JabRef References output

Author	Title	Year	Journal/Proceedings	Reftype	DOI/URL
Alzaga, A.G., Cerdan, M. & Varon, J.	Therapeutic hypothermia. [Abstract]	2006	Resuscitation Vol. 70(3), pp. 369-380	article	DOI
Abstract: Therapeutic hypothermia has been used for millennia, but in recent years was not in much clinical use due to an apparent high risk of complications. More recently, the benefits of induced therapeutic hypothermia have been rediscovered, mainly with the improvement in neurological outcome in out-of-hospital cardiac arrest victims. In addition, therapeutic hypothermia has been suggested to improve outcome in other neurological conditions such as traumatic brain injury, neonatal asphyxia, cerebrovascular accidents and intracranial hypertension. This article reviews the history of the discovery of therapeutic hypothermia, as well as the current therapeutic applications and ways to deliver this treatment. Cooling techniques and recovery processes, as well as potential complications are also reviewed. Clinicians caring for a wide variety of critically ill patients should be familiar with the use of therapeutic hypothermia.
Battin, M.R., Penrice, J., Gunn, T.R. & Gunn, A.J.	Treatment of term infants with head cooling and mild systemic hypothermia (35.0 degrees C and 34.5 degrees C) after perinatal asphyxia. [Abstract]	2003	Pediatrics Vol. 111(2), pp. 244-251	article
Abstract: OBJECTIVE: To assess the safety of selective head cooling in birth-asphyxiated term newborn infants while maintaining the rectal temperature at 35.0 degrees C or 34.5 degrees C. METHODS: Twenty-six term infants with Apgar
Beran, A.V. & Sperling, D.R.	An improved method for inducing hypothermia and rewarming. [Abstract]	1979	Aviat Space Environ Med Vol. 50(8), pp. 844-846	article
Abstract: A hypothermia and rewarming system combining body surface and ventilatory heat exchange is described. The method utilizes body surface heat exchange through conduction, convection, and black body radiation, and ventilatory heat exchange across the lung surface through conduction, convection, and water evaporation. The system consisted of a chamber in which the temperature was maintained at a desired level (+/- 2.5 degrees C) using a refrigeration-heat pump unit. Chamber temperatures during cooling and rewarming were -15.5 +/- 2.7 degrees C and 43.2 +/- 2.3 degrees C, respectively. Inhalate temperatures during cooling were -8.2 +/- 6.5 degrees C and during rewarming they were 41.5 +/- 0.3 degrees C. Helium (100 was supplied to the chamber, while the animal was ventilated with 20% O2 + 80% He. Under these conditions, the cooling and rewarming rates were 0.33 +/- 0.06 degrees C/min and 0.20 +/- 0.04 degrees C/min, respectively, at 38--21 degrees C. The system provided for rapid cooling and rewarming with no evidence of any untoward effects.
Bernard, S.A., Gray, T.W., Buist, M.D., Jones, B.M., Silvester, W., Gutteridge, G. & Smith, K.	Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. [Abstract]	2002	N. Engl. J. Med. Vol. 346(8), pp. 557-563	article	DOI
Abstract: BACKGROUND: Cardiac arrest outside the hospital is common and has a poor outcome. Studies in laboratory animals suggest that hypothermia induced shortly after the restoration of spontaneous circulation may improve neurologic outcome, but there have been no conclusive studies in humans. In a randomized, controlled trial, we compared the effects of moderate hypothermia and normothermia in patients who remained unconscious after resuscitation from out-of-hospital cardiac arrest. METHODS: The study subjects were 77 patients who were randomly assigned to treatment with hypothermia (with the core body temperature reduced to 33 degrees C within 2 hours after the return of spontaneous circulation and maintained at that temperature for 12 hours) or normothermia. The primary outcome measure was survival to hospital discharge with sufficiently good neurologic function to be discharged to home or to a rehabilitation facility. RESULTS: The demographic characteristics of the patients were similar in the hypothermia and normothermia groups. Twenty-one of the 43 patients treated with hypothermia (49 percent) survived and had a good outcome--that is, they were discharged home or to a rehabilitation facility--as compared with 9 of the 34 treated with normothermia (26 percent, P=0.046). After adjustment for base-line differences in age and time from collapse to the return of spontaneous circulation, the odds ratio for a good outcome with hypothermia as compared with normothermia was 5.25 (95 percent confidence interval, 1.47 to 18.76; P=0.011). Hypothermia was associated with a lower cardiac index, higher systemic vascular resistance, and hyperglycemia. There was no difference in the frequency of adverse events. CONCLUSIONS: Our preliminary observations suggest that treatment with moderate hypothermia appears to improve outcomes in patients with coma after resuscitation from out-of-hospital cardiac arrest.
Bernard, S.A., Jones, B.M. & Horne, M.K.	Clinical trial of induced hypothermia in comatose survivors of out-of-hospital cardiac arrest. [Abstract]	1997	Ann Emerg Med Vol. 30(2), pp. 146-153	article
Abstract: STUDY OBJECTIVE: To examine the effects of moderate hypothermia (33 degrees C), induced by surface cooling in the ED and maintained for 12 hours in the ICU, on patients with anoxic brain injury after out-of-hospital cardiac arrest. METHODS: We conducted the study in a teaching hospital in Melbourne, Victoria, Australia. Participants were 22 adults who remained unconscious after return of spontaneous circulation following out-of-hospital cardiac arrest. This treatment group was studied prospectively, and a control group of 22 similar patients was studied by retrospective chart review. Moderate hypothermia (33 degrees C) was induced in the ED by means of surface cooling and maintained for 12 hours in the ICU with rewarming to normothermia over 6 hours; control patients were maintained at normothermia. RESULTS: There were no significant adverse effects of induced hypothermia. Cardiovascular changes included decreased pulse rate, but there were no significant differences in mean arterial blood pressure between the two groups. Small increases in serum potassium and decreases in pH at 18 hours in the hypothermic patients compared with normothermic controls were of no clinical significance. There were no septic complications. There was a significant increase in the number of patients with good outcome (Glasgow Outcome Coma Scale category 1 or 2) with induced hypothermia (11 of 22, versus 3 of 22 for normothermic controls; P<.05), and the mortality rate was significantly lower (10 of 22 versus 17 of 22; P<.05). CONCLUSION: Compared with historical normothermic controls, outcome was significantly improved and there was no increase in complications when moderate hypothermia was induced in comatose survivors of out-of-hospital cardiac arrest and maintained for 12 hours. Larger, prospective, randomized, controlled studies of induced moderate hypothermia in comatose survivors of out-of-hospital cardiac arrest are warranted.
Cabanac, M. & White, M.	Heat loss from the upper airways and selective brain cooling in humans. [Abstract]	1997	Ann N Y Acad Sci Vol. 813, pp. 613-616	article
Abstract: [extract] INTRODUCTION. A necessary condition for selective brain cooling (SBC) is a high heat loss capacity of the head itself. Intense heat loss is achieved in many species with thermal panting, which consists in evaporating water from the upper airways. Contrary to animals, humans are not considered panters. However, calorimetry of the whole head showed that as much as 100 W of convective-evaporative heat was lost from the upper airways during moderate exercise.1 This result triggered a whole series of experiments to check whether this additional heat loss path from the upper airways might be used by humans in a ...
hypothermia after Cardiac Arrest Study Group	Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. [Abstract]	2002	N. Engl. J. Med. Vol. 346(8), pp. 549-556	article
Abstract: BACKGROUND: Cardiac arrest with widespread cerebral ischemia frequently leads to severe neurologic impairment. We studied whether mild systemic hypothermia increases the rate of neurologic recovery after resuscitation from cardiac arrest due to ventricular fibrillation. METHODS: In this multicenter trial with blinded assessment of the outcome, patients who had been resuscitated after cardiac arrest due to ventricular fibrillation were randomly assigned to undergo therapeutic hypothermia (target temperature, 32 degrees C to 34 degrees C, measured in the bladder) over a period of 24 hours or to receive standard treatment with normothermia. The primary end point was a favorable neurologic outcome within six months after cardiac arrest; secondary end points were mortality within six months and the rate of complications within seven days. RESULTS: Seventy-five of the 136 patients in the hypothermia group for whom data were available (55 percent) had a favorable neurologic outcome (cerebral-performance category, 1 [good recovery] or 2 [moderate disability]), as compared with 54 of 137 (39 percent) in the normothermia group (risk ratio, 1.40; 95 percent confidence interval, 1.08 to 1.81). Mortality at six months was 41 percent in the hypothermia group (56 of 137 patients died), as compared with 55 percent in the normothermia group (76 of 138 patients; risk ratio, 0.74; 95 percent confidence interval, 0.58 to 0.95). The complication rate did not differ significantly between the two groups. CONCLUSIONS: In patients who have been successfully resuscitated after cardiac arrest due to ventricular fibrillation, therapeutic mild hypothermia increased the rate of a favorable neurologic outcome and reduced mortality.
Chihara, H., Blood, A.B., Hunter, C.J. & Power, G.G.	Effect of mild hypothermia and hypoxia on blood flow and oxygen consumption of the fetal sheep brain. [Abstract]	2003	Pediatr Res Vol. 54(5), pp. 665-671	article	DOI
Abstract: This study was undertaken to measure the effects of mild hypothermia on cerebral blood flow and metabolism and cardiovascular responses to hypoxia in the fetal sheep. Near-term fetal sheep were chronically instrumented with laser Doppler flowmetry in the parietal cortex for measurement of relative changes in cerebral blood flow, as well as with arterial and sagittal sinus catheters for measurement of oxygen extraction by the brain and a cooling coil around the fetal thorax. Fetuses were studied during cooling alone, cooling with superimposed maternal hypoxia to achieve a fetal arterial Po2 of 1.33 to 1.60 kPa, or hypoxia alone. In response to cooling alone [1.6 degrees +/- 0.1 degrees C (mean +/- SEM) decrease in brain temperature], fetal blood pressure and heart rate both increased significantly whereas cerebral blood flow decreased 14 +/- 4 commensurate with a 24 +/- 8% decline in cerebral metabolic rate. Administration of moderate hypoxia during cooling resulted in a significant increase in cerebral blood flow, decreased heart rate, and no further increase in blood pressure. In response to hypoxia alone, fetal blood pressure was significantly increased, heart rate was decreased, and cerebral blood flow increased by 24 +/- 8 whereas cerebral metabolic rate decreased by 38 +/- 13 Arteriovenous oxygen extraction was unchanged by cooling alone but increased significantly in response to hypoxia administered during cooling. We therefore conclude that oxygen delivery to the fetal sheep brain remains coupled to metabolic rate during hypothermia and that hypothermia does not impair the compensatory cardiovascular responses of the fetus to acute moderate hypoxia.
Clifton, G.L., Miller, E.R., Choi, S.C., Levin, H.S., McCauley, S., Smith, K.R., Muizelaar, J.P., Wagner, F.C., Marion, D.W., Luerssen, T.G., Chesnut, R.M. & Schwartz, M.	Lack of effect of induction of hypothermia after acute brain injury. [Abstract]	2001	N. Engl. J. Med. Vol. 344(8), pp. 556-563	article
Abstract: BACKGROUND: Induction of hypothermia in patients with brain injury was shown to improve outcomes in small clinical studies, but the results were not definitive. To study this issue, we conducted a multicenter trial comparing the effects of hypothermia with those of normothermia in patients with acute brain injury. METHODS: The study subjects were 392 patients 16 to 65 years of age with coma after sustaining closed head injuries who were randomly assigned to be treated with hypothermia (body temperature, 33 degrees C), which was initiated within 6 hours after injury and maintained for 48 hours by means of surface cooling, or normothermia. All patients otherwise received standard treatment. The primary outcome measure was functional status six months after the injury. RESULTS: The mean age of the patients and the type and severity of injury in the two treatment groups were similar. The mean (+/-SD) time from injury to randomization was 4.3+/-1.1 hours in the hypothermia group and 4.1+/-1.2 hours in the normothermia group, and the mean time from injury to the achievement of the target temperature of 33 degrees C in the hypothermia group was 8.4+/-3.0 hours. The outcome was poor (defined as severe disability, a vegetative state, or death) in 57 percent of the patients in both groups. Mortality was 28 percent in the hypothermia group and 27 percent in the normothermia group (P=0.79). The patients in the hypothermia group had more hospital days with complications than the patients in the normothermia group. Fewer patients in the hypothermia group had high intracranial pressure than in the normothermia group. CONCLUSIONS: Treatment with hypothermia, with the body temperature reaching 33 degrees C within eight hours after injury, is not effective in improving outcomes in patients with severe brain injury.
Conroy, B.P., Lin, C.Y., Jenkins, L.W., DeWitt, D.S., Zornow, M.H., Uchida, T. & Johnston, W.E.	Hypothermic modulation of cerebral ischemic injury during cardiopulmonary bypass in pigs. [Abstract]	1998	Anesthesiology Vol. 88(2), pp. 390-402	article
Abstract: BACKGROUND: The aim of this study was to determine whether progressive levels of hypothermia (37, 34, 31, or 28 degrees C) during cardiopulmonary bypass (CPB) in pigs reduce the physiologic and metabolic consequences of global cerebral ischemia. METHODS: Sagittal sinus and cortical microdialysis catheters were inserted into anesthetized pigs. Animals were placed on CPB and randomly assigned to 37 degrees C (n = 10), 34 degrees C (n = 10), 31 degrees C (n = 11), or 28 degrees C (n = 10) management. Next 20 min of global cerebral ischemia was produced by temporarily ligating the innominate and left subclavian arteries, followed by reperfusion, rewarming, and termination of CPB. Cerebral oxygen metabolism (CMRO2) was calculated by cerebral blood flow (radioactive microspheres) and arteriovenous oxygen content gradient. Cortical excitatory amino acids (EAA) by microdialysis were measured using high-performance liquid chromatography. Electroencephalographic (EEG) signals were graded by observers blinded to the protocol. After CPB, cerebrospinal fluid was sampled to test for S-100 protein and the cerebral cortex was biopsied. RESULTS: Cerebral oxygen metabolism increased after rewarming from 28 degrees C, 31 degrees C, and 34 degrees C CPB but not in the 37 degrees animals; CMRO2 remained lower with 37 degrees C (1.8 +/- 0.2 ml x min[-1] x 100 g[-1]) than with 28 degrees C (3.1 +/- 0.1 ml x min[-1] x 100 g[-1]; P < 0.05). The EEG scores after CPB were depressed in all groups and remained significantly lower in the 37 degrees C animals. With 28 degrees C and 31 degrees C CPB, EAA concentrations did not change. In contrast, glutamate increased by sixfold during ischemia at 37 degrees C and remained significantly greater during reperfusion in the 34 degrees C and 37 degrees C groups. Cortical biopsy specimens showed no intergroup differences in energy metabolites except two to three times greater brain lactate in the 37 degrees C animals. S-100 protein in cerebrospinal fluid was greater in the 37 degrees C (6 +/- 0.9 microg/l) and 34 degrees C (3.5 +/- 0.5 microg/l) groups than the 31 degrees C (1.9 +/- 0.1 microg/l) and 28 degrees C (1.7 +/- 0.2 microg/l) animals. CONCLUSIONS: Hypothermia to 28 degrees C and 31 degrees C provides significant cerebral recovery from 20 min of global ischemia during CPB in terms of EAA release, EEG and cerebral metabolic recovery, and S-100 protein release without greater advantage from cooling to 28 degrees C compared with 31 degrees C. In contrast, ischemia during 34 degrees C and particularly 37 degrees C CPB showed greater EAA release and evidence of neurologic morbidity. Cooling to 31 degrees C was necessary to improve acute recovery during global cerebral ischemia on CPB.
Curfman, G.D.	Hypothermia to protect the brain. [Abstract]	2002	N. Engl. J. Med. Vol. 346(8), pp. 546	article	DOI
Abstract: [extract] For decades, cooling the body below the normal physiologic temperature has been used as a therapeutic tool. Hypothermia is used most often during cardiac surgery with cardiopulmonary bypass, as a means of protecting the brain from ischemic injury. Hypothermia is also used during some neurosurgical procedures and is being investigated as a treatment for ischemic stroke and traumatic brain injury. In this issue of the Journal, two groups of investigators report on the use of therapeutic hypothermia to prevent neurologic injury in comatose survivors of cardiac arrest. Out-of-hospital cardiac arrest claims some 225,000 lives each year in the United States ...
Damian, M.S., Ellenberg, D., Gildemeister, R., Lauermann, J., Simonis, G., Sauter, W. & Georgi, C.	Coenzyme Q10 combined with mild hypothermia after cardiac arrest: a preliminary study. [Abstract]	2004	Circulation Vol. 110(19), pp. 3011-3016	article	DOI
Abstract: BACKGROUND: Therapeutic hypothermia can improve survival after cardiopulmonary resuscitation (CPR). Coenzyme Q10 (CoQ10) has shown a protective effect in neurodegenerative disorders. We investigated whether combining mild hypothermia with CoQ10 after out-of-hospital cardiac arrest provides additional benefit. METHODS AND RESULTS: Forty-nine patients were randomly assigned to either hypothermia plus CoQ10 or hypothermia plus placebo after CPR. Hypothermia with a core temperature of 35 degrees C was instituted for 24 hours. Liquid CoQ10 250 mg followed by 150 mg TID for 5 days or placebo was administered through nasogastric tube. Age, sex, premorbidity, cause of arrest, conditions of CPR, and degree of hypoxia were similar in both groups; no side effects of CoQ10 were identified. Three-month survival in the CoQ10 group was 68% (17 of 25) and 29% (7 of 24) in the placebo group (P=0.0413). Nine CoQ10 patients versus 5 placebo patients survived with a Glasgow Outcome Scale of 4 or 5. Mean serum S100 protein 24 hours after CPR was significantly lower in the CoQ10 group (0.47 versus 3.5 ng/mL). CONCLUSIONS: Combining CoQ10 with mild hypothermia immediately after CPR appears to improve survival and may improve neurological outcome in survivors.
