SIGNA VITAE 2012; 7(2): 11 - 16 ORIGINAL

RIMANTAS KEVALAS (  ) • Induced mild hypothermia in DOVILE GRINKEVICIUTE • VAIDOTAS GURSKIS children Department of Pediatric Diseases Lithuanian University of Health Sciences RIMANTAS KEVALAS • DOVILE GRINKEVICIUTE Eiveniu 2, Kaunas 50009, Lithuania VAIDOTAS GURSKIS • ALGIMANTAS MATUKEVIIUS Phone: +370 37 326 963 VYTAUTAS RAGAIŠIS • VIDMANTAS BARAUSKAS Fax: +370 37 327 160 E-mail: [email protected]

ALGIMANTAS MATUKEVIIUS • VYTAUTAS RAGAIŠIS Department of Lithuanian University of Health Sciences Kaunas, Lithuania

VIDMANTAS BARAUSKAS Department of Pediatric Lithuanian University of Health Sciences Kaunas, Lithuania

ABSTRACT The objective of this study was to measure outcomes and to determine the safety and effectiveness of mild induced hypot- hermia in children after traumatic and posthypoxic brain injury. Methods. Forty patients, following traumatic or posthypoxic brain injury, were involved in the study. Mean age was 10.7 ± 0.8 years. Median GCS (Glasgow Scale) was 6.0 (4-7) and mean PIM2 (Pediatric Index of Mortality) 14.6 ± 3.8 %. Results. GOS (Glasgow Outcome Scale) of 5 was assigned for 15 (37.5%) patients, GOS 4 for 14 (35.0%), GOS 3 for 7 (17.5%) and GOS 2 for 4 (10%) patients. The average GOS in patients after severe head trauma was 3.6 ± 0.9 points and in patients with posthypoxic brain injury 5 points, (p < 0.05). No life threatening complications occurred. Conclusion. Mild induced hypothermia can be safely used in pediatric patents after severe traumatic or posthypoxic brain injury. This method may be of benefit while improving outcomes in children.

Key words: , ly associated with tissue hypoxia and are , hypoxia and hyper- posthypoxic brain injury, children, ischemia, secondary injury occurs from capnia. The intracranial events are a hypothermia, outcome, Pediatric reperfusion, sustained acidosis, cere- series of inflammatory changes and Index of Mortality bral edema, hyperglycemia, release pathophysiological perturbations that of excitatory neurotransmitters, seizu- occur immediately after the primary Introduction res, hypotension and impaired cere- injury and continue over time. It remains Brain injury is a significant cause of bral autoregulation. In trauma cases, a challenge to develop therapies that death and disability in children. At least primary brain injury occurs at the time target multiple injury cascades to suc- one third of survivors sustain mode- of impact, either by a direct injury to cessfully improve outcome for a hetero- rate to severe neurological sequelae. the brain parenchyma or by an injury geneous brain injury group. One highly Induced hypothermia can be used to to the long white matter tracts through promising therapy that targets multiple protect the brain from post-ischemic acceleration – deceleration forces. (1) pathological mechanisms caused by and traumatic neuronal injury. Neurolo- Secondary injury is represented by sys- traumatic or posthypoxic brain inju- gical impairment depends not only on temic and intracranial events that occur ry is mild induced hypothermia (MIH). primary, but also on secondary brain in response to the primary injury and The use of cold as a therapeutic agent injury. In case of strangulation or near- further contribute to neuronal damage has received renewed interest in the drowning, primary brain injury is initial- and cell death. The systemic events last decade though it has a long and

