Effect of long-term mild hypothermia or short-term mild hypothermia on outcome of patients with severe traumatic brain injury

Transcription

1 & 2006 ISCBFM All rights reserved X/06 $ Effect of long-term mild or short-term mild on outcome of patients with severe traumatic brain injury Ji-Yao Jiang 1, Wei Xu 2, Wei-Ping Li 3, Guo-Yi Gao 1, Ying-Hui Bao 1, Yu-Min Liang 1 and Qi-Zhong Luo 1 1 Department of Neurosurgery, Renji Hospital, Shanghai Second Medical University, Shanghai, People s Republic of China; 2 Department of Neurosurgery, Second Teaching Hospital of Kuming Medical College, Yuennan Province, People s Republic of China; 3 Department of Neurosurgery, Shenzheng Second People s Hospital, Guangdong Province, People s Republic of China To compare the effect of long-term mild versus short-term mild on the outcome of 215 severe traumatic brain injured patients with cerebral contusion and intracranial hypertension. At three medical centers, 215 patients aged 18 to 45 years old with an admission Glasgow Coma Scale < 8 within 4 h after injury were randomly divided into two groups: long-term mild group (n = 108) for days mild therapy and short-term mild group (n = 107) for days mild therapy. All patients had intracranial hypertension and frontotemporoparietal contusion with midline shift > 1 cm confirmed on computed tomographic scan. Glasgow Outcome Scale at 6-month follow-up, 47 cases had favorable outcome (43.5%), and other 61 cases had unfavorable outcome (56.5%) in the long-term mild group. However, only 31 cases had favorable outcome (29.0%), and other 76 cases had unfavorable outcome (71.0%) in the short-term mild group (P < 0.05). The intracranial pressure significantly rebounded after rewarming in the short-term mild group, but not in the long-term mild (P < 0.05). Furthermore, the incidence of stress ulcer, epilepsy, pulmonary infection, intracranial infection did not significantly differ between the two groups (P > 0.05). Compared with short-term mild, long-term mild significantly improves the outcome of severe traumatic brain injured patients with cerebral contusion and intracranial hypertension without significant complications. Our data suggest that 5 days of longterm cooling is more efficacious than 2 days of short-term cooling when mild is used to control refractory intracranial hypertension in patients with severe traumatic brain injury.. doi: /sj.jcbfm ; published online 23 November 2005 Keywords: contusion; cooling; head injury; head trauma; intracranial hypertension; outcome Introduction Mild to moderate as a treatment of brain injury has been a major area of research during the last decade. Laboratory studies have shown that mild to moderate (321Cto351C) plays a significant protective effects, diminishes the degree Correspondence: Dr J Jiang, Department of Neurosurgery, RenJi Hospital, Shanghai Second Medical University , People s Republic of China. Jiangjyb@online.sh.cn This work was supported by grants from National Key Basic Research Project (No. 2005CB522604), Science and Technology Committee of Shanghai (No. 03JC14038, No. 04DZ14005) and Program for Shanghai Outstanding Medical Academic Leader. Received 3 September 2005; revised 10 October 2005; accepted 18 October 2005; published online 23 November 2005 of neural damage, reduces the mortality as well as improves neurologic outcome (Busto et al, 1987; Chopp et al., 1991; Clark et al, 1996; Clifton et al, 1991; Clifton, 1995; Dixon et al, 1998; Green et al, 1992; Jiang et al, 1991; Pomeranz, 1993; Welsh et al, 1990). It is believed that the beneficial effects of mild to moderate act via metabolic and biochemical processes. Such mechanisms include temperature-dependent reduction of CMRO2, decrease of free radical production (Hagerdal, 1979; Hayashi et al, 1997; Vink et al, 1987), limitation of BBB disruption (Jiang et al, 1992; Smith and Hall, 1996) and brain edema (Shiozaki et al, 1993) attenuation of ionic disruption (Welsh et al, 1990), and decrease of excitatory amino-acid releases (Busto et al, 1989; Mitani and Kataoka, 1991b), reduction of cerebral lactate accumulation (Jiang