Dietrich, W.D. & Kuluz, J.W.	New research in the field of stroke: therapeutic hypothermia after cardiac arrest. [Abstract]	2003	Stroke Vol. 34(4), pp. 1051-1053	article	DOI
Abstract: [extract] Therapeutic hypothermia as a potential treatment for stroke, cerebral ischemia, and other neurological diseases has gained momentum since the initial discovery that relatively small differences in intraischemic brain temperature critically determine ischemic neuronal vulnerability.1 Since that time, laboratories throughout the world have investigated the potential use of mild-to-moderate hypothermia in many ischemia models.2,3 Various studies have also investigated potential mechanisms contributing to hypothermic protection. Pathomechanisms sensitive to intra- and postischemic temperature reductions and elevations include glutamate release, stabilization of the blood-brain barrier, oxygen radical production, intracellular signal conduction, protein synthesis, ischemic depolarization, reduced cerebral metabolism, membrane stabilization, inflammation, activation of ...
Diringer, M.	Reducing neurologic injury from hyperthermia: a hot topic.	2001	Neurology Vol. 56(3), pp. 286-287	article
Diringer, M.N. & Group, N.C.F.R.T.	Treatment of fever in the neurologic intensive care unit with a catheter-based heat exchange system. [Abstract]	2004	Crit Care Med Vol. 32(2), pp. 559-564	article
Abstract: CONTEXT: Elevated temperature worsens injury in experimental focal and global ischemia and brain trauma. Fever is common in patients with acute neurologic illness and independently predicts poor outcome. Conventional means of treating fever are not very effective in this population. OBJECTIVE: To study the effectiveness of a catheter-based heat exchange system in reducing elevated temperatures in critically ill neurologic and neurosurgical patients. DESIGN, INTERVENTION, SETTING, AND POPULATION: This was a prospective randomized, non-blinded trial that compared conventional treatment of fever (acetaminophen and cooling blankets) with conventional treatment plus an intravascular catheter-based heat exchange system (Alsius, Irvine, CA). Patients admitted to one of 13 neurologic intensive care units in academic medical centers were eligible if they a) suffered subarachnoid hemorrhage, intracerebral hemorrhage, ischemic infarction, or traumatic brain injury; b) had a temperature >38 degrees C on two occasions or for >4 continuous hrs; and c) required central venous access. MAIN OUTCOME MEASURE: The fever burden (area under the curve >38 degrees C) for 72 hrs was compared in an intention to treat analysis. Safety of the catheter system was monitored. RESULTS: A total of 296 patients were enrolled over 20 months. Forty-one percent had subarachnoid hemorrhage, 24% had traumatic brain injury, 23% had intracerebral hemorrhage, and 13% had ischemic stroke. The groups were matched in terms of age, body mass index, sex, and Glasgow Coma Scale score distribution. Fever burden was 7.92 vs. 2.87 degrees C-hrs in the conventional group and catheter groups, respectively (64% reduction, p <.01). There was no higher rate of infection or the use of sedatives, narcotics, or antibiotics in the catheter group. The catheter did not significantly increase risk to the patient beyond that of a central catheter. CONCLUSIONS: The addition of this catheter-based cooling system to conventional management significantly improves fever reduction in neurologic intensive care unit patients.
Dixon, S.R., Whitbourn, R.J., Dae, M.W., Grube, E., Sherman, W., Schaer, G.L., Jenkins, J.S., Baim, D.S., Gibbons, R.J., Kuntz, R.E., Popma, J.J., Nguyen, T.T. & O'Neill, W.W.	Induction of mild systemic hypothermia with endovascular cooling during primary percutaneous coronary intervention for acute myocardial infarction. [Abstract]	2002	J Am Coll Cardiol Vol. 40(11), pp. 1928-1934	article
Abstract: OBJECTIVES: The purpose of this study was to evaluate the safety and feasibility of endovascular cooling during primary percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI). BACKGROUND: In experimental models of AMI, mild systemic hypothermia has been shown to reduce metabolic demand and limit infarct size. METHODS: In a multi-center study, 42 patients with AMI (<6 h from symptom onset) were randomized to primary PCI with or without endovascular cooling (target core temperature 33 degrees C). Cooling was maintained for 3 h after reperfusion. Skin warming, oral buspirone, and intravenous meperidine were used to reduce the shivering threshold. The primary end point was major adverse cardiac events at 30 days. Infarct size at 30 days was measured using (99m)Tc-sestamibi SPECT imaging. RESULTS: Endovascular cooling was performed successfully in 20 patients (95%). All achieved a core temperature below 34 degrees C (mean target temperature 33.2 +/- 0.9 degrees C). The mean temperature at reperfusion was 34.7 +/- 0.9 degrees C. Cooling was well tolerated, with no hemodynamic instability or increase in arrhythmia. Nine patients experienced mild episodic shivering. Major adverse cardiac events occurred in 0% vs. 10% (p = NS) of treated versus control patients. The median infarct size was non-significantly smaller in patients who received cooling compared with the control group (2% vs. 8% of the left ventricle, p = 0.80). CONCLUSIONS: Endovascular cooling can be performed safely as an adjunct to primary PCI for AMI. Further clinical trials are required to determine whether induction of mild systemic hypothermia with endovascular cooling will limit infarct size in patients undergoing reperfusion therapy.
Felberg, R.A., Krieger, D.W., Chuang, R., Persse, D.E., Burgin, W.S., Hickenbottom, S.L., Morgenstern, L.B., Rosales, O. & Grotta, J.C.	Hypothermia after cardiac arrest: feasibility and safety of an external cooling protocol. [Abstract]	2001	Circulation Vol. 104(15), pp. 1799-1804	article
Abstract: BACKGROUND: No proven neuroprotective treatment exists for ischemic brain injury after cardiac arrest. Mild-to-moderate induced hypothermia (MIH) is effective in animal models. METHODS AND RESULTS: A safety and feasibility trial was designed to evaluate mild-to-moderate induced hypothermia by use of external cooling blankets after cardiac arrest. Inclusion criteria were return of spontaneous circulation within 60 minutes of advanced cardiac life support, hypothermia initiated within 90 minutes, persistent coma, and lack of acute myocardial infarction or unstable dysrhythmia. Hypothermia to 33 degrees C was maintained for 24 hours followed by passive rewarming. Nine patients were prospectively enrolled. Mean time from advanced cardiac life support to return of spontaneous circulation was 11 minutes (range 3 to 30); advanced cardiac life support to initiation of hypothermia was 78 minutes (range 40 to 109); achieving 33 degrees C took 301 minutes (range 90 to 690). Three patients completely recovered, and 1 had partial neurological recovery. One patient developed unstable cardiac dysrhythmia. No other unexpected complications occurred. CONCLUSIONS: Mild-to-moderate induced hypothermia after cardiac arrest is feasible and safe. However, external cooling is slow and imprecise. Efforts to speed the start of cooling and to improve the cooling process are needed.
Forman, D.L., Bhutani, V.K., Tran, N. & Shaffer, T.H.	A new approach to induced hypothermia. [Abstract]	1986	J Surg Res Vol. 40(1), pp. 36-42	article
Abstract: A variety of methods have been employed for the induction of hypothermia; however, there are still some inherent problems that remain with current techniques. Liquid ventilation, a process used in several other environmental and clinical research areas, may be a feasible method since it takes advantage of the effectiveness of the pulmonary architecture as a heat exchanger. Hypothermia induced by liquid ventilation was studied in 8 newborn lambs, mean age = 10 +/- 8 SEM days. Each lamb was anesthetized with sodium pentobarbitol (20 mg/kg) and intubated. Cardiopulmonary measurements were taken during a control period prior to induced hypothermia. Liquid temperatures of 20 and 30 degrees C were used in cooling the animal while monitoring rectal and surface temperatures. Temperatures decreased producing rectal cooling rates of 8.4 and 4.8 degrees C/hr, respectively. Blood gas analysis showed adequate physiological gas exchange for all lambs during the liquid ventilation period. Based on the data, the process of liquid ventilation offers a unique potential both in experimental and clinical areas as a new approach to the technique of induced hypothermia.
Fukuda, H., Tomimatsu, T., Watanabe, N., Mu, J.W., Kohzuki, M., Endo, M., Fujii, E., Kanzaki, T. & Murata, Y.	Post-ischemic hypothermia blocks caspase-3 activation in the newborn rat brain after hypoxia-ischemia. [Abstract]	2001	Brain Res. Vol. 910(1-2), pp. 187-191	article
Abstract: The effects of hypothermia on caspase-3 activation were investigated in the newborn rat brain after hypoxia-ischemia (HI). Intense caspase-3 activation was observed in the control brains after HI, but this activation was significantly reduced by postischemic hypothermia. These findings suggest that the inhibition of caspase-3 activation may be an interventional point underlying the neuroprotective effect of hypothermia in neonates.
Gaohua, L. & Kimura, H.	A mathematical model of intracranial pressure dynamics for brain hypothermia treatment. [Abstract]	2006	J. Theor. Biol. Vol. 238(4), pp. 882-900	article	DOI
Abstract: Brain hypothermia treatment is used as a neuroprotectant to decompress the elevated intracranial pressure (ICP) in acute neuropatients. However, a quantitative relationship between decompression and brain hypothermia is still unclear, this makes medical treatment difficult and ineffective. The objective of this paper is to develop a general mathematical model integrating hemodynamics and biothermal dynamics to enable a quantitative prediction of transient responses of elevated ICP to ambient cooling temperature. The model consists of a lumped-parameter compartmental representation of the body, and is based on two mechanisms of temperature dependence encountered in hypothermia, i.e. the van't Hoff's effect of metabolism and the Arrhenius' effect of capillary filtration. Model parameters are taken from the literature. The model is verified by comparing the simulation results to population-averaged data and clinical evidence of brain hypothermia treatment. It is possible to assign special model inputs to mimic clinical maneuvers, and to adjust model parameters to simulate pathophysiological states of intracranial hypertension. Characteristics of elevated ICP are quantitatively estimated by using linear approximation of step response with respect to ambient cooling temperature. Gain of about 4.9 mmHg degrees C(-1), dead time of about 1.0 h and a time constant of about 9.8h are estimated for the hypothermic decompression. Based on the estimated characteristics, a feedback control of elevated ICP is introduced in a simulated intracranial hypertension of vasogenic brain edema. Simulation results suggest the possibility of an automatic control of the elevated ICP in brain hypothermia treatment.
Gentilello, L.M., Jurkovich, G.J., Stark, M.S., Hassantash, S.A. & O'Keefe, G.E.	Is hypothermia in the victim of major trauma protective or harmful? A randomized, prospective study. [Abstract]	1997	Ann Surg Vol. 226(4), pp. 439-47; discussion 447-9	article
Abstract: OBJECTIVE: The purpose of this randomized, prospective clinical trial was to determine whether hypothermia during resuscitation is protective or harmful to critically injured trauma patients. SUMMARY BACKGROUND DATA: Hypothermia has both protective and harmful clinical effects. Retrospective studies show higher mortality in patients with hypothermia; however, hypothermia is more common in more severely injured patients, which makes it difficult to determine whether hypothermia contributes to mortality independently of injury severity. There are no randomized, prospective treatment studies to assess hypothermia's impact as an independent variable. METHODS: Fifty-seven hypothermic (T < or = 34.5 C), critically injured patients requiring a pulmonary artery catheter were randomized to a rapid rewarming protocol using continuous arteriovenous rewarming (CAVR) or to a standard rewarming (SR) control group. The primary outcome of interest was first 24-hour blood product and fluid resuscitation requirements. Other comparative analyses included coagulation assays, hemodynamic and oxygen transport measurements, length of stay, and mortality. RESULTS: The two groups were well matched for demographic and injury severity characteristics. CAVR rewarmed significantly faster than did SR (p < 0.01), producing two groups with different amounts of hypothermia exposure. The patients who underwent CAVR required less fluid during resuscitation to the same hemodynamic goals (24,702 mL vs. 32,540 mL, p = 0.05) and were significantly more likely to rewarm (p = 0.002). Only 2 (7 of 29 patients who underwent CAVR failed to warm to 36 C and both died, whereas 12 (43 of 28 patients who underwent SR failed to reach 36 C, and all 12 died. Patients who underwent CAVR had significantly less early mortality (p = 0.047). CONCLUSION: Hypothermia increases fluid requirements and independently increases acute mortality after major trauma.
Georgiadis, D., Schwarz, S., Kollmar, R. & Schwab, S.	Endovascular cooling for moderate hypothermia in patients with acute stroke: first results of a novel approach. [Abstract]	2001	Stroke Vol. 32(11), pp. 2550-2553	article
Abstract: BACKGROUND AND PURPOSE: We undertook this study to evaluate the feasibility of inducing and maintaining moderate hypothermia with the use of endovascular rather than surface cooling. METHODS: Six patients with severe acute ischemic stroke were treated with moderate hypothermia. This was induced and maintained by circulating temperature-adjusted normal saline in a closed-loop system entailing 3 balloons located near the tip of a central line, which dwelled in the inferior vena cava. RESULTS: The mean+/-SD initial temperature of the patients was 37+/-1 degrees C (range, 35.5 degrees C to 38.4 degrees C). The pace of cooling was 1.4+/-0.6 degrees C/h, and target temperature was reached after 3+/-1 hours (range, 2 to 4.5 hours). During hypothermia, the maximal temperature observed was 33.4 degrees C, and the minimal temperature was 32.2 degrees C. Temperature deviations >0.2 degrees C or >0.3 degrees C were observed during 21% or 10% of the hours under hypothermia, respectively. Singultus was the only device-related complication encountered. Pulmonary infection, arterial hypotension, bradycardia, arrhythmia, and thrombocytopenia were the most common side effects. CONCLUSIONS: Induction and maintenance of hypothermia with an intravenous cooling device are feasible. The safety of this approach remains to be evaluated.
Ginsberg, M.D.	Adventures in the pathophysiology of brain ischemia: penumbra, gene expression, neuroprotection: the 2002 Thomas Willis Lecture. [Abstract]	2003	Stroke Vol. 34(1), pp. 214-223	article
Abstract: BACKGROUND: The pathophysiology of cerebral ischemia is well studied in small-animal models, which offer reproducibility and control of confounding variables-factors essential to hypothesis-testing. This presentation first highlights insights into the ischemic penumbra enabled by a multimodal experimental approach; second, discusses gene expression in ischemia; and third, confronts the challenges of neuroprotectant therapy. SUMMARY OF REVIEW: The ischemic penumbra: Transient (2-hour) middle cerebral artery suture-occlusion in anesthetized rats gives rise to highly consistent neurological and histopathological sequelae. Autoradiographic local cerebral blood flow (LCBF) studies at 2 hours of occlusion define the penumbra as a region of intermediate CBF depression (20% to 40% of control) surrounding the densely ischemic core (5% to 20% of control) and constituting one half of the entire lesion. Local glucose metabolic rate in the acute penumbra is not reduced despite the critical CBF reduction, so that the penumbral metabolism/blood flow ratio is markedly elevated. In contrast, following 1 hour of recirculation, glucose metabolism throughout the previously ischemic hemisphere has become markedly depressed, and the metabolism/flow ratio has pseudonormalized. By correlating these data with histopathology using multimodal image analysis, the probability of infarction is shown to be highly determined by the degree of antecedent CBF reduction. These animal data agree strikingly with published results in patients with acute stroke studied by positron emission tomography. This remarkable correspondence belies the assertion that data from lower species may not be relevant to human stroke. Gene expression: Perfusion gradients also determine differential patterns of gene expression in ischemia. This can be demonstrated by correlating in situ hybridization autoradiographs for gene expression with autoradiographic LCBF data and histological infarct maps derived from replicate series. In other studies, DNA microarray technology is used to screen for thousands of expressed genes. In the 2-hour middle cerebral artery occlusion model with 3-hour recirculation, we have identified 28 known ischemia-hypoxia response genes that are upregulated and 6 that are downregulated, together with 35 upregulated and 41 downregulated genes newly connected with ischemia. These findings underscore the enormous complexity of ischemic biology and suggest possible novel mechanisms for future exploration. NEUROPROTECTION: A desirable neuroprotectant would, in theory, antagonize multiple injury mechanisms. We have explored 2 such therapies of particular promise. Mild brain hypothermia (32 degrees C target temperature, for 5 hours) is highly neuroprotective even when initiated at the onset of recirculation. Another highly protective agent is human albumin, administered in doses of 1.25 to 2.5 g/kg--a therapy that reduces infarct volume in this ischemia model by 60% to 65 markedly diminishes brain swelling, and has a therapeutic window extending to 4 hours. CONCLUSION: The careful study of rodent ischemia models can yield valuable, clinically relevant insights into the pathophysiology of ischemic stroke.
Gluckman, P.D., Wyatt, J.S., Azzopardi, D., Ballard, R., Edwards, A.D., Ferriero, D.M., Polin, R.A., Robertson, C.M., Thoresen, M., Whitelaw, A. & Gunn, A.J.	Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. [Abstract]	2005	Lancet Vol. 365(9460), pp. 663-670	article	DOI
Abstract: BACKGROUND: Cerebral hypothermia can improve outcome of experimental perinatal hypoxia-ischaemia. We did a multicentre randomised controlled trial to find out if delayed head cooling can improve neurodevelopmental outcome in babies with neonatal encephalopathy. METHODS: 234 term infants with moderate to severe neonatal encephalopathy and abnormal amplitude integrated electroencephalography (aEEG) were randomly assigned to either head cooling for 72 h, within 6 h of birth, with rectal temperature maintained at 34-35 degrees C (n=116), or conventional care (n=118). Primary outcome was death or severe disability at 18 months. Analysis was by intention to treat. We examined in two predefined subgroup analyses the effect of hypothermia in babies with the most severe aEEG changes before randomisation--ie, severe loss of background amplitude, and seizures--and those with less severe changes. FINDINGS: In 16 babies, follow-up data were not available. Thus in 218 infants (93, 73/110 (66 allocated conventional care and 59/108 (55 assigned head cooling died or had severe disability at 18 months (odds ratio 0.61; 95% CI 0.34-1.09, p=0.1). After adjustment for the severity of aEEG changes with a logistic regression model, the odds ratio for hypothermia treatment was 0.57 (0.32-1.01, p=0.05). No difference was noted in the frequency of clinically important complications. Predefined subgroup analysis suggested that head cooling had no effect in infants with the most severe aEEG changes (n=46, 1.8; 0.49-6.4, p=0.51), but was beneficial in infants with less severe aEEG changes (n=172, 0.42; 0.22-0.80, p=0.009). INTERPRETATION: These data suggest that although induced head cooling is not protective in a mixed population of infants with neonatal encephalopathy, it could safely improve survival without severe neurodevelopmental disability in infants with less severe aEEG changes.