www.signavitae.com 11 colorful history reaching back to 3500 1000 children per year and providing and received analgesia through conti- B.C., when Edwin Smith Papyrus, the the services of a pediatric intensive nuous intravenous morphine infusion, most ancient medical text known, made care physician, pediatric neurosurgeon, sedation with benzodiazepines and numerous references to the use of cold pediatric surgeon, pediatric neurologist muscle relaxation intravenously. as a therapy. (2) In the 18th century sur- and radiologist 24 hours a day. Intracranial pressure (ICP) was measu- geon-in-chief of the Napoleonic armies, red only in patients after traumatic brain Baron Dominique Jean Larrey, obser- Patients injury. All patients after traumatic brain ved that severely wounded soldiers All pediatric patients treated with mild injury were treated according to severe lying closer to the campfires died at a induced hypothermia at the PICU treatment protocol based higher rate than those in more remote, of HLUHS, after severe traumatic or on ICP and cerebral perfusion pressure colder areas. (3) Intentional cooling posthypoxic brain injury, during a 60 (CPP) targeted therapy. to induce a state of hypothermia was – month period (January 1, 2005, to Nutritional support by the enteral route described as clinical therapy for malig- January 1, 2010), were enrolled. Inclu- was started during the rewarming period. nancies and head injuries by Temple sion criteria were: post- Cooling procedures included surface Fay in 1938. (2,4) Since the 1950s, Glasgow Coma Scale (GCS) 8, or cooling techniques (cooling blankets, induced hypothermia has been used rapid deterioration of (2 ice pads and cool pads), gastric lavage in an attempt to attenuate secondary or more points of GCS in one hour) and with iced fluid, external ventilator for brain injury following a variety of primary ability to start the hypothermia protocol body surface cooling and use of room – insults including carbon monoxide poi- in the first six hours after the event. temperature air in the ventilation circuit. soning, status epilepticus, ischemic Patients were divided into two groups The cooling protocol was commenced stroke and more recently for patients according to the type of injury (trauma- within six hours of the event. The aim with hepatic encephalopathy.(2) tic or posthypoxic). of the induction phase was to reach The mechanism by which hypothermia 33-34°C core temperature within 2 – conveys its neuroprotective effect is Data collection 3 hours. The aim of the maintenance unclear. We know that hypothermia In – hospital variables (age, sex, dia- phase was to maintain core temperature reduces global cerebral metabolism, gnosis, length of PICU stay and arti- at 33 – 34°C, to maintain hemodynamic cerebral oxygen demands, lactic acid ficial ventilation) were recorded in the stability and normal physiological and accumulation, calcium influx in neu- patient’s hospital chart and in an electro- laboratory parameters. The duration of rocytes, free radicals production, lipid nic database. Temperature, heart rate, this phase according to our protocol peroxidation, posttraumatic level of mean arterial pressure, urine output, was 48 hours for traumatic brain injury excitatory neurotransmitter, inhibition of volumes and types of intravenous fluids and 24 hours for posthypoxic brain apoptosis, and lowers the damage of administered were recorded hourly on injury. The aim of the rewarming phase cytoskeletal structure. (5) patients’ care sheets. Laboratory valu- was to achieve normal body temperatu- There is clear evidence of a beneficial es (serum sodium, potassium, glucose, re (36 – 37°C). Passive rewarming was effect of induced hypothermia on neu- lactate level, blood gases, coagulation used. The rewarming rate had to be no rological outcome in patients following indicators) were analyzed every four faster than 1°C per four – hour period. cardiac arrest (6,7) or in neonates with hours. C reactive protein and blood hypoxic – ischemic encephalopathy, (8) count were performed daily. Hypother- Measuring of outcome but things in traumatic brain injury are mia induced complications were recor- Outcome measure was the assessment controversial. (9) ded in the patient’s hospital chart at the of patients according to the five – cate- In our study we aimed to determine moment of their occurrence. GCS and gory Glasgow Outcome Scale (GOS), the safety and effectiveness of MIH Pediatric Index of Mortality (PIM2) were which was conducted on discharge for pediatric patients after traumatic or calculated within the first hour of admi- from hospital. GOS of 1 was applied to posthypoxic brain injury. ssion. Calculation of GCS was based patients who died, GOS of 2 – for those on eye opening, motor response and who appeared to be in a vegetative Material and methods verbal response; calculation of PIM2 state (unresponsive, unable to interact Setting was calculated from the eight variables with the environment), GOS of 3 – for This prospective, observational, clinical recorded at the first hour of admission severe disability (able to follow com- trial was conducted at the Hospital of to the PICU. Rectal temperature was mands, unable to live independently), Lithuanian University of Health Sciences measured continuously electronically GOS of 4 – for moderate disability (able (HLUHS), Department of Pediatric Dise- starting with temperature on arrival to to live independently, unable to return to ases, Kaunas, Lithuania. The study took temperature at the end of rewarming. work or school), GOS of 5 – for full reco- place in the Pediatric very (able to return to work or school). (PICU) – an eight bed unit admitting, on Patient care Outcome was assessed on patient’s a non – elective basis, approximately All patients were artificially ventilated discharge from the hospital.