2 772 et al, 2004), shunt of an increased fraction of glucose metabolism (Kaibara et al, 1999), inhibition of excessive calcium neuronal entry and intracellular calcium overload (Mitani and Kataoka, 1991a). Since 1990s, more than 25 clinical studies have reported effects of therapeutic on outcome of traumatic brain injury (TBI), as well as its secondary injury mechanisms and complications after TBI (Kochanek and Safar, 2003; McIntyre et al, 2003). McIntyre and co-workers report a systemic review of 12 trials of therapeutic involving 1069 patients. The results show an overall beneficial effect of mild to moderate in severe TBI, with a 19% relative reduction in the risk of death and a 22% relative reduction in the risk of poor neurologic outcome compared with normothermia (McIntyre et al, 2003). Furthermore, the finding of this systemic review also suggest that patients with severe TBI may benefit most from a longer duration of cooling, that is, more than 48 h. In fact, beneficial effects on secondary injury mechanisms may have occurred in patients treated with mild or moderate for longer than 48 h, despite the established risks of complications from prolonged moderate (Shann, 2003). Clifton et al (2001) report that treatment with short-term mild fails to show the beneficial effects on outcome after severe TBI in adults. However, several important limitations in that trail were later identified (Clifton et al, 2002a; Kochanek and Safar, 2003). For instance, although a cerebral perfusion pressure-targeted therapeutic protocol was used in the study, the means by which that therapeutic goal was achieved varied between centers and may have created an impossible challenge for the therapeutic. Furthermore, the duration of mild by Clifton et al is only 48 h, which may have been too short to control brain edema and intracranial hypertension, because cerebral swelling and brain edema are often greatest at 48 h after injury (Shann, 2003). Until now, the duration of mild to moderate, short-term (24 or 48 h) or long-term (5 days), for treatment of severe TBI patients has not been well explored. We have performed a randomized study to compare the effect of long-term mild versus short-term mild on outcome of 215 severe TBI patients with cerebral contusion and intracranial hypertension (Glasgow Coma Scale (GCS)r8). Materials and methods Patients From May 2000 through May 2003, 215 patients aged 18 to 45 years old with an admission GCS score of 8 or less within 4 h after injury were admitted to three hospitals and randomly divided into two groups: long-term (571.3 days) mild (n = 108) and short-term (270.6 days) mild (n = 107). The protocol and consent procedures were approved by the expert review board of each participating center. The criteria for inclusion in the trial were age 18 to 45 years, a nonpenetrating head injury, a GCS score 3 to 8 after resuscitation, frontotemporoparietal contusion with midline shift > 1 cm on computed tomographic scan, and intracranial pressure (ICP) > 20 mm Hg. Patients were excluded if they had a score of 3 with un-reactive pupils and no spontaneous breathing, a life-threatening injury to an organ other than the brain, a systolic blood pressure of less than 90 mm Hg after resuscitation, oxygen saturation of less than 94% after resuscitation, pregnancy, or known preexisting medical conditions (e.g., severe heart disease), or if doctors were not able to initiate cooling within 4 h after injury. Eligible patients were randomly assigned to long-term or short-term according to the day of the month, with patients assigned to long-term on odd-numbered days. Treatment Protocol For all 215 patients with severe TBI, cooling began immediately after randomization and was continued during surgery (if required) using cooling blankets (Gaymar MTA-4702, USA) placed below and above the patients with extensive application of ice packs around the neck and limbs as we described before (Jiang et al, 2000). When patient s rectal temperature reached 331C to 351C, this temperature was maintained days for long-term mild group, and days for short-term mild group. Patients were continuously sedated and paralyzed with tracrium (l0 mg to 40 mg/h) and chlorpromazine (5 to 10 mg/h) with infusion pump to prevent shivering during cooling and rewarming periods. All patients of both groups were passively rewarmed to 36.81C70.51C at a rate no greater than 11C per hour, by a gradual adjustment of the blanket thermostat (Jiang et al, 2000). All patients received the tracheotomy for ventilation (Aridyne 3600, USA) during treatment. The patients were treated according to the principles described in Guidelines for the management of severe head injury (Bullock et al, 2000). We rapidly evacuated large intracranial hematomas and hemorrhagic contusions. Intracranial pressure was monitored with fiberoptic catheter (Camino 3000, USA) in all patients. Increased intracranial pressure ( > 20 mm Hg) was treated with bolus intravenous infusion of Mannitol (25 to 50 g every 6 to 8 h), albumin (10 to 20 g every 8 to 12 h) and flurosemide (20 to 40 mg every 6 to 8 h), as well as ventricular drainage. The cerebral perfusion pressure was maintained at a level higher than 70 mm Hg at all time by keeping the mean arterial pressure at a level between 90 and 110 mm Hg. Corticosteroids were not used in all patients. The patient s temperature, respiratory rate, heart rate, blood pressure, cardiac rhythm, oxygen saturation were continuously monitored (Hewlett-Packard, USA) in neurosurgical intensive care unit. Serum glucose, blood gases and serum electrolytes were regularly determined (Table 1).

3 Vigilance with regard to respiratory care and monitoring for infection was in place related to the use of. Nutritional support by either the enteral or the parenteral route was started 48 h after injury. Assessment of Neurologic Outcome A specialist in physical medicine and rehabilitation, who was unaware of the patients treatment assignment, determined the neurologic outcome 6 months after the injury. The neurologic outcome was scored according to the five-category Glasgow Outcome Scale (Teasdale and Jennet, 1974) as follows: 1, death; 2, vegetative state unable to interact with the environment; 3, severe disability unable to live independently but able to follow commands; 4, moderate disability capable of living independently but unable to return to work or school; and 5, good recovery able to return to work or school. Good recovery and moderate disability were designated as favorable outcomes; severe disability, a vegetative state, and death were designated as unfavorable outcomes. Statistical Analysis The baseline characteristics, complications, blood glucose values, serum electrolytes and outcomes in the two groups were analyzed by two-sided w 2 tests or Fisher s exact tests. Comparisons for some simple continuous variables (e.g., ICP) were performed with two-sided t-tests. All data are expressed as means7s.d. A P-value of < 0.05 was considered significant. Results Patients did not significantly differ in terms of age, the initial Glasgow Coma Scale, intracranial hematoma, cerebral contusion, pupil abnormalities or craniotomy between the long- and short-term group (P > 0.05) (Table 2). Cooling began at h after injury for longterm group and h after injury for short-term mild, respectively (P > 0.05). Once the rectal temperature reached target temperature (331C to 351C), this temperature was maintained days in long-term mild group, and days in short-term mild group, respectively. The rate of rewarming was not different between the two groups (P > 0.05) (Figure 1). The ICP significantly rebounded after rewarming in short-term mild group, and was significantly higher than that of the long-term mild (P < 0.05) (Figure 1). The Glasgow Outcome Scale at 6-month follow-up indicated that 47 cases had a favorable outcome (43.5%), and 61 cases had unfavorable outcome (56.5%) in the long-term mild group. In contrast, only 31 cases had a favorable outcome (29.0%), and 76 cases had an unfavorable outcome (71.0%) in the short-term mild group (P < 0.05) (Table 3). The incidence of stress ulcer, epilepsy, pulmonary infection, and cardio-arrhythmia was not significantly different between the two groups (P > 0.05) (Table 4). Discussion We have found that long-term mild significantly improves the outcome of severe TBI patients with cerebral contusion and intracranial hypertension without significant complications compared with short-term mild. Our clinical data strongly suggest that 5 days of cooling is more efficacious than 2 days of cooling when mild Table 2 Base-line characteristics of patients with severe TBI Long-term Short-term (n = 108) (n = 107) P-value Age year Sex M/F 85/23 82/ GCS 6 8(%) 70 (64.8) 68 (63.6) GCS 3 5(%) 38 (35.2) 39 (36.4) Car accident (%) 76 (70.4) 73 (68.2) Other causes (%) 32 (29.6) 34 (31.8) Pupillary abnormalities (%) 44 (40.7) 41 (38.3) Prehospital hypotension (%) 18 (16.7) 16 (15.0) Prehospital hypoxia (%) 34 (31.5) 30 (28.0) Craniotomy (%) 73 (67.6) 69 (64.5) Table 1 Serum electrolytes and blood gases of patients with severe TBI Long-term (n = 108) Short-term (n = 107) Before cooling During cooling After rewarming Before cooling During cooling After rewarming K Na Cl Ca PaO PaCO ph