Granger, D.N.	Role of xanthine oxidase and granulocytes in ischemia-reperfusion injury. [Abstract]	1988	Am. J. Physiol. Vol. 255(6 Pt 2), pp. H1269-H1275	article
Abstract: In this lecture, evidence is presented to support the following hypothesis regarding the roles of xanthine oxidase-derived oxidants and granulocytes in ischemia-reperfusion-induced microvascular injury. During the ischemic period, ATP is catabolized to yield hypoxanthine. The hypoxic stress also triggers the conversion of NAD-reducing xanthine dehydrogenase to the oxygen radical-producing xanthine oxidase. During reperfusion, molecular oxygen is reintroduced into the tissue where it reacts with hypoxanthine and xanthine oxidase to produce a burst of superoxide anion and hydrogen peroxide. In the presence of iron, superoxide anion and hydrogen peroxide react via the Haber-Weiss reaction to form hydroxyl radicals. This highly reactive and cytotoxic radical then initiates lipid peroxidation of cell membrane components and the subsequent release of substances that attract, activate, and promote the adherence of granulocytes to microvascular endothelium. The adherent granulocytes then cause further endothelial cell injury via the release of superoxide and various proteases.
Guluma, K.Z., Hemmen, T.M., Olsen, S.E., Rapp, K.S. & Lyden, P.D.	A trial of therapeutic hypothermia via endovascular approach in awake patients with acute ischemic stroke: methodology. [Abstract]	2006	Acad Emerg Med Vol. 13(8), pp. 820-827	article	DOI
Abstract: BACKGROUND: Therapeutic hypothermia has been shown to be of benefit in improving neurological outcome in cardiac arrest. It now is being investigated in acute stroke and myocardial infarction. The majority of the literature describes its use in intubated, pharmacologically paralyzed patients, using surface cooling techniques that are susceptible to patient shivering, imprecise temperature control, time lag to target-temperature acquisition, and rebound hyperthermia. OBJECTIVES: To develop a method of inducing therapeutic hypothermia in a rapid, precise, and tolerable fashion in awake, nonintubated patients. METHODS: This method was developed for an ongoing clinical trial investigating a combination of therapeutic hypothermia and intravenous thrombolysis for acute ischemic stroke. In the protocol, an endovascular cooling device is placed in the inferior vena cava of a patient, and a combination of buspirone, meperidine, and cutaneous warming with a heating blanket is used to suppress shivering as the patient is cooled to a target temperature of 33 degrees C, kept there for a total of 24 hours from hypothermia initiation, and then rewarmed in a controlled fashion during the next 12 hours. RESULTS: Ten patients underwent the therapeutic hypothermia protocol. The median pretreatment core temperature was 36.1 degrees C (interquartile range [IQR]: 35.8 degrees C-36.4 degrees C). On initiation of cooling, the core temperatures dropped rapidly and then leveled off, approaching a median plateau value of 33.4 degrees C (IQR: 33.2 degrees C-33.9 degrees C) in a mean time of 1.7 (+/- 0.7) hours from cooling initiation, with a median average postplateau temperature during the cooling phase of 33.8 degrees C (IQR: 33.3 degrees C-34.6 degrees C), and a median lowest temperature of 33.1 degrees C (IQR: 33.0 degrees C-33.3 degrees C). The procedure was well tolerated, with minimal shivering and no rebound hyperthermia. CONCLUSIONS: This is a method by which a rapid and precise therapeutic decrease in core temperature can be achieved without the necessity for intubation or neuromuscular blockade and with minimal patient discomfort or shivering.
Gunn, A.J., Battin, M., Gluckman, P.D., Gunn, T.R. & Bennet, L.	Therapeutic hypothermia: from lab to NICU. [Abstract]	2005	J Perinat Med Vol. 33(4), pp. 340-346	article	DOI
Abstract: The possibility of a therapeutic role for cerebral hypothermia during or after resuscitation from perinatal asphyxia has been a long-standing focus of research. However, early studies had limited and contradictory results. It is now known that severe hypoxia-ischemia may not cause immediate cell death, but may precipitate a complex biochemical cascade leading to the delayed development of neuronal loss. These phases include a latent phase after reperfusion, with initial recovery of cerebral energy metabolism but EEG suppression, followed by a secondary phase characterized by accumulation of cytotoxins, seizures, cytotoxic edema, and failure of cerebral oxidative metabolism from 6 to 15 h post insult. Although many of the secondary processes can be injurious, they appear to be primarily epiphenomena of the 'execution' phase of cell death. This conceptual framework allows a better understanding of the experimental parameters that determine effective hypothermic neuroprotection, including the timing of initiation of cooling, its duration and the depth of cooling attained. Moderate cerebral hypothermia initiated in the latent phase, between one and as late as 6 h after reperfusion, and continued for a sufficient duration in relation to the severity of the cerebral injury, has been consistently associated with potent, long-lasting neuroprotection in both adult and perinatal species. The results of the first large multicentre randomized trial of head cooling for neonatal encephalopathy and previous phase I and II studies now strongly suggest that prolonged cerebral hypothermia is both generally safe - at least in an intensive care setting - and can improve intact survival up to 18 months of age. Both long-term followup studies and further large studies of whole body cooling are in progress.
Haque, I.U., Latour, M.C. & Zaritsky, A.L.	Pediatric critical care community survey of knowledge and attitudes toward therapeutic hypothermia in comatose children after cardiac arrest. [Abstract]	2006	Pediatr Crit Care Med Vol. 7(1), pp. 7-14	article
Abstract: OBJECTIVE: Therapeutic hypothermia improves neurologic outcome and survival after adult out-of-hospital cardiac arrest. To help us design a prospective hypothermia trial in children, we developed a survey to assess current knowledge and attitude of pediatric critical care providers regarding therapeutic hypothermia and potential impediments to implementing a prospective study. DESIGN: Anonymous survey. SETTING: Internet-based survey of pediatric critical care community. INTERVENTIONS: None. RESULTS: A total of 159 responders completed the survey. Most respondents (92 were fellowship-trained in pediatric critical care, with 9.9 +/- 6.5 yrs of experience. Many (85 worked in the United States; 89% were in large tertiary care centers with residency or fellowship training programs. Most (65 were aware of the adult randomized trials of therapeutic hypothermia, but only 9% (always) or 38% (sometimes) utilize this therapy. The most common reason to use hypothermia was likelihood of patient recovery, absence of life-limiting disease, and presence of coma for >/=1 hr after resuscitation. The majority of responders using therapeutic hypothermia cool their patients to 33-35 degrees C for a duration ranging from as short as 12 hrs to as long as 96 hrs; 91% do not actively rewarm the patient. A majority (81 agree that a randomized, controlled trial of therapeutic hypothermia in children is ethical, and 95% would be willing to randomize their patients. Finally, 81% thought that therapeutic hypothermia should be studied in other ischemic insults and not just cardiac arrest. CONCLUSIONS: Despite widespread awareness of therapeutic hypothermia's beneficial effects after arrest, it is not widely used by pediatric critical care clinicians sampled in our survey. Among those using hypothermia, there is wide variation in methodology and end points of therapy. This seems to result from a lack of evidence, difficulty with the technique, and unavailability of explicit protocols. Pediatric studies are needed to assess the safety, feasibility, and effectiveness of therapeutic hypothermia after cardiac arrest and other causes of brain injury.
Hayashi, S., Takayasu, M., Inao, S., Yoshida, J. & Group, N.T.H.S.	Balance of risk of therapeutic hypothermia. [Abstract]	2005	Acta Neurochir Suppl Vol. 95, pp. 269-272	article
Abstract: The complications of therapeutic hypothermia sometimes undermine its clinical effects. In this study we investigated the efficacy and safety of therapeutic hypothermia based on analysis of 20 severe head injury cases from 6 institutions treated with therapeutic hypothermia in 1999. The twenty patients with severe head injury were enrolled prospectively based on the following indications; Glasgow Coma Scale of 7 or less on admission, age 60 or younger, and systric BP over 100 mmHg. A control group consisting of 21 patients with severe head injury met the same criteria but were treated without therapeutic hypothermia in other institutions. Clinical benefit were evaluated by a comparison of clinical result in the two groups defined according to the Glasgow Outcome Scale six months after injury. The hypothermia group was divided into two groups based on a target temperature [mild hypothermia group: 32-34 degrees C (n = 10); very mild hypothermia group: 35-36 degrees C (n = 10)]. The complication rate, clinical results and the duration of therapeutic hypothermia were analyzed between two groups. In the hypothermia group, 12 patients obtained a favorable outcome (Good Recovery or Moderate Disabled in GOS) and the mortality rate was 35 In the control group, however only 5 patients had a favorable outcome and the mortality rate was 57 Comparison between mild hypothermia and very mild hypothermia groups revealed no difference in clinical outcome. In the hypothermia group, severe pneumonia was seen in three patients, all in the mild hypothermia group with a hypothermic duration of over 120 hours. Mild hypothermia should be ended within 120 hours to avoid severe complication. When long-lasting therapeutic hypothermia of more than 120 hours is planned, very mild hypothermia is the treatment of choice.
Heidenreich, T., Giuffre, M. & Doorley, J.	Temperature and temperature measurement after induced hypothermia. [Abstract]	1992	Nurs Res Vol. 41(5), pp. 296-300	article
Abstract: This study was designed to assess factors associated with afterdrop, the fall in core temperature following completion of cardiac surgery, and determine the validity of noninvasive measures of temperature to predict core temperature in the severely hypothermic patient. Twenty-five postcardiac surgery patients served as subjects. Core temperature was measured using the pulmonary artery, bladder, and esophageal sites. The less invasive measures included a tympanic membrane thermometer, oral and axillary electronic thermometers, and a forehead surface temperature indicator. Temperatures were recorded every 10 minutes for 2 hours. End-of-surgery temperatures ranged from 30.3-38.3 degrees C (86.5-100.9 degrees F) with a mean of 36.02 degrees C (96.84 degrees F). Temperature change over the next hour ranged from a rise of 2.5 degrees C (4.5 degrees F) to a fall of 4.1 degrees C (7.2 degrees F). Factors associated with afterdrop included age, end-of-surgery temperature (both positively) and body mass (negatively). No noninvasive measure appeared to be a valid indicator of core temperature in these hypothermic patients.
Henderson, W.R., Dhingra, V.K., Chittock, D.R., Fenwick, J.C. & Ronco, J.J.	Hypothermia in the management of traumatic brain injury. A systematic review and meta-analysis. [Abstract]	2003	Intensive Care Med Vol. 29(10), pp. 1637-1644	article	DOI
Abstract: OBJECTIVE: Brain injury remains the leading cause of death in cases of trauma in North America and Europe. This article critically appraised and summarised all published and peer-reviewed, randomised, controlled trials of the use of hypothermia in traumatic brain injury. DESIGN: To be included, a study had to be a published, randomised, controlled trial of the use of hypothermia in the management of traumatic brain injury. Pooling of data and meta-analysis of results occurred. SETTING: Conducted at a tertiary level Canadian teaching hospital. PATIENTS AND PARTICIPANTS: Patients were combined from eight randomised, controlled trials to generate a population of 748 severely head-injured patients. MEASUREMENTS AND RESULTS: Eight studies provided data on the efficacy of hypothermia in the management of traumatic brain injury. The pooled odds ratio of mortality in the hypothermic group was 0.81 (95%CI =0.59-1.13, p=0.22). The OR of a poor neurological outcome (GOS 1,2 or 3) was 0.75 (95% CI=0.56-1.01, p=0.06). The odds ratio for pneumonia in the normothermic group was 0.42 (95%CI =0.25-0.70, p=0.001). CONCLUSIONS: Although meta-analysis suggests that iatrogenic hypothermia may confer a marginal benefit in neurological outcome, there does not appear to be clear evidence of lower mortality rates in unselected traumatic brain injury patients. Prolonged hypothermia may confer a benefit, particularly in patients with elevated intracranial pressure refractory to conventional manipulations. Conclusions regarding the use of hypothermia are controversial and not strongly supported by the available evidence.
Hindman, B.J., Todd, M.M., Gelb, A.W., Loftus, C.M., Craen, R.A., Schubert, A., Mahla, M.E. & Torner, J.C.	Mild hypothermia as a protective therapy during intracranial aneurysm surgery: a randomized prospective pilot trial. [Abstract]	1999	Neurosurgery Vol. 44(1), pp. 23-32; discussion 32-3	article
Abstract: OBJECTIVE: To conduct a pilot trial of mild intraoperative hypothermia during cerebral aneurysm surgery. METHODS: One hundred fourteen patients undergoing cerebral aneurysm clipping with (n = 52) (World Federation of Neurological Surgeons score < or =III) and without (n = 62) acute aneurysmal subarachnoid hemorrhage (SAH) were randomized to normothermic (target esophageal temperature at clip application of 36.5 degrees C) and hypothermic (target temperature of 33.5 degrees C) groups. Neurological status was prospectively evaluated before surgery, 24 and 72 hours postoperatively (National Institutes of Health Stroke Scale), and 3 to 6 months after surgery (Glasgow Outcome Scale). Secondary outcomes included postoperative critical care requirements, respiratory and cardiovascular complications, duration of hospitalization, and discharge disposition. RESULTS: Seven hypothermic patients (12 could not be cooled to within 1 degrees C of target temperature; three of the seven were obese. Patients randomized to the hypothermic group more frequently required intubation and rewarming for the first 2 hours after surgery. Although not achieving statistical significance, patients with SAH randomized to the hypothermic group, when compared with patients in the normothermic group, had the following: 1) a lower frequency of neurological deterioration at 24 and 72 hours after surgery (21 versus 37-41, 2) a greater frequency of discharge to home (75 versus 57, and 3) a greater incidence of good long-term outcomes (71 versus 57. For patients without acute SAH, there were no outcome differences between the temperature groups. There was no suggestion that hypothermia was associated with excess morbidity or mortality. CONCLUSION: Mild hypothermia during cerebral aneurysm surgery is feasible in nonobese patients and is well tolerated. Our results indicate that a multicenter trial enrolling 300 to 900 patients with acute aneurysmal SAH will be required to demonstrate a statistically significant benefit with mild intraoperative hypothermia.
Holzer, M., Bernard, S.A., Hachimi-Idrissi, S., Roine, R.O., Sterz, F. & Müllner, M.	Mild Resuscitative Hypothermia Improves Favorable Neurological Recovery After Cardiac Arrest: Systematic Review of the Literature and Individual Patient Data Meta-Analysis.	2003	AHA Sci Sess Abstr Posters	misc
Holzer, M., Kliegel, A., Schreiber, W., Havel, C., Losert, H., Bur, A., Sterz, F. & Laggner, A.N.	Effectiveness and feasibility of rapid endovascular cooling for resuscitative hypothermia.	2002	AHA Sci Sess	misc
Holzer, M., Müllner, M., Sterz, F., Robak, O., Kliegel, A., Losert, H., Sodeck, G., Uray, T., Zeiner, A. & Laggner, A.N.	Efficacy and safety of endovascular cooling after cardiac arrest: cohort study and Bayesian approach. [Abstract]	2006	Stroke Vol. 37(7), pp. 1792-1797	article	DOI
Abstract: BACKGROUND AND PURPOSE: Recently 2 randomized trials in comatose survivors of cardiac arrest documented that therapeutic hypothermia improved neurological recovery. The narrow inclusion criteria resulted in an international recommendation to cool only a restricted group of primary cardiac arrest survivors. In this retrospective cohort study we investigated the efficacy and safety of endovascular cooling in unselected survivors of cardiac arrest. METHODS: Consecutive comatose survivors of cardiac arrest, who were either cooled for 24 hours to 33 degrees C with endovascular cooling or treated with standard postresuscitation therapy, were analyzed. Complication data were obtained by retrospective chart review. RESULTS: Patients in the endovascular cooling group had 2-fold increased odds of survival (67/97 patients versus 466/941 patients; odds ratio 2.28, 95% CI, 1.45 to 3.57; P<0.001). After adjustment for baseline imbalances the odds ratio was 1.96 (95% CI, 1.19 to 3.23; P=0.008). When discounting the observational data in a Bayesian analysis by using a sceptical prior the posterior odds ratio was 1.61 (95% credible interval, 1.06 to 2.44). In the endovascular cooling group, 51/97 patients (53%) survived with favorable neurology as compared with 320/941 (34%) in the control group (odds ratio 2.15, 95% CI, 1.38 to 3.35; P=0.0003; adjusted odds ratio 2.56, 1.57 to 4.17). There was no difference in the rate of complications except for bradycardia. CONCLUSIONS: Endovascular cooling improved survival and short-term neurological recovery compared with standard treatment in comatose adult survivors of cardiac arrest. Temperature control was effective and safe with this device.
Hovland, A., Nielsen, E.W., Klüver, J. & Salvesen, R.	EEG should be performed during induced hypothermia. [Abstract]	2006	Resuscitation Vol. 68(1), pp. 143-146	article	DOI
Abstract: Induced hypothermia has improved neurological outcome after cardiac arrest. Even though anoxic insults to the brain often provoke epileptic activity, it is unclear whether EEG monitoring is necessary in these patients. We report the case of a 53-year-old female who suffered cardiac arrest. During induced hypothermia extensive shivering was managed by sedation and curare. After their discontinuation convulsions appeared and status epilepticus was disclosed on EEG recording, and was treated by thiopental infusion for 10 days. The patient recovered slowly and has now regained independent living (CPC 1). In induced hypothermia several factors including the use of curare, may conceal clinical signs of epileptic activity. We therefore suggest a broader use of EEG in these patients.
