5 (4): , 2007.