4 774 Figure 1 Physiological parameters in patients with severe traumatic brain injury. Mild was kept for days in long-term mild group, and only days in short-term mild group. The ICP significantly rebounded after rewarming in short-term mild group, which did not show in long-term mild group (P < 0.05). Table 3 Outcome of patients with severe traumatic brain injury Glasgow outcome scale Long-term (n = 108) Short-term (n = 107) Favorable outcome (%) 47 (43.5) 31 (29.0) Unfavorable outcome (%) 61 (56.5) 76 (71.0) Table 4 Complications of patients with severe TBI Complications Long-term (n = 108) Short-term (n = 107) P-value Pneumonia (%) 32 (29.63) 29 (27.10) Cardio-arrhythmia (%) 12 (11.11) 9 (8.41) Stress ulcer (%) 6 (5.56) 8 (7.48) Seizure (%) 5 (4.63) 5 (4.67) is used to control refractory intracranial hypertension in patients with severe TBI. Furthermore, early rewarming may not be optimal and can lead to both rebound intracranial hypertension and poor long-term outcome, when mild-to moderate is used to control refractory intracranial hypertension in patients with severe TBI. Mild to moderate may be beneficial after cardiac arrest in human beings (Bernard et al, 2002; The Hypothermia after cardiac arrest group, 2002) and after TBI in laboratory animals (Safar and Kochanek, 2002). It is still controversial whether mild to moderate improves the outcome of patients with severe TBI. Cochrane review of 12 trials with 812 participants found no evidence that is beneficial after TBI in humans (Gadkary et al, 2003). However, in another recent systemic review of 12 trials with 1069 participants, McIntyre et al (2003) report that the relative risk of death with was only 0.81 (95% CI 0.69 to 0.96), and that for longer than 48 h the risk of death was only 0.7 (95% CI 0.56 to 0.87). These researchers add that many of the trials are likely to have underestimated the benefits of because the participants were not cooled to low enough temperature or for long enough. Hypoxic-ischemic damage occurs in 90% patients who die from TBI, which suggests that such patients need to be cooled soon enough, cold enough, and long enough to minimize hypoxicischemic damage (Shann, 2003). How soon is soon enough to be beneficial for brain injury? The previous studies have showed that must be achieved within 2 to 6 h of severe hypoxic-ischemic injury in sheep, gerbils and rats to afford protection. For example, cooling sheep to 341C for 72 h gave good protection if started 90 min after the injury, was partly effective if started at 5.5 h, and ineffective if started at 8.5 h (Gunn, 2000). Most clinical trails have suggested that the earlier that mild is initiated, the more likely beneficial effects may be obtained. Clinical data further show that mild within 6 h after injury may be effective (Shann, 2003). Hypothermia is currently being induced by surface cooling with use of cooling blankets, which usually requires 4 to 8 h to get the target temperature (331C to 351C) (Clifton et al, 2001; Jiang et al, 2000; Schwab et al, 1998). Bernard et al (2003) recently reported that cooling can be achieved more rapidly (21C over 30 mins) by intravenous administration of iced (41C) crystalloid solution. This use of cold intravenous fluids may represent a logical strategy for future clinical trails for in severe TBI. What depth of cooling is necessary to be beneficial for brain injury? In severe hypoxic-ischemic injury, animal models suggest that the optimum temperature is between 321C and 341C. Clinical trial also shows that 331C to 351C, but not higher than 351C, significantly improves the outcome of severe TBI patients (Clifton et al, 2002b). As body temperature decreases below 321C, there is an increased risk of infection (Clifton et al, 2002b). Most clinical trials have suggested that 321C to 351C may be effective and not cause major complications (Clifton et al, 2002b; Shann, 2003).