Janata, A., Holzer, M., Sterz, F., Koehler, C., Ochsenhofer, H.S., Deckert, Z., Losert, U., Laggner, A.N. & Behringer, W.	Extracorporal veno-venous cooling versus endovascular cooling in pigs, preliminary results.	2003	AHA Sci Sess Abstr Posters	misc
Jeremitsky, E., Omert, L., Dunham, C.M., Protetch, J. & Rodriguez, A.	Harbingers of poor outcome the day after severe brain injury: hypothermia, hypoxia, and hypoperfusion. [Abstract]	2003	J Trauma Vol. 54(2), pp. 312-319	article	DOI
Abstract: BACKGROUND: Traumatic brain injury (TBI) can be compounded by physiologic derangements that produce secondary brain injury. The purpose of this study is to elucidate the frequency with which physiologic factors that are associated with secondary brain injury occur in patients with severe closed head injuries and to determine the impact of these factors on outcome. METHODS: The records of 81 adult blunt trauma patients with Glasgow Coma Scale scores < or = 8 and transport times < 2 hours to a Level I trauma center were retrospectively reviewed searching for the following 11 secondary brain injury factors (SBIFs) in the first 24 hours postinjury: hypotension, hypoxia, hypercapnia, hypocapnia, hypothermia, hyperthermia, metabolic acidosis, seizures, coagulopathy, hyperglycemia, and intracranial hypertension. We recorded the worst SBIF during six time periods: hours 1, 2, 3, 4, 5 to 14, and 16 to 24. Occurrence of each SBIF was then correlated with outcome. RESULTS: Hypocapnia, hypotension, and acidosis occurred more frequently than other SBIFs (60-80. Hypotension, hyperglycemia, and hypothermia were associated with increased mortality rate. Patients with episodes of hypocapnia, acidosis, and hypoxia had significantly longer intensive care unit length of stay (LOS). These three SBIFs and hyperglycemia related to longer hospital LOS as well. Hypotension and acidosis were associated with discharge to a rehabilitation facility rather than home. Finally, multivariate regression analysis revealed that hypotension, hypothermia, and Abbreviated Injury Scale score of the head were independently related to mortality, whereas other SBIFs, age, Injury Severity Score, and Glasgow Coma Scale score were not. Metabolic acidosis and hypoxia were related to longer intensive care unit and hospital LOS. CONCLUSION: Our early management of head-injured patients stresses avoidance and correction of SBIFs at all costs. Nonetheless, SBIFs occur frequently in the first 24 hours after traumatic brain injury. Six of the 11 factors studied are associated with significantly worse outcomes. Hypotension and hypothermia are independently related to mortality. Because these SBIFs are potentially preventable, protocols could be developed to decrease their frequency.
Ji, Y. & Liu, J.	Numerical studies on the effect of lowering temperature on the oxygen transport during brain hypothermia resuscitation. [Abstract]	2002	Comput Biol Med Vol. 32(6), pp. 495-514	article
Abstract: There have been arguments about the advantage and shortcoming of hypothermia on the brain resuscitation during circulation arrest. People usually accepted that hypothermia may decrease the cerebral oxygen demands, which is beneficial for the patient to sustain longer time when subjected to a hypoxia. However, there are also quite a few disputes claiming that the blood viscosity would increase with the reduction of temperature, which may lead to an increase of cerebral vascular resistance and thus worsen the hypoxia state. To resolve this critical issue, a heat transfer model was established to characterize the thermal response of brain tissue during hypothermia resuscitation. Combined with this model, a compartmental model taking account of the temperature effect was further developed to analyze the transient oxygen partial pressure (PO(2)) distribution over the successive branches of the vascular network during circulation arrest. Using the morphological and physiological data of a sheep brain, effects of lowering temperature on the oxygen consumption dynamics were studied. Calculations indicated that the lower the temperature, the slower the decreasing rate for the PO(2). Although immediately lowering the brain temperature may induce an evident increase in blood viscosity and subsequently a decrease in blood flow rate, which is responsible for oxygen delivery, it seems to always result in a monotonic increase of PO(2). The results show a good qualitative accord with the experimental data. They also present better understanding on the transient oxygen transport in brain hypothermia during circulation arrest.
Jiang, J.-Y., Xu, W., Li, W.-P., Gao, G.-Y., Bao, Y.-H., Liang, Y.-M. & Luo, Q.-Z.	Effect of long-term mild hypothermia or short-term mild hypothermia on outcome of patients with severe traumatic brain injury. [Abstract]	2006	J Cereb Blood Flow Metab Vol. 26(6), pp. 771-776	article	DOI
Abstract: To compare the effect of long-term mild hypothermia versus short-term mild hypothermia 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 < or =8 within 4 h after injury were randomly divided into two groups: long-term mild hypothermia group (n = 108) for 5+/-1.3 days mild hypothermia therapy and short-term mild hypothermia group (n = 107) for 2+/-0.6 days mild hypothermia 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 hypothermia group. However, only 31 cases had favorable outcome (29.0, and other 76 cases had unfavorable outcome (71.0 in the short-term mild hypothermia group (P < 0.05). The intracranial pressure significantly rebounded after rewarming in the short-term mild hypothermia group, but not in the long-term mild hypothermia (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 hypothermia, long-term mild hypothermia 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 long-term cooling is more efficacious than 2 days of short-term cooling when mild hypothermia is used to control refractory intracranial hypertension in patients with severe traumatic brain injury.
Kandzari, D.E., Chu, A., Brodie, B.R., Stuckey, T.A., Hermiller, J.B., Vetrovec, G.W., Hannan, K.L., Krucoff, M.W., Christenson, R.H., Gibbons, R.J., Sigmon, K.N., Garg, J., Hasselblad, V., Collins, K., Harrington, R.A., Berger, P.B., Chronos, N.A., Hochman, J.S. & Califf, R.M.	Feasibility of endovascular cooling as an adjunct to primary percutaneous coronary intervention (results of the LOWTEMP pilot study). [Abstract]	2004	Am J Cardiol Vol. 93(5), pp. 636-639	article	DOI
Abstract: In a nonrandomized feasibility study of therapeutic hypothermia in acute myocardial infarction, 18 patients were treated with endovascular cooling (Alsius, Irvine, California) as adjunctive therapy to primary percutaneous coronary intervention to assess measures of infarct size (area under the curve creatinine kinase-MB and technetium-99m single-photon emission computed tomography sestamibi) and the quality of myocardial perfusion (continuous ST-segment monitoring). Periprocedural endovascular cooling successfully decreased core body temperature (median 33.5 degrees C) and was well tolerated, which supports the evaluation of adjunctive hypothermia in pivotal trials to limit infarct size and decrease reperfusion injury.
Khan, J.N., Prasad, N. & Glancy, J.M.	QTc prolongation during therapeutic hypothermia: are we giving it the attention it deserves? [Abstract]	2009	Europace	article	DOI
Abstract: Aims Therapeutic hypothermia (TH) is used in neuroprotection following cardiac arrest due to ventricular tachycardia (VT) and ventricular fibrillation (VF). Accidental hypothermia is itself known to cause prolongation of the corrected QT interval (QTc). QTc prolongation can cause polymorphic VT and VF. If this also occurs in TH, it may induce refibrillation. We investigated the effect of TH on the QTc interval. Methods and results Prospective case series of all patients undergoing TH following cardiac arrest following VT/VF at our hospital between July 2008 and January 2009. We studied the effect of temperature on QTc. All electrocardiograms (ECGs) undertaken during TH were studied and compared with the ECG prior to this. Four patients underwent TH. A total of 10 ECGs were undertaken during TH. The QTc was normal prior to TH. It became prolonged (>460 ms) in all cases during TH and normalized after cessation of TH, apart from Patient 4 who did not have an ECG post-TH since she died from cardiogenic shock. There was a negative correlation between temperature and QTc (Pearson's correlation coefficient, r= -0.71). Conclusion Our series illustrates QTc prolongation during TH. This carries potential for refibrillation. Guidelines on ECG monitoring during TH are needed, especially since hypothermic myocardium is intrinsically prone to arrhythmias and commonly used antiarrythmic drugs such as amiodarone can prolong the QTc.
Kilpatrick, M.M., Lowry, D.W., Firlik, A.D., Yonas, H. & Marion, D.W.	Hyperthermia in the neurosurgical intensive care unit. [Abstract]	2000	Neurosurgery Vol. 47(4), pp. 850-5; discussion 855-6	article
Abstract: OBJECTIVE: In patients with traumatic or ischemic brain injury, hyperthermia is thought to worsen the neurological injury. We studied fever in the neurosurgical intensive care unit (ICU) population using a definition common to surgical practice (rectal temperature >38.5 degrees C). We sought to determine fever incidence, fever duration, and peak temperature and to quantify the use of antipyretic therapy. We also attempted to determine the patient subgroups that are at highest risk for development of fever. METHODS: In a retrospective chart review of a 6-month period, all febrile episodes that occurred in a consecutive series of neurosurgical ICU patients in a university hospital setting were studied. A febrile episode was defined as a rectal temperature of at least 38.5 degrees C; an episode lasted until the temperature fell below this threshold. RESULTS: The 428 patients studied had 946 febrile episodes. Fever occurred in 47% of patients, with a mean of 4.7 febrile episodes in each febrile patient. Fevers occurred in more than 50% of patients who were admitted to the ICU for subarachnoid hemorrhage, a central nervous system infection, seizure control, or hemorrhagic stroke, but they occurred in only 27% of patients admitted for spinal disorders. Fevers occurred in 15% of the patients who stayed in the ICU less than 24 hours, but in 93% of those who remained longer than 14 days. Despite the use of antipyretic therapy for 86% of the febrile episodes, 57% lasted longer than 4 hours and 5% lasted longer than 12 hours. CONCLUSION: Fever is common in critically ill neurosurgical patients, especially those with a prolonged length of stay in the ICU or a cranial disease. If hyperthermia worsens the functional outcome after a primary ischemic or traumatic injury, as has been suggested by several studies of stroke patients, treatment of fever is a clinical issue that requires better management.
Krieger, D.W., Georgia, M.A.D., Abou-Chebl, A., Andrefsky, J.C., Sila, C.A., Katzan, I.L., Mayberg, M.R. & Furlan, A.J.	Cooling for acute ischemic brain damage (cool aid): an open pilot study of induced hypothermia in acute ischemic stroke. [Abstract]	2001	Stroke Vol. 32(8), pp. 1847-1854	article
Abstract: 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 degrees 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.
Lampe, J.W. & Becker, L.B.	Rapid cooling for saving lives: a bioengineering opportunity. [Abstract]	2007	Expert Rev Med Devices Vol. 4(4), pp. 441-446	article	DOI
Abstract: The induction of mild hypothermia, lowering body temperature by 4 degrees C, is gaining acceptance as an acute therapy for the treatment of hypoxia and ischemia following cardiac arrest and many life-threatening injuries. When hypothermia is used following ischemia (as opposed to before ischemia), it needs to be performed rapidly for the greatest benefit, preferably within 5 min. When we consider the basic heat-transfer problem and define the engineering parameter space, we find that almost 3900 W of cooling are required in order to achieve 4 degrees C cooling within 5 min. A simple model reveals that this poses a significant bioengineering challenge as the rate of heat transfer is severely limited, owing to a relatively confined fundamental parameter space. Current methods of cooling include external cooling devices, such as cooling blankets or ice bags, which are simple to use, relatively inexpensive but slow. Internal cooling has the best ability to cool more rapidly but current devices are more invasive, costly and most are still not able to provide cooling within the rapid 5-min interval. Cardiopulmonary bypass and recirculating coolants can achieve the cooling rate but are currently extremely invasive and require a highly skilled team to implement. Future therapies may include phase-change coolants, such as microparticulate ice-saline slurries or evaporative cooling technologies specifically designed for human use. With continuing research and investment, methods for rapid cooling can be developed and will translate into saving lives.
Laptook, A.R., Shalak, L. & Corbett, R.J.	Differences in brain temperature and cerebral blood flow during selective head versus whole-body cooling. [Abstract]	2001	Pediatrics Vol. 108(5), pp. 1103-1110	article
Abstract: OBJECTIVE: To compare brain temperature and cerebral blood flow (CBF) during head and body cooling, with and without systemic hypoxemia. METHODS: Seventeen newborn swine were studied for either measurement of brain temperature alone (n = 9) or measurement of brain temperature and CBF (n = 8). All animals were ventilated and instrumented, and temperature probes were inserted into the rectum, into the brain at depths of 2 and 1 cm from the cortical surface, and on the dural surface. Blood flow was measured with microspheres. The protocol consisted of a control period, an interval of either head or body cooling, and cooling with 15 minutes of superimposed hypoxia. After a 1-hour recovery period, animals were exposed to the same sequence except that the alternate mode of cooling was evaluated. RESULTS: Head cooling with a constant rectal temperature resulted in an increase in the temperature gradient across the brain from the warmer central structures to the cooler periphery (brain 2 cm - dura temperature: 1.3 +/- 1.1 degrees C at control to 7.5 +/- 3.5 degrees C during cooling). Hypoxia superimposed on head cooling decreased the temperature gradient by at least 50 In contrast, body cooling was associated with an unchanged temperature gradient across the brain (brain 2 cm - dura temperature: 1.5 +/- 1.2 degrees C at control to 1.1 +/- 0.9 degrees C during cooling). Hypoxia superimposed on body cooling did not change brain temperature. Both modes of brain cooling resulted in similar reductions of global CBF ( approximately 40 and O(2) uptake. CONCLUSION: Brain hypothermia achieved through head or body cooling results in different brain temperature gradients. Alterations in systemic variables (ie, hypoxemia) alters brain temperature differently in these 2 modes of brain cooling. The mode of brain cooling may affect the efficacy of modest hypothermia as a neuroprotective therapy.
Laver, S.R., Padkin, A., Atalla, A. & Nolan, J.P.	Therapeutic hypothermia after cardiac arrest: a survey of practice in intensive care units in the United Kingdom. [Abstract]	2006	Anaesthesia Vol. 61(9), pp. 873-877	article	DOI
Abstract: A telephone survey was carried out on the use of hypothermia as part of the management of unconscious patients following cardiac arrest admitted to United Kingdom (UK) intensive care units (ICUs). All 256 UK ICUs listed in the Critical Care Services Manual 2004 were contacted to determine how many units have implemented therapeutic hypothermia for unconscious patients admitted following cardiac arrest, how it is implemented, and the reasons for non-implementation. Two hundred and forty-six (98.4 ICUs agreed to participate. Sixty-seven (28.4 ICUs have cooled patients after cardiac arrest, although the majority of these have treated fewer than 10 patients. The commonest reasons given for not using therapeutic hypothermia in this situation are logistical or resource issues, or the perceived lack of evidence or consensus within individual ICU teams.
Leeuwen, G.M.V., Hand, J.W., Lagendijk, J.J., Azzopardi, D.V. & Edwards, A.D.	Numerical modeling of temperature distributions within the neonatal head. [Abstract]	2000	Pediatr Res Vol. 48(3), pp. 351-356	article
Abstract: Introduction of hypothermia therapy as a neuroprotection therapy after hypoxia-ischemia in newborn infants requires appraisal of cooling methods. In this numerical study thermal simulations were performed to test the hypothesis that cooling of the surface of the cranium by the application of a cooling bonnet significantly reduces deep brain temperature and produces a temperature differential between the deep brain and the body core. A realistic three-dimensional (3-D) computer model of infant head anatomy was used, derived from magnetic resonance data from a newborn infant. Temperature distributions were calculated using the Pennes heatsink model. The cooling bonnet was at a constant temperature of 10 degrees C. When modeling head cooling only, a constant body core temperature of 37 degrees C was imposed. The computed result showed no significant cooling of the deep brain regions, only the very superficial regions of the brain are cooled to temperatures of 33-34 degrees C. Poor efficacy of head cooling was still found after a considerable increase in the modeled thermal conductivities of the skin and skull, or after a decrease in perfusion. The results for the heatsink thermal model of the infant head were confirmed by comparison of results computed for a scaled down adult head, using both the heatsink description and a discrete vessel thermal model with both anatomy and vasculature obtained from MR data. The results indicate that significant reduction in brain temperature will only be achieved if the infant's core temperature is lowered.
Liu, W.G., Qiu, W.S., Zhang, Y., Wang, W.M., Lu, F. & Yang, X.F.	Effects of selective brain cooling in patients with severe traumatic brain injury: a preliminary study. [Abstract]	2006	J Int Med Res Vol. 34(1), pp. 58-64	article
Abstract: We prospectively investigated non-invasive selective brain cooling (SBC) in patients with severe traumatic brain injury. Sixty-six in-patients were randomized into three groups. In one group, brain temperature was maintained at 33 - 35 degrees C by cooling the head and neck (SBC); in a second group, mild systemic hypothermia (MSH; rectal temperature 33 - 35 degrees C) was produced with a cooling blanket; and a control group was not exposed to hypothermia. Natural rewarming began after 3 days. Mean intracranial pressure 24, 48 or 72 h after injury was significantly lower in the SBC group than in the control group. Mean serum superoxide dismutase levels on Days 3 and 7 after injury in the SBC and MSH groups were significantly higher than in the control group. The percentage of patients with a good neurological outcome 2 years after injury was 72.7 57.1% and 34.8% in the SBC, MSH and control groups, respectively. Complications were managed without severe sequelae. Non-invasive SBC was safe and effective.