5 How long of duration of to be beneficial for brain injury? The optimum duration of for hypoxic-ischemic injury depends on the severity of the injury and the delay before is achieved. Within limits, a more severe injury or a longer delay can be compensated for by cooling longer. For example, when gerbils or rats are cooled to 321C, 24 h of cooling is effective when started 1 h after injury, but not when started after 4 h; and cooling for 48 h or more has an effect when it begun 6 h after injury. Cooling for 72 h after a delay of 5.5 h partly protects sheep (Gunn, 2000). Because of the importance of raised ICP in patients with severe TBI, its use in TBI may importantly differ from hypothermic treatment for patients with cardiac arrest. European and Australia randomized prospective clinical trials have found that relatively brief period (24 to 48 h) of mild significantly improve outcome (Bernard et al, 2002; Hypothermia after cardiac arrest group, 2002), yet short-term cooling was not effective in the randomized prospective clinical trial of in adults with TBI by Clifton et al (2001), and was not as efficacious as more prolonged cooling in our current study in TBI. Why might prolonged cooling be needed in TBI to optimize outcome? Prior studies (Adelson et al, 2005) and our current work suggest that rebound intracranial hypertension often occurs with early but not late rewarming. This is unlikely to occur in cardiac arrest where intracranial hypertension is not thought to be an important factor in salvageable patients. Patients with severe TBI may benefit from being cooled for longer than patients with pure hypoxic-ischemic injury. Intracranial pressure often increases progressively and then remains high for several days following TBI. Mild to moderate reliably reduces intracranial pressures, which suggests that it may be sensible to cool patients with severe TBI to 321C to 351C within 6 h of the injury for more than 48 h, and continue at 321C to 351C if the ICP is higher than 20 mm Hg, of if it rises with gradual rewarming. Iida et al (2003) recently monitored the velocity of blood flow in the internal carotid arteries in 11 patients with severe head injury who were cooled within 6 h of injury to 321C to351c for 48 to 72 h. Three of them had evidence of cerebral hyperemia followed by an increase in ICP during rewarming. The hyperemia resolved and ICP decreased when the patients were cooled again with mannitol, and barbiturates. More recently, Adelson et al (2005) have also found that rebound ICP elevations in group compared with those in normothermia are noted for up to 10 to 12 h after rewarming if mild only kept 24 or 48 h in 48 pediatric TBI patients. This clinical data have further showed that ICP markedly increased again during rewarming period in short-term group, but not happened in long-term group. This suggests that mild should not be discontinued within 48 h after injury because cerebral swelling and brain edema is often greatest (Shann, 2003). In a summary of 12 clinical trials of for treatment of severe TBI, McIntyre et al (2003) report that in nine of the studies when body temperature was allowed to rise after either 24 or 48 h (a time when cerebral swelling is often greatest) outcome of is ineffective compared with normothermia group. However, in three of the studies when was continued until ICP stabilized (3 to 14 days), it significantly reduces mortality and morbidity. Our present clinical study further supports the finding that long-term mild to moderate is more efficacious than short-term mild to moderate for severe TBI patients with intracranial hypertension. This indicates that early rewarming may not be optimal and can lead to both rebound intracranial hypertension and poor long-term outcome, when mild-to moderate is used to control refractory intracranial hypertension in patients with severe TBI. Finally, systemic long-term mild with neuromuscular blockade and sedatives may predispose patients to an increased risk of pneumonia or other infections complications (Tateishi et al, 1998). Enhanced vigilance in respiratory care and monitoring for infection, along with appropriate antimicrobial and nutritional support are likely to represent essential adjuncts to the prolong use of mild. Acknowledgements The authors thank Professor Bruce Lyeth at Department of Neurosurgery, University of California at Davis for his assistance of English. References Adelson PD, Ragheb J, Muizelaar JP, Kanev P, Brockmeyer D, Beers SR, Brown SD, Cassidy LD, Chang Y, Levin H (2005) Phase II clinical trial of moderate after severe traumatic brain injury in children. Neurosurgery 56: Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, Smith K (2002) Treatment of comatose survivors of out-hospital cardiac arrest with induced. N Engl J Med 346: Bernard SA, Buist M, Monteiro O, Smith K (2003) Induced using large volume, ice-cold intravenous fluid in comatose survivors of out-of-hospital cardiac arrest: a preliminary report. Resuscitation 56: 9 13 Bullock R, Chesnut RM, Clifton GL (2000) Guidelines for the management of severe head injury. Brain trauma foundation. J Neurotrauma 17: Busto R, Dietrich WD, Globus MYT, Valde I, Scheinberg P, Ginsberg MD (1987) Small differences in ultraischemic brain temperature critically determine the extent of ischemic neuronal injury. J Cereb Blood Flow Metab 7:

6 776 Busto R, Globus MYT, Dietrich WD, Martinez E, Valdes I, Ginsberg MD (1989) Effect of mild on ischemia-induced release of neurotransmitters and free fatty acids in rat brain. Stroke 20: Chopp M, Chen H, Dereski MO (1991) Mild intervention after graded ischemic stress in rats. Stroke 22:37 43 Clark RSB, Kochanek PM, Marion DW et al (1996) Mild posttraumatic reduces mortality after severe controlled cortical impact in rats. J Cereb Blood Flow Metab 16: Clifton GL (1995) Systemic in treatment of severe brain injury: a review and update. J Neurotrauma 12:923 7 Clifton GL, Jiang JY, Lyeth BG, Jenkins LW, Hamm RJ, Hayes RL (1991) Marked protection by moderate after experimental TBI. J Cereb Blood Flow Metab 11: Clifton GL, Miller ER, Choi SC, Levin HS (2002a) Fluid thresholds and outcome from severe brain injury. Crit Care Med 30: Clifton GL, Miller ER, Choi SC, Levin HS, McCauley S, Smith KR, Muizelaar JP, Wagner FC, Marion DW, Luerssen TG (2002b) Hypothermia on admission in patients with severe brain injury. JNeurotrauma19: Clifton GL, Miller ER, Choi SC, Levin HS, McCauley S, Smith KR, Muizelaar JP, Wagner FC, Marion DW, Luerssen TG, Chesnut RM, Schwartz M (2001) Lack of effect of induction of after acute brain injury. N Eng J Med 344: Dixon CE, Markgraf CG, Angileri F (1998) Protective effects of moderate on behavioral deficits but not necrotic cavitation following cortical impact injury in the rat. J Neurotrauma 15: Gadkary CA, Alderson P, Signorini DF (2003) Therapeutic for head injury (Cochrane Review). The Cochrane Library, Oxford, Update software, Issue 3 Green EJ, Dietrich WD, Van DF (1992) Protective effects of brain on behavior and histopathology following global cerebral ischemia in rats. Brain Res 580: Gunn AJ (2000) Cerebral for prevention of brain injury following perinatal asphyxia. Curr Opin Pediatr 12:111 5 Hagerdal M (1979) Additive effects of and phenobarbital upon