Manole, M.D., Kochanek, P.M., Fink, E.L. & Clark, R.S.B.	Postcardiac arrest syndrome: focus on the brain. [Abstract]	2009	Curr Opin Pediatr Vol. 21(6), pp. 745-750	article	DOI
Abstract: PURPOSE OF REVIEW: The field of pediatric cardiac arrest experienced recent advances secondary to multicenter collaborations. This review summarizes developments during the last year and identifies areas for further research. RECENT FINDINGS: A large retrospective review demonstrated important differences in cause, severity, and outcome of in-hospital vs. out-of-hospital pediatric cardiac arrest. This distinction is relevant to interpretation of retrospective studies that may not distinguish between these entities, and in planning therapeutic clinical trials. Hypothermia was further evaluated as a treatment strategy after neonatal hypoxia and leaders in the field of neonatology recommend universal use of hypothermia in term neonates at risk. In infants and children after cardiac arrest, there are inadequate data to make a specific recommendation. Two retrospective studies evaluating hypothermia in children after cardiac arrest found that it tended to be administered more frequently to sicker patients. However, similar or worse outcomes of patients treated with hypothermia were observed. Use of extracorporeal membrane oxygenation is another emerging area of research in pediatric cardiac arrest, and surprisingly good outcomes have been seen with this modality in some cases. SUMMARY: Therapeutic hypothermia and extracorporeal membrane oxygenation continue to be the only treatment modalities over and above conventional care for pediatric cardiac arrest. New approaches to monitoring, treatment, and rehabilitation after cardiac arrest remain to be explored.
Mariak, Z., White, M.D., Lewko, J., Lyson, T. & Piekarski, P.	Direct cooling of the human brain by heat loss from the upper respiratory tract. [Abstract]	1999	J Appl Physiol Vol. 87(5), pp. 1609-1613	article
Abstract: This study is the first report on human intracranial temperature in conscious patients during and after an upper respiratory bypass. Temperatures were measured in four subjects subdurally between the frontal lobes and cribriform plate (T(cr)) and on the vault of the skull (T(sd)). Further measurements were taken in the esophagus (T(es)) and on the tympanic membrane. Reinstitution of airflow in the upper respiratory tract under conditions of mild hyperthermia gave a rapid drop in T(cr) of 0.4-0.8 degrees C. In three patients the intracranial temperature at the basal aspect of the frontal lobes fell below T(es). Thus local selective cooling of the brain surface below that of the trunk temperature was shown to occur. Intensive breathing by the patients after extubation for a 3-min period produced a cooling at the site of T(cr) measurement at a rate of up to 0.1 degrees C/min, and this response could be evoked on demand. The results support the view that cooling of the upper airway can directly influence human brain temperature.
Marion, D.W.	Controlled normothermia in neurologic intensive care. [Abstract]	2004	Crit Care Med Vol. 32(2 Suppl), pp. S43-S45	article
Abstract: Preclinical studies of cerebral ischemia and trauma find increased brain tissue injury and worsened functional outcomes if the brain temperature exceeds 39 degrees C. Several retrospective studies of patients with new-onset stroke, intracerebral hemorrhage, or subarachnoid hemorrhage support these observations. However, fever is very common among these patients early after the onset of their disease, particularly if they are in the ICU for a week or more, and brain temperatures are likely to be as much as 2 degrees C higher than rectal temperatures. Finally, intravascular temperature modulation has been shown to be more effective for preventing fever than conventional methods, such as antipyretic medications or surface-cooling techniques. Further study is needed to establish if such better control of temperature will lead to improved outcomes.
Marion, D.W.	Fever in the neuro ICU: current prevention methods are inadequate.	1999		booklet
McDonagh, D.L., Allen, I.N., Keifer, J.C. & Warner, D.S.	Induction of hypothermia after intraoperative hypoxic brain insult. [Abstract]	2006	Anesth Analg Vol. 103(1), pp. 180-1, table of contents	article	DOI
Abstract: Hypoxic brain injury can be a devastating complication of anesthesia. Fortunately, it has become increasingly rare. Here we report a case of suspected intraoperative hypoxic brain injury treated with moderate hypothermia. Anesthesiologists should be aware of the option of using this therapy and how to employ it in the setting of suspected hypoxic brain injury.
McIntyre, L.A., Fergusson, D.A., Hébert, P.C., Moher, D. & Hutchison, J.S.	Prolonged therapeutic hypothermia after traumatic brain injury in adults: a systematic review. [Abstract]	2003	JAMA Vol. 289(22), pp. 2992-2999	article	DOI
Abstract: CONTEXT: The benefits of therapeutic hypothermia as a treatment for traumatic brain injury (TBI) remain unclear. OBJECTIVE: To explore the effects of depth, duration, and rate of rewarming after discontinuation of hypothermia on mortality and neurologic outcome in adults after TBI. DATA SOURCES: An electronic search of MEDLINE (OVID), EMBASE, Current Contents, the Cochrane library and a hand search of key journals were performed. Corresponding authors of identified studies were contacted for additional unpublished or ongoing clinical trials. STUDY SELECTION: All randomized controlled trials of therapeutic hypothermia for at least 24 hours vs normothermia in adults with TBI. DATA EXTRACTION: Demographic and clinical data, hypothermia interventions and cointerventions, mortality and neurologic outcomes, and methodological quality were abstracted by 2 independent reviewers. DATA SYNTHESIS: Twelve trials met eligibility criteria and were included in the analysis. We also performed subanalyses by different hypothermia interventions (ie, depth, duration, and rapidity of rewarming after hypothermia) and methodological quality. Therapeutic hypothermia was associated with a 19% reduction in the risk of death (95% confidence interval [CI], 0.69-0.96) and a 22% reduction in the risk of poor neurologic outcome (95% CI, 0.63-0.98) compared with normothermia. Hypothermia longer than 48 hours was associated with a reduction in the risks of death and of poor neurologic outcome (relative risk [RR], 0.70; 95% CI, 0.56-0.87 and RR, 0.65; 95% CI, 0.48-0.89, respectively) compared with normothermia. Hypothermia to a target temperature between 32 degrees C and 33 degrees C, a duration of 24 hours, and rewarming within 24 hours were all associated with reduced risks of poor neurologic outcome compared with normothermia. Assessment of methodological quality did not reveal evidence of bias. CONCLUSIONS: Therapeutic hypothermia may reduce the risks of mortality and poor neurologic outcome in adults with TBI. Outcomes were influenced, however, by depth and duration of hypothermia as well as rate of rewarming (
Merchant, R.M., Soar, J., Skrifvars, M.B., Silfvast, T., Edelson, D.P., Ahmad, F., Huang, K.-N., Khan, M., Hoek, T.L.V., Becker, L.B. & Abella, B.S.	Therapeutic hypothermia utilization among physicians after resuscitation from cardiac arrest. [Abstract]	2006	Crit Care Med Vol. 34(7), pp. 1935-1940	article	DOI
Abstract: OBJECTIVE: We sought to evaluate current physician use of therapeutic hypothermia after cardiac arrest, to ascertain reasons for nonadoption of this treatment, and to determine current cooling techniques employed. DESIGN: Web-based survey. SETTING: International physician cohort in the United States, UK, and Finland. SUBJECTS: Physicians (MD or DO) caring for resuscitated cardiac arrest patients. INTERVENTIONS: An anonymous Web-based survey was distributed to physicians identified through United States-based critical care, cardiology, and emergency medicine directories and critical care networks in the UK and Finland. Recipients were queried regarding use of postresuscitation therapeutic hypothermia. MEASUREMENTS AND MAIN RESULTS: Of the final 13,272 surveys actually distributed to physicians, 2,248 (17 were completed. Most respondents were attending physicians (82 at teaching hospitals (76 who practiced critical care (35, cardiology (20, or emergency medicine (22. Of all replies, 74% of United States respondents and 64% of non-United States respondents had never used therapeutic hypothermia. United States emergency medicine physician adoption of cooling was significantly less than that of United States intensivists (16% vs. 34 p < .05). The most often cited reasons for nonuse by respondents were "not enough data," "not part of Advanced Cardiac Life Support guidelines," and "too technically difficult to use." Factors associated with increased use included non-United States residence, critical care specialty, and larger hospital size. CONCLUSIONS: Physician utilization of cooling after cardiac arrest remains low. For improved adoption of therapeutic hypothermia, our data suggest that development of better cooling methodology and recent incorporation into resuscitation guidelines may improve use.
Michenfelder, J.D.	A valid demonstration of barbiturate-induced brain protection in man--at last. [Abstract]	1986	Anesthesiology Vol. 64(2), pp. 140-142	article
Abstract: [extract] T0 MY KNOWLEDGE, there are only three definitive valid studies in man that have examined for possible brain protection induced by barbiturate therapy in three very different clinical circumstances. Abramson et aI. reported in an abstract that a randomized clinical trial of thiopental therapy following cardiac arrest failed to demonstrate even a suggestion of improved outcome. Ward el al. reported that randomized pentobarbital therapy in acute head-injury patients also failed to yield even a suggestion of improved outcome. While, in this issue, Nussmier et al. demonstrate that randomized thiopental therapy during certain cardiopulmonary bypass procedures does improve neuropsychiatric ...
Mrlian, A., Smrcka, M. & Klabusay, M.	The use of controlled mild hypothermia and immune system status in patients with severe brain injury. [Abstract]	2006	Bratisl Lek Listy Vol. 107(4), pp. 113-117	article
Abstract: INTRODUCTION: Severe brain injuries pose one of the most important problems on our health care because of their high morbidity and mortality. MATERIAL AND METHODS: A group of 89 patients after severe brain injury (Glasgow Coma Scale< or =8) was included into our research of detecting the changes of immune system parameters and their relation to the application of mild hypothermia during the early period after the insult. RESULTS: In both of the groups CD3+ and CD4+ lymphocytic levels decreased significantly after the insult and gradually got to normal (p<0.01). The NK cells levels have changed in correlation with the course of infection. Immunoglobulin (IgA, IgG) levels were normal or slightly increased. IgM levels changes had a close relation to the occurrence of inflammatory complications, especially that of pneumonia (p<0.01). The most surprising moment in our research was the level of IgE antibodies. They had been high and got even higher. They achieved the values typical for atopic reactions or parasitic diseases. 77.52 % of the patients with decreased parameters of immune system developed extra cranial complications. Immune system disorders appeared more frequently in the patients with lower Glasgow Coma Scale after admission (p<0.01). The application of mild hypothermia caused an unimportant increase in extra cranial complications (p>0.05) having no relation to immunity disorders. CONCLUSION: Intensive treatment of intracranial hypertension fundamentally affects results of our treatment (Glasgow Outcome Score). The application of controlled mild hypothermia doesn't escalate the occurrence of extra cranial inflammatory complications after severe brain injury (Tab. 2, Fig. 11, Ref. 15).
Murthy, H.S., Chidanandaswamy, M.N., Rao, G.S.U. & Kolluri, S.	Spontaneous intraoperative hypothermia and cerebral protection in aneurysmal subarachnoid hemorrhage. [Abstract]	2005	Middle East J Anesthesiol Vol. 18(2), pp. 313-332	article
Abstract: BACKGROUND: In patients with aneurysmal subarachnoid hemorrhage (SAH), a trend towards cerebral protection has been demonstrated with intraoperative mild hypothermia. Mild to moderate spontaneous hypothermia occurs intraoperatively if no active measures are taken to warm the patient. The present study investigated the cerebral protective role of such spontaneous intraoperative hypothermia in patients with aneurysmal SAH. METHODS: In 50 patients undergoing surgery for aneurysmal subarachnoid hemorrhage, nasopharyngeal temperatures were monitored from the time of endotracheal intubation till the end of surgery. The patients were observed for any neurological deterioration during the first 24 h postoperatively. The temperatures of the deteriorated and nondeteriorated patients, at different stages during surgery, were compared. RESULTS: Ten out of the 50 patients showed neurological deterioration within the first 24 h after surgery. The nondeteriorated patients had significantly lower nasopharyngeal temperatures compared to the deteriorated group at the time of dural opening, temporary vessel occlusion (TVO), dural closure and the end of surgery (p < or = 0.05). They also had a significantly lower temperature for 2 h starting from the time of temporary vessel occlusion (p < or = 0.05). When the patients were divided into hypothermic (< 34.5 degrees C) and normothermic groups (> 34.5 degrees C) on the basis of their nasopharyngeal temperature at the time of TVO, the normothermic group tended to have a higher incidence of postoperative neurological deterioration (p = 0.07). When the aneurysms were classified according to their anatomical location, a significant intraoperative temperature difference between the deteriorated and nondeteriorated groups was evident only in patients with anterior communicating artery aneurysms (p < or = 0.02) and not others. Infective complications were more frequent in hypothermic patients (p = 0.02). CONCLUSIONS: The findings of the current study suggest that mild spontaneous intraoperative hypothermia offers cerebral protection in patients undergoing surgery for aneurysmal subarachnoid hemorrhage. This protective role of seems to be related to the anatomical location of the aneurysm.
Mégarbane, B., Résière, D., Delahaye, A. & Baud, F.J.	Endovascular hypothermia for heat stroke: a case report. [Abstract]	2004	Intensive Care Med Vol. 30(1), pp. 170	article	DOI
Abstract: [extract] Sir: During August 2003, a historical heat wave was registered in France, with several thousands of deaths. Heat stroke may result in central nervous system dysfunction and life-threatening multi-organ injury [1]. Lowering the body temperature is the corner therapy, in association with supportive care. We report a case of a severely hyperthermic patient successfully treated with endovascular cooling. A 52-year-old baker was admitted for hyperthermia (43°C), coma (GCS: 3) and hypotension (90/51 mmHg, heart rate: 160/min). He was found unconscious near his furnace, promptly intubated and transferred to our ICU. He was obese (BMI: 37 kg/m2), but had no significant ...
Nolan, J.P., Morley, P.T., Hoek, T.L.V., Hickey, R.W., Kloeck, W.G.J., Billi, J., Böttiger, B.W., Morley, P.T., Nolan, J.P., Okada, K., Reyes, C., Shuster, M., Steen, P.A., Weil, M.H., Wenzel, V., Hickey, R.W., Carli, P., Hoek, T.L.V., Atkins, D. & on Resuscitation, I.L.C.	Therapeutic hypothermia after cardiac arrest: an advisory statement by the advanced life support task force of the International Liaison Committee on Resuscitation. [Abstract]	2003	Circulation Vol. 108(1), pp. 118-121	article	DOI
Abstract: [extract] On the basis of the published evidence to date, the Advanced Life Support (ALS) Task Force of the International Liaison Committee on Resuscitation (ILCOR) made the following recommendations in October 2002: Unconscious adult patients with spontaneous circulation after out-of-hospital cardiac arrest should be cooled to 32°C to 34°C for 12 to 24 hours when the initial rhythm was ventricular fibrillation (VF). Such cooling may also be beneficial for other rhythms or in-hospital cardiac arrest. Introduction. Induction of moderate hypothermia (28°C to 32°C) before cardiac arrest has been used successfully since the 1950s to protect the brain against the global ischemia ...
Oda, J., Kuwagata, Y., Nakamori, Y., Noborio, M., Hayakata, T., Fujimi, S. & Sugimoto, H.	Mild hypothermia alters the oxygen consumption/delivery relationship by decreasing the slope of the supply-dependent line. [Abstract]	2002	Crit Care Med Vol. 30(7), pp. 1535-1540	article
Abstract: OBJECTIVE: To evaluate the effect of mild hypothermia on the relationship between systemic oxygen consumption and oxygen delivery. DESIGN: Prospective animal study. SETTING: University research laboratory. SUBJECTS: Anesthetized and ventilated rabbits. INTERVENTIONS: Rabbits were subjected to stepwise cardiac tamponade to reduce oxygen delivery while body temperature was maintained at 34 degrees C (group H, n = 8) or 39 degrees C (group N, n = 8). MEASUREMENTS AND MAIN RESULTS: The oxygen consumption/oxygen delivery relationship was analyzed by the dual-line method. The slope of the supply-dependent line was significantly decreased in group H (y = 0.57x + 1.3) compared with that in group N (y = 0.72x + 1.7), indicating that the ability of tissues to extract oxygen was impaired during hypothermia. Consequently, the proportion of the supply-independent area over the entire range of oxygen delivery was decreased in response to hypothermia. CONCLUSION: The potential for tissue hypoxia is likely to be increased during hypothermia when the circulation becomes unstable and oxygen delivery decreases.
Oddo, M., Schaller, M.-D., Feihl, F., Ribordy, V. & Liaudet, L.	From evidence to clinical practice: effective implementation of therapeutic hypothermia to improve patient outcome after cardiac arrest. [Abstract]	2006	Crit Care Med Vol. 34(7), pp. 1865-1873	article	DOI
Abstract: OBJECTIVES: Therapeutic hypothermia has been recommended for postcardiac arrest coma due to ventricular fibrillation. However, no studies have evaluated whether therapeutic hypothermia could be effectively implemented in intensive care practice and whether it would improve the outcome of all comatose patients with cardiac arrest, including those with shock or with cardiac arrest due to nonventricular fibrillation rhythms. DESIGN: Retrospective study. SETTING: Fourteen-bed medical intensive care unit in a university hospital. PATIENTS: Patients were 109 comatose patients with out-of-hospital cardiac arrest due to ventricular fibrillation and nonventricular fibrillation rhythms (asystole/pulseless electrical activity). INTERVENTIONS: We analyzed 55 consecutive patients (June 2002 to December 2004) treated with therapeutic hypothermia (to a central target temperature of 33 degrees C, using external cooling). Fifty-four consecutive patients (June 1999 to May 2002) treated with standard resuscitation served as controls. Efficacy, safety, and outcome at hospital discharge were assessed. Good outcome was defined as Glasgow-Pittsburgh Cerebral Performance category 1 or 2. MEASUREMENTS AND MAIN RESULTS: In patients treated with therapeutic hypothermia, the median time to reach the target temperature was 5 hrs, with a progressive reduction over the 18 months of data collection. Therapeutic hypothermia had a major positive impact on the outcome of patients with cardiac arrest due to ventricular fibrillation (good outcome in 24 of 43 patients [55.8 of the therapeutic hypothermia group vs. 11 of 43 patients [25.6 of the standard resuscitation group, p = .004). The benefit of therapeutic hypothermia was also maintained in patients with shock (good outcome in five of 17 patients of the therapeutic hypothermia group vs. zero of 14 of the standard resuscitation group, p = .027). The outcome after cardiac arrest due to nonventricular fibrillation rhythms was poor and did not differ significantly between the two groups. Therapeutic hypothermia was of particular benefit in patients with short duration of cardiac arrest (<30 mins). CONCLUSIONS: Therapeutic hypothermia for the treatment of postcardiac arrest coma can be successfully implemented in intensive care practice with a major benefit on patient outcome, which appeared to be related to the type and the duration of initial cardiac arrest and seemed maintained in patients with shock.
Orliaguet, G.A., Meyer, P.G. & Baugnon, T.	Management of critically ill children with traumatic brain injury. [Abstract]	2008	Paediatr Anaesth Vol. 18(6), pp. 455-461	article	DOI
Abstract: The management of critically ill children with traumatic brain injury (TBI) requires a precise assessment of the brain lesions but also of potentially associated extra-cranial injuries. Children with severe TBI should be treated in a pediatric trauma center, if possible. Initial assessment relies mainly upon clinical examination, trans-cranial Doppler ultrasonography and body CT scan. Neurosurgical operations are rarely necessary in these patients, except in the case of a compressive subdural or epidural hematoma. On the other hand, one of the major goals of resuscitation in these children is aimed at protecting against secondary brain insults (SBI). SBI are mainly because of systemic hypotension, hypoxia, hypercarbia, anemia and hyperglycemia. Cerebral perfusion pressure (CPP = mean arterial blood pressure - intracranial pressure: ICP) should be monitored and optimized as soon as possible, taking into account age-related differences in optimal CPP goals. Different general maneuvers must be applied in these patients early during their treatment (control of fever, avoidance of jugular venous outflow obstruction, maintenance of adequate arterial oxygenation, normocarbia, sedation-analgesia and normovolemia). In the case of increased ICP and/or decreased CPP, first-tier ICP-specific treatments may be implemented, including cerebrospinal fluid drainage, if possible, osmotic therapy and moderate hyperventilation. In the case of refractory intracranial hypertension, second-tier therapy (profound hyperventilation with P(a)CO(2) < 35 mmHg, high-dose barbiturates, moderate hypothermia, decompressive craniectomy) may be introduced, after a new cerebral CT scan.
Otremba, W.	Einfluss milder Hypothermie auf das Outcome von reanimierten Patienten nach präklinischem Kreislauf-Stillstand. Referate.	1999	Notarzt Vol. 14, pp. A50	article
Park, W.S., Chang, Y.S. & Lee, M.	Effect of hypothermia on brain cell membrane function and energy metabolism after transient global hypoxia-ischemia in the newborn piglet. [Abstract]	2001	J Korean Med Sci Vol. 16(3), pp. 335-341	article
Abstract: This study was done to determine the effects of hypothermia on brain cell membrane function and energy metabolism after transient hypoxia-ischemia (HI) in the newborn piglet. Cerebral HI was induced by temporarily complete occlusion of bilateral common carotid arteries with surgical clips and simultaneous breathing with 8% oxygen for 30 min, followed by release of carotid occlusion and normoxic ventilation for 4 hr. Rectal temperature was maintained between 38.0 and 39.0 degrees C in normothermic groups, and between 34.0 and 35.0 degrees C in hypothermic groups for 4 hr after HI. During HI, heart rate, glucose and lactate level in the blood and cerebrospinal fluid increased, and base excess, pH and blood pressure decreased significantly in both normothermic and hypothermic groups. After HI, these abnormalities returned to normal in normothermic group, but lactic acidosis persisted in hypothermic group. Decreased cerebral Na+,K+- ATPase activity and increased lipid peroxidation products, indicative of HI- induced brain injury, were more profound in hypothermic group than in normothermic group. Brain ATP and phosphocreatine levels were not different between normothermic and hypothermic groups. In summary, hypothermia applied immediately after HI for 4 hr did not improve the recovery of brain cell membrane function and energy metabolism in the newborn piglet.
Park, W.S., Chang, Y.S. & Lee, M.	Effect of hypothermia on brain cell membrane function and energy metabolism in experimental Escherichia coli meningitis in the newborn piglet. [Abstract]	2001	Neurochem. Res. Vol. 26(4), pp. 369-374	article
Abstract: We evaluated the anti-inflammatory and neuroprotective effects of hypothermia during the early phase of experimental Escherichia coli meningitis in the newborn piglet. Hypothermia significantly attenuated the meningitis-induced acute inflammatory responses such as increased intracranial pressure, decreased glucose level, increased lactate concentration, increased tumor necrosis factor-alpha level and leukocytosis in the cerebrospinal fluid. Decreased cerebral cortical cell membrane Na+,K+-ATPase activity and increased lipid peroxidation products, indicative of meningitis-induced brain damage, were significantly improved with hypothermia. Hypothermia also significantly improved the meningitis-induced reduction in brain ATP and phosphocreatine levels. In summary, hypothermia significantly attenuated the acute inflammatory responses and the ensuing brain injury in experimental neonatal bacterial meningitis.
Perlman, J.M.	Brain injury in the term infant. [Abstract]	2004	Semin Perinatol Vol. 28(6), pp. 415-424	article
Abstract: Perinatal brain injury in the term infant is a relatively uncommon event. The principal lesions are intracranial hemorrhage including subarachnoid, subdural, intraparenchymal, intraventricular, focal cerebral infarction and hypoxic ischemic cerebral injury secondary to intrapartum hypoxia-ischemia. Both intracranial hemorrhage and focal cerebral infarction are invariably identified at the time of clinical symptoms, ie, seizures or apnea. This clearly limits the potential for prevention. The mechanisms contributing to brain injury secondary to intrapartum hypoxia-ischemia have become more clearly defined. Secondary or reperfusion injury is potentially amenable to neuroprotective strategies. Modest hypothermia is one such therapy that has been studied in high-risk newborn infants with some initial success. Future studies need to focus on additional neuroprotective strategies.
Polderman, K.H.	Hypothermia and neurological outcome after cardiac arrest: state of the art. [Abstract]	2008	Eur J Anaesthesiol Suppl Vol. 42, pp. 23-30	article	DOI
Abstract: Multi-centred studies in patients who remain comatose after cardiac arrest and also in newborn babies with perinatal asphyxia have clearly demonstrated that mild hypothermia (32-34 degrees C) can improve neurological outcome after post-anoxic injury. This represents a highly promising development in the field of neurocritical care. This review discusses the place of mild therapeutic hypothermia in the overall therapeutic strategy for cardiac arrest patients. Cooling should not be viewed in isolation but in the context of a 'treatment bundle,' which together can significantly improve outcome after cardiac arrest. Favourable outcomes of 50-60% are now routinely achieved in many centres in patients with witnessed arrest and an initial rhythm of ventricular fibrillation or ventricular tachycardia. These results have been achieved by combining a number of therapeutic strategies, including early and effective resuscitation with greater emphasis on continuing chest compressions throughout various procedures (including resumption of compressions immediately after defibrillation even if rhythm has been restored) as well as prevention of hypoxia and hypotension in all stages following restoration of spontaneous circulation. Regarding the use of hypothermia, early induction and proper management of side-effects are the key elements of successful implementation. Treatment should include the rapid infusion of 1500-3000 mL of cold fluids to induce hypothermia and prevent hypovolaemia and hypotension. Educational activities to increase awareness and acceptance of new therapeutic options and European Resuscitation Council guidelines are urgently required.
Polderman, K.H.	Can controlled therapeutic hypothermia act as a neuroprotective in severely head-injured patients?	2003	Internat J Intensive Care Med Vol. 10, pp. 121-128	article
Reith, A. & Pfenninger, E.	[Limits of cerebral resuscitation. Pathophysiologic background and therapeutic approaches]	1992	Anasthesiol Intensivmed Notfallmed Schmerzther Vol. 27(4), pp. 238-243	article
Rohrbach, K., Hindinger, D., Holzer, M. & Sterz, F.	Anasthesie und Intensivpflege - Milde Hypothermie nach Herzstillstand und erfolgreicher Reanimation.	1999	Schwest/Pfleg Vol. 38(6), pp. 494-498	article
Safar, P. & Sterz, F.	Mild hypothermic cardiopulmonary resuscitation. [Abstract]	1991	Crit Care Med Vol. 19(9), pp. 1217	article
Abstract: [extract] To the Editor: We thank Drs. Weil and Gazmuri (l) for their editorial on our paper (2). We agree that these studies “should be used to trigger additional investigations" We do not agree that mechanisms of potentially effective treatments must be clarified before their clinical use. Had this been a rule, humanity would not have benefited from anesthetics, insulin, corticosteroids, antibiotics. and other medical breakthroughs. Even the mechanism of therapeutic hypothermia is unknown, but is probably a synergism of several potentially beneficial elects (3). Therapeutic hypothermia cannot be explained merely by the reduction of oxygen demand ...
Safar, P.J. & Kochanek, P.M.	Therapeutic hypothermia after cardiac arrest. [Abstract]	2002	N. Engl. J. Med. Vol. 346(8), pp. 612-613	article	DOI
Abstract: [extract] In this issue of the Journal, the reported results of two randomized clinical trials, one in Australia [1] and the other in Europe, [2] showed a neurologic benefit of mild therapeutic hypothermia (33 degreesC in the first study and 32 degreesC to 34 degreesC in the second) in survivors of out-of-hospital cardiac arrest. [3] In the Australian study, which involved a total of 77 patients who remained comatose after the restoration of spontaneous circulation, 49 percent of those treated with hypothermia were discharged home or to a rehabilitation facility, as compared with 26 percent of those not treated with ...
Sahuquillo, J., Poca, M.A. & Amoros, S.	Current aspects of pathophysiology and cell dysfunction after severe head injury. [Abstract]	2001	Curr. Pharm. Des. Vol. 7(15), pp. 1475-1503	article
Abstract: Traumatic brain injury is a major health problem in all developed countries. The main aim of this review is to provide a short update on the most recent advances in our knowledge of the brains response to mechanical injuries, focusing on metabolic, cellular, subcellular, and molecular events that take place in severe head injuries. Knowledge of these events is essential for a better understanding of new pharmacological avenues and non-pharmacological strategies, such as moderate hypothermia, which are being developed to improve the outcome of this silent epidemic. We will focus on several topics that we consider to be the most significant: diffuse axonal injury, ischemia and the cascades it generates, metabolic derangements, excitotoxicity, oxidative stress, and other phenomena that have been included in the term tertiary injuries. Recent evidence has clearly demonstrated that traumatic brain lesions are highly dynamic and that the different lesions observed after closed head injury are not single events but processes set in motion by the mechanical impact. These processes are not finished until an unpredictable time after injury. We will discuss recent evidence showing that in diffuse axonal injury, primary immediate damage can coexist with axons that, although initially intact, may be evolving towards secondary disconnection. The concept of ischemic penumbra and the more recent concept of traumatic penumbra are discussed, together with recent experimental and clinical data that shed light on the non-ischemic forms of brain hypoxia. The role of excitotoxicity in mechanically-induced cell death and the molecular events that excessive release of glutamate induce, including apoptosis and delayed inflammatory processes, are reviewed. Finally, new knowledge on how central nervous system cells regulate their volume, the new family of channel water molecules known as aquaporins and their possible role in the physiopathology of the swollen brain are discussed. Basic and clinical investigations are still needed to translate the huge amount of pathophysiological knowledge acquired in the last decade into effective treatments for these patients.
Sahuquillo, J. & Vilalta, A.	Cooling the injured brain: how does moderate hypothermia influence the pathophysiology of traumatic brain injury. [Abstract]	2007	Curr. Pharm. Des. Vol. 13(22), pp. 2310-2322	article
Abstract: Neither any neuroprotective drug has been shown to be beneficial in improving the outcome of severe traumatic brain injury (TBI) nor has any prophylactically-induced moderate hypothermia shown any beneficial effect on outcome in severe TBI, despite the optimism generated by preclinical studies. This contrasts with the paradox that hypothermia still is the most powerful neuroprotective method in experimental models because of its ability to influence the multiple biochemical cascades that are set in motion after TBI. The aim of this short review is to highlight the most recent developments concerning the pathophysiology of severe TBI, to review new data on thermoregulation and induced hypothermia, the regulation of core and brain temperature in mammals and the multiplicity of effects of hypothermia in the pathophysiology of TBI. Many experimental studies in the last decade have again confirmed that moderate hypothermia confers protection against ischemic and non-ischemic brain hypoxia, traumatic brain injury, anoxic injury following resuscitation after cardiac arrest and other neurological insults. Many posttraumatic adverse events that occur in the injured brain at a cellular and molecular level are highly temperature-sensitive and are thus a good target for induced hypothermia. The basic mechanisms through which hypothermia protects the brain are clearly multifactorial and include at least the following: reduction in brain metabolic rate, effects on cerebral blood flow, reduction of the critical threshold for oxygen delivery, blockade of excitotoxic mechanisms, calcium antagonism, preservation of protein synthesis, reduction of brain thermopooling, a decrease in edema formation, modulation of the inflammatory response, neuroprotection of the white matter and modulation of apoptotic cell death. The new developments discussed in this review indicate that, by targeting many of the abnormal neurochemical cascades initiated after TBI, induced hypothermia may modulate neurotoxicity and, consequently, may play a unique role in opening up new therapeutic avenues for treating severe TBI and improving its devastating effects. Furthermore, greater understanding of the pathophysiology of TBI, new data from both basic and clinical research, the good clinical results obtained in randomized clinical trials in cardiac arrest and better and more reliable cooling methods have given hypothermia a second chance in treating TBI patients. A critical evaluation of hypothermia is therefore mandatory to elucidate the reasons for previous failures and to design further multicenter randomized clinical trials that would definitively confirm or refute the potential of this therapeutic modality in the management of severe traumatic brain injuries.
Schmutzhard, E., Beer, R., Brössner, G. & Pfausler, B.	Prophylactic normothermia - a new concept with innovative technology.	2003	Internat J Intensive Care Med Vol. 10(1), pp. 21-24	article
Schmutzhard, E., Engelhardt, K., Beer, R., Brössner, G., Pfausler, B., Spiss, H., Unterberger, I. & Kampfl, A.	Safety and efficacy of a novel intravascular cooling device to control body temperature in neurologic intensive care patients: a prospective pilot study. [Abstract]	2002	Crit Care Med Vol. 30(11), pp. 2481-2488	article	DOI
Abstract: OBJECTIVE: To determine the safety and efficacy of a novel intravascular cooling device (Cool Line catheter with Cool Gard system) to control body temperature (temperature goal <37 degrees C) in neurologic intensive care patients. DESIGN: A prospective, uncontrolled pilot study in 51 consecutive neurologic intensive care patients. SETTING: A neurologic intensive care unit at a tertiary care university hospital. PARTICIPANTS: Patients were 51 neurologic intensive care patients with an intracranial disease requiring a central venous catheter due to the primary (intracranial) disease. We excluded patients under the age of 19 yrs and those with active cardiac arrhythmia, full sepsis syndrome, bleeding diathesis and infection, or bleeding at the site of the intended catheter insertion. Male to female ratio was 31:20, and the median age was 55 yrs (range, 24-85 yrs). Forty-four of 51 patients (86.3 had an initial Glasgow Coma Scale score of 3, three patients had a Glasgow Coma Scale score of 9, one patient presented with an initial Glasgow Coma Scale score of 11, two patients had an initial Glasgow Coma Scale score of 13, and one patient had an initial Glasgow Coma Scale score of 15. The mean initial tissue injury severity score was 45.1 and the median initial tissue injury severity score 45.0 (range, 19-70). INTERVENTIONS: Patients were enrolled prospectively in a consecutive way. Within 12 hrs after admission, the intravascular cooling device (Cool Line catheter) was placed, the temperature probe was located within the bladder (by Foley catheter), and the Cool Gard cooling device was initiated. This Cool Gard system circulates temperature-controlled sterile saline through two small balloons mounted on the distal end of the Cool Line catheter. The patient's blood is gently cooled as it is passed over the balloons. The Cool Gard system has been set with a target temperature of 36.5 degrees C. The primary purpose and end point of this study was to evaluate the cooling capacity of this intravascular cooling device. Efficacy is expressed by the calculation formula of fever burden, which is defined as the fever time product ( degrees C hours) under the fever curve. MEASUREMENTS AND MAIN RESULTS: The cooling device was in operation for a mean of 152.4 hrs. The ease of insertion was judged as easy in 42 of 51 patients; in a single patient, the catheter was malpositioned within the jugular vein, requiring early removal. The rate of infectious and noninfectious complications (nosocomial pneumonia, bacteremia, catheter-related ventriculitis, pulmonary embolism, etc.) was comparable to the rate usually observed in our neurologic intensive care patients with such severe intracranial diseases. The total fever burden within the entire study period of (on average) 152.4 hrs was 4.0 degrees C hrs/patient, being equivalent to 0.6 degrees C hrs/patient and day. Thirty of 51 patients showed an elevation of the body temperature (>37.9 degrees C) within 24 hrs after termination of the cooling study. One awake patient (subarachnoid hemorrhage, Glasgow Coma Scale score 15) experienced mild to moderate shivering throughout the entire period of 7 days. The mortality rate was 23.5 CONCLUSION: This novel intravascular cooling device (Cool Line catheter and Cool Gard cooling device) was highly efficacious in prophylactically controlling the body temperature of neurologic intensive care patients with very severe intracranial disease (median Glasgow Coma Scale score, 3-15). Morbidity and mortality rates were consistent with the ranges reported in the literature for such neurologic intensive patients.
Schneider, A., Popp, E. & Böttiger, B.W.	[Regulated hypothermia after cardiac arrest. A glimpse into the future] [Abstract]	2006	Anaesthesist Vol. 55(12), pp. 1247-1254	article	DOI
Abstract: The introduction of therapeutic mild hypothermia after cardiac arrest allows the neuronal damage caused by global cerebral ischemia to be advantageously influenced for the first time. Currently, hypothermia is induced by external or internal cooling of the patient (forced hypothermia). However, this results in activation of counter-regulation mechanisms which could be possible risk factors for the patient. The aim of this article is to give a review of possible, but at present only experimental, methods which could allow the body temperature set point to be decreased pharmacologically (regulated hypothermia). Various classes of substances will be discussed based on their effect on thermoregulation and their performance in animal experiments on cerebral ischemia.