cerebral oxygen consumption in the rat. Acta Aneathesiol Scand 23:89 92 Hayashi N, Kinosita K, Utagawa A (1997) Prevention of cerebral thermo-pooling, free radical reactions, and protection of A10 nervous system by control of brain tissue temperature in severely brain injured patients. In: Hayashi N (ed), Neurochemistry. New York: Plenum Press, pp Iida K, Kurisu K, Arita K, Ohtani M (2003) Hyperemia prior to acute brain swelling during rewarming of patients who have been treated with moderate for severe head injuries. J Neurosurg 98:793 9 Jiang JY, Liang YM, Luo QZ, Zhu C (2004) Effect of mild on brain dialysate lactate after fluid percussion brain injury in rodents. Neurosurgery 54:713 8 Jiang JY, Lyeth BG, Clifton GL, Jenkins LW, Hamm RJ, Hayes RL (1991) Relationship between body and brain temperature in traumatically brain-injured rodents. J Neurosurg 74:492 6 Jiang JY, Lyeth BG, Kapasi MZ, Jenkins LW, Povlishock JT (1992) Moderate reduces blood-brainbarrier disruption following traumatic-brain injury in the rat. Acta Neuropathol 84: Jiang JY, Zhu C, Yu MK, Zhu C (2000) Effect of long-term mild on patients with severe traumatic brain injury. 1 year follow up of 87 cases. J Neurosurg 93:546 9 Kaibara T, Sutherland GR, Colbourne F et al (1999) Hypothermia:depression of tricarboxylic acid cycle flux and evidence for pentose phosphate shunt upregulation. J Neurosurg 90: Kochanek PM, Safar PJ (2003) Therapeutic for severe traumatic brain injury. JAMA 289: McIntyre LA, Fergusson DA, Hebert PC, Moher D, Hutchison JS (2003) Prolonged therapeutic after traumatic brain injury in adults. JAMA 289: Mitani A, Kataoka K (1991b) Critical levels of extracellular glutamate mediating gerbil hippocampal delayed neuroral death during : brain microdialysis study. Neuroscience 42: Mitani A, Kadoya F, Kataoka K (1991a) Temperature dependence of hypoxia induced calcium accumulation in gerbil hippocampal slices. Brain Res 562: Pomeranz S, Safar P, Radovsky A, Tisherman SA, Alexander H, Stezoski W (1993) The effect of resuscitative moderate following epidural brain compression on cerebral damage in a canine outcome model. J Neurosurg 79: Safar PJ, Kochanek PM (2002) Therapeutic after cardiac arrest. N Engl J Med 346:612 3 Schwab S, Schwarz S, Spranger M, Keller E, Bertram M, Hacke W (1998) Moderate in the treatment of patients with severe middle cerebral artery infarction. Stroke 29: Shann F (2003) Hypothermia for traumatic brain injury: how soon, how cold, and how long? Lancet 362: Shiozaki T, Sugimoto H, Taneda M, Yoshida H, Iwai A, Yoshioka T, Sugimoto T (1993) Effect of mild on uncontrolled intracranial hypertension after severe head injuries: a preliminary report. J Neurosurg 79:363 8 Smith SL, Hall ED (1996) Mild pre- and posttraumatic attenuates blood brain barrier damage following controlled cortical impact injury in the rat. J Neurotrauma 13:1 9 Tateishi A, Soejima Y, Taira Y, Nakashima K, Fujsawa H, Tsuchida E, Makawa T, Ito H (1998) Feasibility of the titration method of mild in severely head injured patients with intracranial hypertension. Neurosurgery 42: Teasdale G, Jennet B (1974) Assessment of coma and impaired consciousness: a practical scale. Lancet 2:81 4 The after cardiac arrest study group (2002) Mild therapeutic to improve the neurologic outcome after cardiac arrest. N Engl J Med 346: Vink R, McIntosh TK, Weiner MW (1987) Effects of traumatic brain injury on cerebral high-energy phosphates and PH: a 31 P magnetic resonance spectroscopy study. J Cereb Blood Flow Metab 7: Welsh FA, Sims RE, Harris VA (1990) Mild prevents ischemic injury in gerbil hippocampus. J Cereb Blood Flow Metab 10:557 63