Schwab, S.	Therapy of severe ischemic stroke: breaking the conventional thinking. [Abstract]	2005	Cerebrovasc Dis Vol. 20 Suppl 2, pp. 169-178	article	DOI
Abstract: Large hemispheric infarcts must be recognized in the emergency department as a life-threatening condition that requires prompt and massive intervention. After stabilization of the airway, breathing, and circulation, the initial diagnostic work-up and transfer to a neurointensive care unit should not be delayed. Today several new therapeutic options can be offered. Surgical decompression seems to be effective in lowering increased intracranial pressure, preventing transtentorial herniation and reducing mortality in patients with malignant middle cerebral artery infarction. Another option may be therapeutic hypothermia, which has been found to be neuroprotective in animal models, as well as in clinical studies after cardiac arrest. Experience in stroke patients suggest that hypothermia may offer a new approach for the treatment of acute cerebral ischemia.
Smrcka, M., Vidlák, M., Máca, K., Smrcka, V. & Gál, R.	The influence of mild hypothermia on ICP, CPP and outcome in patients with primary and secondary brain injury. [Abstract]	2005	Acta Neurochir Suppl Vol. 95, pp. 273-275	article
Abstract: Aim of this study was to examine the hypothesis that only a subgroup of patients with lesser primary brain damage after severe head injury may benefit from therapeutic hypothermia. We prospectively analysed 72 patients with severe head injury, randomized into groups with (n = 37) and without (n = 35) hypothermia of 34 degrees C maintained for 72 hours. The influence of hypothermia on ICP, CPP and neurological outcome was analysed in the context of the extent of primary brain damage. Patients with normothermia and primary lesions (n = 17) values: GCS on admission 5 (median), ICP 18.9 (mean), CPP 73 (mean), GOS 4 (median). Patients with normothermia and extracerebral hematomas (n = 20): GCS 4, ICP 16, CPP 71, GOS 3. Patients with hypothermia and primary lesions (n = 21): GCS 4,62, ICP 10, 81, CPP 78,1, GOS 4. Patients with hypothermia and extracerebral hematomas (n = 14): GCS 5, ICP 13.2, CPP 78, GOS 5. Hypothermia decreased ICP and increased CPP regardless of the type of brain injury. Hypothermia was not able to improve outcome in patients with primary brain lesions but this pilot study suggests that it significantly improves outcome in patients with extracerebral hematomas.
Sterz, F. & Holzer, M.	Resucitative hypothermia after cardiac arrest. Annual meeting handout. [PDF]	2003	Acad Emerg Med Vol. 1, pp. 1-4	article
Sterz, F. & Zeiner, A.	[hypothermia for resuscitation]	1996	Anasthesiol Intensivmed Notfallmed Schmerzther Vol. 33(1), pp. 57-66	article
Sterz, F., Zeiner, A., Kürkciyan, I., Janata, K., Müllner, M., Domanovits, H. & Safar, P.	Mild resuscitative hypothermia and outcome after cardiopulmonary resuscitation. [Abstract]	1996	J Neurosurg Anesthesiol Vol. 8(1), pp. 88-96	article
Abstract: Recovery without residual neurological damage after cardiac arrest with global cerebral ischemia is still a rare event. Severe impairment of bodily or cognitive functions is often the result. The individual, emotional, and social aspects of brain damage and rehabilitation are seldom taken into account. Efforts to improve the prevention of brain damage immediately after successful resuscitation of patients are missing. The efficacy of hypothermia in preserving neurologic function when instituted before and during certain no-flow cardiovascular states has been well documented both clinically and experimentally since the 1950s. Most studies have used moderate (28-33 degrees C) to deep (20-28 degrees C) hypothermia to demonstrate these protective effects. Considering the use of hypothermia for preservation and resuscitation, the lack of controlled outcome trials, the long period of time required to reach therapeutic hypothermia, and the incidence of rewarming complications such as infection, arrhythmia, and coagulopathy have made it difficult to apply these methods to emergency situations such as cardiac arrest. Recent experimental evidence in dogs has shown that hypothermia induced after cardiac arrest does indeed mitigate the effects of the postresuscitation syndrome and improves neurologic function and reduces histologic brain damage. More importantly, such benefits can be demonstrated with mild (34-36 degrees C) hypothermia, thus minimizing complications and requiring less time for induction of hypothermia. Ice water nasal lavage, direct carotid infusion of cold fluids, use of a cooling helmet, and peritoneal cooling are promising techniques for clinical cerebral cooling. External auditory canal temperature (e.g., tympanic membrane temperature changes) could provide an approximation to brain temperatures. For accurate temperature monitoring, however, a central pulmonary artery thermistor probe should be inserted. Temperature monitoring is needed to avoid temperature < 30 degrees C. Mild hypothermia may prove to be an important and secure component for cerebral preservation and resuscitation during and after global ischemia; it may also prove to be a useful method of cerebral resuscitation after global ischemic states, thereby promoting the prevention of neuromental diseases.
Sunde, K.	Therapeutic hypothermia with endovascular cooling [PDF]	2004	Scand J Trauma Res Emerg Med Vol. 12, pp. 23-25	article
Sunde, K., Dunlop, O., Rostrup, M., Sandberg, M., Sjøholm, H. & Jacobsen, D.	Determination of prognosis after cardiac arrest may be more difficult after introduction of therapeutic hypothermia. [Abstract]	2006	Resuscitation Vol. 69(1), pp. 29-32	article	DOI
Abstract: A 50-year-old patient had status epilepticus and no adequate reactions nine days after prolonged out-of-hospital cardiac arrest. The cause of the arrest was acute myocardial infarction which was treated successfully with percutaneous cardiac intervention (PCI) and a stent placement. He was treated with therapeutic hypothermia (33 degrees C) for 24h and in intensive care with respiratory support for 42 days. One year later he has fully recovered and is back to normal life and academic work. The previously reported 100% prognosis of a poor neurological outcome in the presence of seizures 72 h post arrest may need to be re-examined after introduction of therapeutic hypothermia.
Takino, M. & Okada, Y.	Hyperthermia following cardiopulmonary resuscitation. [Abstract]	1991	Intensive Care Med Vol. 17(7), pp. 419-420	article
Abstract: To clarify the clinical nature of post-resuscitation hyperthermia, we reviewed the charts of 18 patients who had cardiac arrest on arrival and regained cardiovascular stability for a study period of sufficient length. Patients with trauma, burns, poisoning and cerebrovascular accidents were excluded. We analyzed the hyperthermia (above 38 degrees C) occurring in the initial 48 h after resuscitation. After resuscitation, most patients showed a rapid rise in body temperature. Patients with later brain death showed significantly earlier appearance of hyperthermia (6.2 h after cardiac resuscitation; median) and a higher peak temperature (39.8 degrees C; median) compared with patients showing prolonged coma (12.7 h and 38.3 degrees C, respectively). Hyperthermia above 39 degrees C was associated with subsequent brain death. The incidence of factors influencing body temperature did not differ between the brain death and prolonged coma groups. Patients achieving full recovery did not show hyperthermia. In conclusion, hyperthermia is an early indicator of brain damage after resuscitation.
Taylor, D.L., Mehmet, H., Cady, E.B. & Edwards, A.D.	Improved neuroprotection with hypothermia delayed by 6 hours following cerebral hypoxia-ischemia in the 14-day-old rat. [Abstract]	2002	Pediatr Res Vol. 51(1), pp. 13-19	article
Abstract: Since hypothermia may be a potential treatment for perinatal cerebral hypoxic-ischemic injury, we used an established neonatal model of hypoxia-ischemia to determine the time after injury at which cooling had the best protective effect. Fourteen-day-old Wistar rats were subjected to right carotid artery ligation and hypoxia (8% O(2) for 90 min). Immediately at the end of hypoxia (defined as 0h), animals were either maintained at normal body temperature until sacrifice (normothermia) or subjected to hypothermia. In a preliminary study, the effects of a reduction in temperature and the duration of such cooling were investigated; animals were cooled (until brain temperature reached 33 degrees C or 30 degrees C) for 2, 4, or 6 h commencing immediately after hypoxia. In a second study, animals were cooled (brain temperature 30 degrees C) for 6 h commencing at either 0, 2, 4, or 6 h after the end of hypoxia. Sham-operated animals were used as controls. Twenty-four hours after hypoxia-ischemia, cerebral energy metabolism was measured by phosphorus magnetic resonance spectroscopy, and at 5 d cerebral infarction was measured by planimetry. In normothermic animals the ratio of phosphocreatine/inorganic phosphate (PCr/Pi) had fallen markedly 24 h following hypoxia-ischemia. In contrast, animals cooled between 6 and 12 h displayed high PCr/Pi ratios similar to those in control animals. Similarly, after 5 d, infarct area was significantly reduced only in animals cooled between 6 and 12 h after injury. These results indicate that cooling between 6 and 12 h after hypoxia-ischemia is more effective in reducing cerebral injury than other cooling regimes and suggest that the physiologic events during this period are critical for understanding cerebral infarction.
Thoresen, M., Satas, S., Løberg, E.M., Whitelaw, A., Acolet, D., Lindgren, C., Penrice, J., Robertson, N., Haug, E. & Steen, P.A.	Twenty-four hours of mild hypothermia in unsedated newborn pigs starting after a severe global hypoxic-ischemic insult is not neuroprotective. [Abstract]	2001	Pediatr Res Vol. 50(3), pp. 405-411	article
Abstract: Three to 12 h of mild hypothermia (HT) starting after hypoxia-ischemia is neuroprotective in piglets that are anesthetized during HT. Newborn infants suffering from neonatal encephalopathy often ventilate spontaneously and are not necessarily sedated. We aimed to test whether mild posthypoxic HT lasting 24 h was neuroprotective if the animals were not sedated. Thirty-nine piglets (median weight 1.6 kg, range 0.8-2.2 kg; median age 24 h, range 7-48 h) were anesthetized and ventilated and subjected to a 45-min hypoxic (FiO(2) approximately 6 global insult (n = 36) or sham hypoxia (n = 3). On reoxygenation, 18 were maintained normothermic (NT, 39.0 degrees C) for 72 h, and 21 were cooled from 39 (NT) to 35 degrees C (HT) for the first 24 h before NT was resumed (18 experimental, three sham hypoxia). Cardiovascular parameters and intermittent EEG were documented throughout. The brain was perfusion fixed for neuropathology and five main areas examined using light microscopy. The insult severity (duration in minutes of EEG amplitude < 7 microV) was similar in the NT and HT groups, mean +/- SD (28 +/- 7.2 versus 27 +/- 8.6 min), as was the mean FiO(2) (5.9 +/- 0.7 versus 5.8 +/- 0.8 during the insult. Six NT and seven HT piglets developed posthypoxic seizures that lasted 29 and 30% of the time, respectively. The distribution and degree of injury (0.0-4.0, normal-maximal damage) within the brain (hippocampus, cortex/white matter, cerebellum, basal ganglia, thalamus) were similar in the NT and HT groups (overall score, mean +/- SD, 2.3 +/- 1.5 versus 2.4 +/- 1.3) as was the EEG background amplitude at 3 h (13 +/- 3.5 versus 10 +/- 3.3 microV). The HT animals shivered and were more active. The sham control group (n = 3) shivered but had normal physiology and neuropathology. Plasma cortisol was significantly higher in the HT group during the HT period, 766 +/- 277 versus 244 +/- 144 microM at 24 h. Mild postinsult HT for 24 h was not neuroprotective in unsedated piglets and did not reduce the number of animals that developed posthypoxic seizures. Cortisol reached 3 times the NT value at the end of HT. We speculate that the stress of shivering and feeling cold interfered with the previously shown neuroprotective effect of HT. Research on the appropriateness of sedation during clinical HT is urgent.
Tooley, J., Satas, S., Eagle, R., Silver, I.A. & Thoresen, M.	Significant selective head cooling can be maintained long-term after global hypoxia ischemia in newborn piglets. [Abstract]	2002	Pediatrics Vol. 109(4), pp. 643-649	article
Abstract: OBJECTIVE: Selective head cooling (SHC) combined with mild body cooling is currently being evaluated as a potentially therapeutic option in the management of neonatal hypoxic-ischemic encephalopathy. It is proposed that SHC enables local hypothermic neuroprotection while minimizing the deleterious side effects of systemic hypothermia. However, there is little evidence that it is possible to cool the brain more than the body for a prolonged period of time. The aim of this study was to examine whether the brain (T(deep brain)) could be cooled to below the rectal temperature (T(rectal)) in our piglet hypoxia ischemia (HI) model for a period of 24 hours, using a head-cooling cap. METHODS: Eight anesthetized piglets (median age: 15 hours) had subdural and intracerebral basal ganglia temperature probes inserted. After a 45-minute global HI insult (known to produce permanent brain damage), SHC using a cap perfused with cold water (5 degrees C-24 degrees C) combined with overhead body heating to maintain T(rectal) at 34 to 35 degrees C was performed for 24 hours. RESULTS: The piglets were cooled to a median T(rectal) of 35.0 degrees C (interquartile range [IQR]: 34.7-35.3) for 24 hours. During this time, the median T(deep brain) was 31.4 degrees C (IQR: 30 degrees C-32.2 degrees C), with a median T(rectal) to T(deep brain) gradient of 3.4 degrees C (IQR: 2.7 degrees C-4.8 degrees C). At the end of the cooling period, this gradient was still maintained at a median of 3.3 degrees C (IQR: 2.9 degrees C-3.7 degrees C). The ability to obtain the gradient was not influenced by the size of the piglet (1300-1840 g). Cap cooling lowered scalp temperature (T(scalp)) to a median of 24.9 degrees C (IQR: 22.2 degrees C-29.2 degrees C) and subdural temperature to a median of 28.1 degrees C (IQR: 25.8 degrees C-29.5 degrees C) but did not result in either skin injury or superficial brain hemorrhage. There was no clinically useful correlation between T(scalp) and T(deep brain) or between T(scalp) and T(subdural). CONCLUSIONS: This study using our piglet HI model shows that it is possible by means of a head-cooling cap to cool the brain more than the body for a 24-hour period while keeping the core temperature mildly hypothermic. However, we were unable to predict temperatures inside the brain using surface temperature probes on the head.
Utagawa, A., Sakurai, A., Kinoshita, K., Moriya, T., Okuno, K. & Tanjoh, K.	Organ dysfunction assessment score for severe head injury patients during brain hypothermia. [Abstract]	2006	Acta Neurochir Suppl Vol. 96, pp. 33-36	article
Abstract: The purpose of this study was to evaluate the utility of a novel organ dysfunction assessment score developed for patients with severe traumatic brain injury during therapeutic brain hypothermia. The Brain Hypothermia Organ Dysfunction Assessment (BHODA) score is calculated through the combined assessment of 6 indices: central nervous system (CNS) function, respiratory function, cardiovascular function, hepatosplanchnic circulation, coagulation, and metabolism. The CNS, hepatosplanchnic circulation, and metabolic indices were based on measurements of cerebral perfusion pressure, gastric tonometry, and blood glucose, respectively. Thirty-nine patients with severe closed head injuries (scores of 3 to 8 on the Glasgow Coma Scale) were enrolled. Seven patients (18 died during hospitalization. Outcome was favorable in 20 patients and unfavorable in 19. The BHODA score proved useful in describing sequences of complications during therapeutic brain hypothermia. A total maximum BHODA score of more than 13 points corresponded to a mortality of 70 In a multivariate model, the total maximum BHODA score was independently associated with neurological outcome (odds ratio for unfavorable neurological outcome, 2.590: 95% confidence interval, 1.260, 5.327). In conclusion, the BHODA score can help assess multiple organ dysfunction/failure during therapeutic hypothermia and may be useful for predicting outcome.
Wagner, B.P., Nedelcu, J. & Martin, E.	Delayed postischemic hypothermia improves long-term behavioral outcome after cerebral hypoxia-ischemia in neonatal rats. [Abstract]	2002	Pediatr Res Vol. 51(3), pp. 354-360	article
Abstract: Hypothermia may be an ideal neuroprotective intervention in hypoxic-ischemic encephalopathy after perinatal asphyxia. The present study describes the long-term effects of prolonged resuscitative whole-body hypothermia initiated 2 h after hypoxic-ischemic injury on brain morphology and neuropsychological behavior in 7-d-old rats. After right common carotid artery ligation and exposure to hypoxia of 8% O(2) for 105 min, 10 animals were kept normothermic at 37 degrees C and 10 animals were cooled to 30 degrees C rectal temperature for 26 h, starting 2 h after the hypoxic-ischemic insult. All hypoxic-ischemic animals were gavage fed to guarantee long-term survival. Neuroprotection was evaluated by magnetic resonance imaging and behavioral testing. Hypothermia significantly reduced the final size of cerebral infarction by 23% at 6 wk after the insult. The most extended tissue rescue was found in the hippocampus (21 p = 0.031), followed by the striatum (13 p = 0.143) and the cortex (11 p = 0.160). Cooling salvaged spatial memory deficits verified at 5 wk of recovery with Morris Water Maze test; whereas circling abnormalities after apomorphine injection and sensory motor dysfunctions on rotating treadmill improved, yet did not reach statistical significance. When compared with controls, hypoxic-ischemic animals performed worse in all behavioral tests. Hypothermia did not influence functional outcome in controls. Significant correlations between behavioral performance and corresponding regional brain volumes were found. We conclude that 26 h of mild to moderate resuscitative hypothermia leads not only to brain tissue rescue, but most important to long-lasting behavioral improvement throughout brain maturation despite severity of injury and delayed onset of cooling.
Wainwright, M.S., Sheng, H., Sato, Y., Mackensen, G.B., Steffen, R.P., Pearlstein, R.D. & Warner, D.S.	Pharmacological correction of hypothermic P(50) shift does not alter outcome from focal cerebral ischemia in rats. [Abstract]	2002	Am J Physiol Heart Circ Physiol Vol. 282(5), pp. H1863-H1870	article	DOI
Abstract: Hypothermia decreases the arterial PO(2) at which hemoglobin is 50% saturated (P(50)), increasing hemoglobin O(2)-binding affinity. We used RSR13, a synthetic allosteric modifier of hemoglobin that increases P(50), to study the role of altered hemoglobin O(2)-binding affinity in mild hypothermic neuroprotection. RSR13 (150 mg/kg iv) restored P(50) to normothermic values. Rats underwent 70 min of middle cerebral artery occlusion (MCAO) at 30.0, 34.0, or 37.5 degrees C with hemoglobin saturation held at 98-100 The 34.0 degrees C group received RSR13 or vehicle before ischemia. After 7 days of recovery, infarct volumes were reduced in all hypothermic groups, without evidence of a detrimental effect on infarct size or neurological score as a result of P(50) correction. To examine for a beneficial effect of P(50) correction, ischemia duration was increased to 120 min in rats maintained at 34.0 degrees C. Correction of P(50) by RSR13 did not alter cerebral infarct sizes or neurological scores. The decrease in P(50), caused by mild hypothermia, could not be associated with infarct size or neurological deficit resulting from ischemic brain hypoxia in rats.
Walger, P.	Therapeutische Hypothermie. Evidenz basierte Empfehlung der internationalen Fachgesellschaft der Reanimationsmedizin.	2005	Notfall Intensivmed Vol. 1, pp. 48-49	article
Wanderer, A.A.	Ischemic-reperfusion syndromes: biochemical and immunologic rationale for IL-1 targeted therapy. [Abstract]	2008	Clin Immunol Vol. 128(2), pp. 127-132	article	DOI
Abstract: Ischemic-reperfusion injury (IRI) can affect many organ systems. Examples include strokes, coronary occlusion, accidental hypothermia, compartment syndrome and neonatal hypoxia. To date no mechanism has been fully accepted to explain acute inflammation associated with IRI. There is circumstantial evidence from animal and human ex-vivo cardiac experiments to support the hypothesis that acute inflammation associated with IRI is in part caused by IL-1 beta and/or IL-1 alpha secretion. Danger signal formation, such as uric acid/calcium pyrophosphate crystallization and other cellular stresses, may occur in IRI. These in turn may stimulate innate immune pathways (i.e. cryopyrin-inflammasome; and/ or toll-like receptors 2 and 4) to secrete IL-1 beta. Most IL-1 targeted therapy studies have focused on chronic human diseases and hopefully this discussion will create a framework to encourage use of this therapy in acute inflammation associated with IRI.
Wang, H., Olivero, W., Wang, D. & Lanzino, G.	Cold as a therapeutic agent. [Abstract]	2006	Acta Neurochir (Wien) Vol. 148(5), pp. 565-70; discussion 569-70	article	DOI
Abstract: The use of cold as a therapeutic agent has a long and colorful history. The Edwin Smith Papyrus, the most ancient medical text known, dated 3500 B.C., made numerous references to the use of cold as therapy. Baron de Larrey, a French army surgeon during Napoleon's Russian campaign, packed the limbs in ice prior to amputations to render the procedures painless. In the early twentieth century, a neurosurgeon, Temple Fay, pioneered "human refrigeration" as a treatment for malignancies and head injuries. In 1961, Irving Cooper developed the first closed cryoprobe system and ushered in the modern era of cryogenic surgery with his imperturbable convictions. Fay's early work fell victim to the disruptive sequel of the World War II. The Nazis confiscated his data (presented before the Third International Cancer Congress in 1939) forwarded to Belgium for publication and brutally applied his refrigeration techniques experimentally without any benefit of anesthesia in the concentration camps, especially Dachau. Hypothermia became associated in the public mind with the atrocities exposed at the war trials in Nürnberg. After lying dormant for decades, the interest was rekindled in the late 80s when mild hypothermia was shown to confer dramatic neuroprotection in a number of experimental models of brain injury. With several large multi-center clinical studies currently under way, hypothermia is receiving unprecedented attention from the medical and scientific communities.
Weil, M.H. & Gazmuri, R.J.	Hypothermia after cardiac arrest. [Abstract]	1991	Crit Care Med Vol. 19(3), pp. 315	article
Abstract: [extract] Shen et al. (1), in this issue of Critical Care Medicine. provide evidence that mild hypothermia may mitigate cerebral reperfusion injury after cardiac arrest in dogs. The notion that hypothermia reduces cellular metabolism and therefore may protect against ischemic injury is rational and well supported. Hypothermia sustains the patient during operations on the heart (2, 3), and it is a mainstay for preservation of organs before transplantation preservation (4, 5). Moreover, Sterz and associates cited evidence by their group and others that hypothermia protects against adverse effects of cardiac arrest (6-9). In addition, Vincent and coworkers (10), more than ...
Werner, C.	[Mild and moderate hypothermia as a new therapy concept in treatment of cerebral ischemia and craniocerebral trauma. Pathophysiologic principles] [Abstract]	1997	Anasthesiol Intensivmed Notfallmed Schmerzther Vol. 32(4), pp. 210-218	article
Abstract: Hypothermia protects the brain and other vital organs during periods of ischaemia. We differentiate between mild (36-34 degrees C), moderate (33-29 degrees C), deep (28-17 degrees C) and profund (16-4 degrees C) hypothermia. During hypothermia, cerebral metabolic rate and cerebral blood flow decrease dependent on temperature. The relation between temperature and cerebral metabolism is expressed by the temperature coeffizient Q10, which is the ratio between two metabolic rates separated by 10 degrees C. The following factors contribute to decreases in cerebral blood flow seen during hypothermia: cerebral metabolic depression, decreases in cardiac output, and decreases in arterial blood pressure with pH-stat management, increases in hematocrit and in blood viscosity. Mild or moderate hypothermia reduces histopathological damage and neurological deficits if started before and during cerebral ischaemia. Hypothermia may also improve neurologic outcome if initiated following focal cerebral ischaemia, but is less effective after global ischaemic insults. Mild hypothermia appears to be safer and more effective compared to moderate hypothermia. In most instances, deep hypothermia renders neurologic outcome worse, which is most likely related to the generation of toxic metabolites and inadequate myocardial function during rewarming. The neuroprotective effects of hypothermia are related to several mechanisms along the ischaemic cascade: prevention of postischaemic hypoperfusion, reduction of functional and basal metabolism, decreased accumulation of lactic acid and oedema formation, inhibition of excitatory neurotransmitter release, prevention of Ca(++)- and Na(+)-influx, inhibition of lipid peroxidase activity, and free radical formation, stimulation of regenerative immediate early genes. The side effects of hypothermia include myocardial ischaemia, cardiac arrhythmias, decreased left ventricular contractility, coagulation abnormalities, and suppression of metabolic and immunological processes.
Whitelaw, A. & Thoresen, M.	Clinical trials of treatments after perinatal asphyxia. [Abstract]	2002	Curr Opin Pediatr Vol. 14(6), pp. 664-668	article
Abstract: Following critical hypoxia-ischemia during labor and delivery, there is a window of therapeutic opportunity during hypoxic-ischemic encephalopathy. Meta-analysis of three randomized trials of prophylactic barbiturate therapy for neonatal hypoxic-ischemic encephalopathy showed no significant effect on death or disability. One randomized trial of allopurinol showed short-term benefits but was too small to test death or disability. No adequate trials of dexamethasone, calcium channel blockers, or magnesium sulphate have yet been completed, but pilot studies in infants have shown the cardiovascular risks of magnesium sulphate and calcium channel blockers. There is considerable evidence from animal studies that posthypoxic mild hypothermia reduces brain injury. One small randomized trial of mild hypothermia found no adverse effects but was too small to examine death or disability. One large randomized trial of selective head cooling has finished recruitment and a number of large trials of systemic mild hypothermia are ongoing. As time is critical with post-hypoxic interventions, the delay involved in obtaining informed parental consent for such trials might obscure a clinically important therapeutic effect.
Wira, C., Martin, G., Stoner, J., Margolis, K. & Donnino, M.	Application of normothermic cardiac arrest algorithms to hypothermic cardiac arrest in a canine model. [Abstract]	2006	Resuscitation Vol. 69(3), pp. 509-516	article	DOI
Abstract: BACKGROUND: International guidelines (2000) do not recommend vasopressor and antiarrhythmic medications during ventricular fibrillation (VF) with a core temperature below 30 degrees C. The efficacy of normothermic AHA algorithms using standard doses of epinephrine (EPI) (adrenaline) followed by amiodarone (AMIO) in hypothermic VF is uncertain. OBJECTIVES: To determine the effects of EPI followed by the combination of EPI/AMIO in the treatment of VF in a canine model of severe hypothermia. METHODS: An un-blinded, placebo controlled experiment using 21 mechanically ventilated dogs. Coronary perfusion pressure (CPP), temperature, and electrocardiogram (ECG) were monitored. Animals were cooled to 22 degrees C or the onset of spontaneous VF. VF was induced if necessary. Animals in the treatment group received EPI (0.01 mg/kg IV) and defibrillation. This was followed by EPI (0.01 mg/kg IV), AMIO (10 mg/kg IV) and defibrillation if there was no sustained return of spontaneous circulation (ROSC) for 15 min. RESULTS: Mean CPP in the treatment group increased after the administration of EPI/AMIO (24.7+/-13.3 mmHg to 46.6+/-7.7 mmHg, p<0.004). Cumulatively, the administration of EPI followed by EPI/AMIO achieved ROSC after defibrillation in 10 of 11 animals compared to 3 of 10 in the control group (91% versus 30 n=21, p=0.0075). CONCLUSIONS: In this model of severe hypothermia, the use of standard 2000 protocols for VF resulted in a significant increase of CPP, and, a higher ROSC rate compared to placebo controls. This study suggests that AHA normothermic algorithms may be beneficial in severe hypothermia.
Wolfrum, S., Pierau, C., Radke, P.W., Schunkert, H. & Kurowski, V.	Mild therapeutic hypothermia in patients after out-of-hospital cardiac arrest due to acute ST-segment elevation myocardial infarction undergoing immediate percutaneous coronary intervention. [Abstract]	2008	Crit Care Med Vol. 36(6), pp. 1780-1786	article	DOI
Abstract: OBJECTIVE: Mild therapeutic hypothermia (MTH) has been integrated into international resuscitation guidelines. In the majority of patients, sudden cardiac arrest is caused by myocardial infarction. This study investigated whether a combination of MTH with primary percutaneous coronary intervention (PCI) is feasible, safe, and potentially beneficial in patients after cardiac arrest due to acute myocardial infarction. DESIGN: Single-center observational study with a historical control group. SETTING: University clinic. PATIENTS: Thirty-three patients after cardiac arrest with ventricular fibrillation as initial rhythm and restoration of spontaneous circulation who remained unconscious at admission and presented with acute ST elevation myocardial infarction (STEMI). INTERVENTIONS: In 16 consecutive patients (2005-2006), MTH was initiated immediately after admission and continued during primary PCI. Seventeen consecutive patients who were treated in a similar 2-yr observation interval before implementation of MTH (2003-2004) served as a control group. Feasibility, safety, mortality, and neurologic outcome were documented. MEASUREMENTS AND MAIN RESULTS: Initiation of MTH did not result in longer door-to-balloon times compared with the control group (82 vs. 85 mins), indicating that implementation of MTH did not delay the onset of primary PCI. Target temperature (32-34 degrees C) in the MTH group was reached within 4 hrs, consistent with previous trials and suggesting that primary PCI did not affect the velocity of cooling. Despite a tendency to increased bleeding complications and infections, patients treated with MTH tended to have a lower mortality after 6 months (25% vs. 35 p = .71) and an improved neurologic outcome as determined by a Glasgow-Pittsburgh Cerebral Performance Scale score of 1 or 2 (69% vs. 47% in the control group, p = .30). CONCLUSIONS: MTH in combination with primary PCI is feasible and safe in patients resuscitated after cardiac arrest due to acute myocardial infarction. A combination of these therapeutic procedures should be strongly considered as standard therapy in patients after out-of-hospital cardiac arrest due to STEMI.
Wolfrum, S., Radke, P.W., Pischon, T., Willich, S.N., Schunkert, H. & Kurowski, V.	Mild therapeutic hypothermia after cardiac arrest - a nationwide survey on the implementation of the ILCOR guidelines in German intensive care units. [Abstract]	2007	Resuscitation Vol. 72(2), pp. 207-213	article	DOI
Abstract: AIM: To investigate the implementation of mild therapeutic hypothermia (MTH) after cardiac arrest into clinical practice. METHODS AND RESULTS: A structured evaluation questionnaire was sent to all German hospitals registered to have ICUs; 58% completed the survey. A total of 93 ICUs (24 reported to use MTH. Of those, 93% started MTH in patients after out-of-hospital resuscitation with observed ventricular fibrillation and 72% when other initial rhythms were observed. Only a minority of ICUs initiate MTH in patients after cardiac arrest with cardiogenic shock (28, whereas 48% regarded cardiogenic shock as a contra-indication for MTH. On average, target temperature was 33.1+/-0.6 degrees C and duration of cooling 22.9+/-4.9 h. Many centres used economically priced cold packs (82 and cold infusions (80 for cooling. The majority of the ICUs considered infection, hypotension and bleeding as relevant complications of hypothermia which was of therapeutic relevance in less than 25% of the cases. CONCLUSIONS: MTH is underused in German ICUs. Centres which use MTH widely follow the recommendations of ILCOR with respect to the indication and timing of cooling. In hospitals that use MTH the technique is considered to be safe and inexpensive. More efforts are needed to promote this therapeutic option and hypothermia since MTH has now been included into European advanced cardiovascular life support protocols.
Yanagawa, Y., Ishihara, S., Norio, H., Takino, M., Kawakami, M., Takasu, A., Okamoto, K., Kaneko, N., Terai, C. & Okada, Y.	Preliminary clinical outcome study of mild resuscitative hypothermia after out-of-hospital cardiopulmonary arrest. [Abstract]	1998	Resuscitation Vol. 39(1-2), pp. 61-66	article
Abstract: The effects of mild hypothermia (MH) were investigated. From 1995 to 1996, 28 adult patients with out-of-hospital cardiopulmonary arrest (CPA) had return of spontaneous circulation and survived for more than two days. Thirteen patients were in the MH group. In the MH group, core temperature was maintained between 33 and 34 degrees C for 48 h, and then re-warmed to a temperature of 37 degrees C, at a rate of no greater than 1 degrees C per day. Fifteen patients, admitted before the MH protocol was instituted, were in the control group. Despite the fact that the number of witnessed arrests in the control group were greater than in the MH group, there were both more survivors (7/13 vs. 5/15) and more fully recovered patients (3/13 vs. 1/15) in the MH vs Control groups. Eleven of 13 MH patients, as compared to 6/15 controls developed pneumonia. Our study, although preliminary, suggests that MH might confer improved outcome, as has been shown in animal models, after CPA. This treatment is associated with an increase in pneumonic complications.
Zhu, C., Wang, X., Cheng, X., Qiu, L., Xu, F., Simbruner, G. & Blomgren, K.	Post-ischemic hypothermia-induced tissue protection and diminished apoptosis after neonatal cerebral hypoxia-ischemia. [Abstract]	2004	Brain Res Vol. 996(1), pp. 67-75	article
Abstract: Hypothermia is possibly the single most effective method of neuroprotection developed to date. However, the mechanisms are not completely understood. The aim of this study was to investigate the effects of post-ischemic hypothermia on brain injury and apoptotic neuronal cell death as well as related biochemical changes after neonatal hypoxia-ischemia (HI). Seven-day-old rats were subjected to left common carotid artery ligation and hypoxia (7.8 for 1 h. Systemic hypothermia was induced immediately after hypoxia-ischemia, and body temperature was maintained at 30 degrees C for 10 h. The normothermic group was kept at 36 degrees C. Brain infarct volumes and neuronal loss in the CA1 area of the hippocampus were significantly reduced at 72 h post-HI in the hypothermia group. Cytochrome c release and activation of caspase-3 and -2 at 24 h post-HI were significantly diminished by hypothermia. The numbers of cytochrome c- and TUNEL-positive cells in the cortex and dentate gyrus of the hippocampus were significantly reduced in the hypothermia group compared with the normothermia group at 72 h post-HI. These results indicate that hypothermia may, at least partially, act through inhibition of the intrinsic pathway of caspase activation in the neonatal brain, thereby preventing apoptotic cell death.
Zhu, C., Wang, X., Xu, F., Qiu, L., Cheng, X., Simbruner, G. & Blomgren, K.	Intraischemic mild hypothermia prevents neuronal cell death and tissue loss after neonatal cerebral hypoxia-ischemia. [Abstract]	2006	Eur J Neurosci Vol. 23(2), pp. 387-393	article	DOI
Abstract: The effectiveness of hypothermia in preventing ischemic brain damage depends on when it is started. The purpose of this study was to investigate the effects of temperature reduction during a hypoxic-ischemic (HI) insult on brain injury and signalling pathways of neuronal cell death and survival. Seven-day-old mice were subjected to left common carotid artery ligation and hypoxia (10% oxygen) at different temperatures (37, 36 or 34 degrees C) for 50 min. Brain injury at 7 days post-HI was significantly reduced from 67.4% at 37 degrees C to 31.6% at 36 degrees C and 10% at 34 degrees C, with no observable injury in the cortex of the 34 degrees C group. Cytochrome c release, caspase-3 activation and apoptosis-inducing factor translocation from mitochondria to nuclei were all significantly inhibited after intraischemic temperature reduction. Concurrently, the cell survival signalling pathway involving Akt was significantly sustained (the phosphorylated form of Akt was maintained) when the hypoxia temperature was decreased. These results indicate that intraischemic hypothermia diminished apoptosis through inhibition of both caspase-dependent and caspase-independent neuronal cell death pathways and promoted cell survival by inhibition of phosphorylated Akt dephosphorylation in the neonatal brain, thereby preventing neuronal cell death.

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