12 www.signavitae.com Statistical analysis Table 1. Baseline characteristics of the groups. Statistical analysis was performed with SPSS 13 for Windows. Quantitative vari- Posthypoxic Traumatic brain ables were expressed as mean ± stan- brain injury injury group dard deviation or median (interquartile group Characteristic (N = 30) p value range) as appropriate. Qualitative vari- (N = 10) ables were expressed as numbers and Age (years)* 11.0 ± 0.8 10.1 ± 1.8 > 0.05 percentages. For comparing distributi- on of variables in two Mann – Whitney Male sex – no. (%) 20 (66.7) 7 (70.0) > 0.05 U test was used. Statistical significance Weight – kg (IQR) 40.0 (20.0 – 60.0) 34.0 (15.0 – 55.0) > 0.05 was taken as p < 0.05. GCS on admission – 6 (4.7 – 8.0) 4.5 (3.0 – 6.2) > 0.05 Results median (IQR) Patient’s characteristics PIM2 on admission* 5.9 ± 0.4 40.3 ± 12.0 < 0.05 Mild hypothermia was used in 43 cases during the research period. Three pati- *Means ± SD ents were excluded from the study; GCS, Glasgow Coma Scale; IQR, interquartile range; PIM2, Pediatric Index of Mortality. one patient was excluded because of misdiagnosis of encephalitis, one pati- ent had congenital cerebral dysplasia Table 2. Duration of and length-of-stay in PICU and and severe psychomotor retardation, HLUHS according to type of injury. and one patient died on the first day of admission from severe lung injury Traumatic brain Posthypoxic (major aspiration of oilseed rape). The Variable p value injury brain injury study involved 40 patients: 27 (67.5%) boys and 13 (32.53%) girls. Mean age Mechanical ventila- 8.9 ± 5.5 3.2 ± 2.0 < 0.05 was 10.7 ± 0.8 years, median weight tion (days) 39.6 (12 – 70) kg, median GCS 6.0 (4 Length-of-stay in 13.0 ± 7.8 4.7 ± 2.7 < 0.05 –7) and mean PIM2 14.6 ± 3.8 %. The PICU (days) origin of brain injury was trauma in 30 Length-of-stay in cases (pedestrian – 10 cases; pass- 42.4 ± 23.9 14.0 ± 9.9 < 0.05 enger – 16 cases; falls – 4 cases) and HLUHS (days) posthypoxic brain injury in 10 cases (submersion – 4 cases; strangulation – Values are expressed as means ± SD 5 cases, one patient was buried under HLUHS, Hospital of Lithuanian University of Health Sciences; PICU, Pediatric Intensive Care the snow). We had no patients with car- Unit. diac rhythm disturbances in our study. Baseline characteristics of the patients, according to the type of brain injury, are and two vasoactive agents – dopamine of mechanical ventilation, length-of- shown in table 1. Demographic data + norepinephrine - were required in stay in PICU and total length-of-stay were similar in both groups, but PIM 2 9 (22,5 %) cases. In 7 (17.5 %) cases was significantly longer in patients with was significantly higher in the posthy- vasopressors were not administered. traumatic brain injury as compared with poxic group. Distribution of vasopressor require- posthypoxic patients. ments according to the type of head Patient management and injury is shown in figure 1. Enteral nutri- Outcome analysis length of stay tion was administered to all patients. No Full recovery (GOS 5) and moderate All patients were managed accord- was used. disability (GOS 4) that are designated ing to strict protocols: cooling proto- Mean length of stay in PICU was 10.9 ± as a favorable outcome were present in col for all patients plus ICP targeted 7.7 days, whereas total length of hospi- 29 (72.5 %) cases: GOS 5 was assigned severe head trauma protocol for head tal stay was 34.9 ± 24.5 days. The mean to 14 (35.0%) patients and GOS 4 to trauma patients. Normovolaemia was duration of mechanical ventilation was 15 (37.5%) patients. Seven patients maintained in all patients. Thirty three 7.5 ± 5.4 days. The distribution of ven- (17.5%) appeared to have severe dis- patients required vasoactive agents for tilation time and length-of-stay in PICU ability and 4 (10.0%) a persistent veg- achieving hemodynamic stability. Dop- and UHLUHS according to the type of etative state. Average GOS in patients amine was required in 24 (60.0 %) cases injury is shown in table 2. The duration after severe head trauma was 3.6 ± 0.9

www.signavitae.com 13 (11) Children suffer primary traumatic brain injury similar to that in adults, but approximately 50% of children will develop diffuse cerebral swelling in the early hours after trauma. (12) In 2002, two clinical trials proved that imple- mentation of therapeutic hypothermia for survival in adult patients after out – of – hospital cardiac arrest results in good neurological outcome. (6,7) As we know, cardiac arrest due to cardiac rhythm disturbances in children is very p<0.05 rare. Accidents such as trauma, stran- gulation and near drowning are more Figure 1. Requirements of vasoactive drugs according to the type of head frequent reasons for secondary brain injury. injury in children, resulting in poor neu- rologic outcome. Some studies in adults showed that therapeutic hypothermia points and in patients with posthypoxic may reduce the risks of mortality and brain injury 5 points, (p < 0.05). All poor neurologic outcome in adults with patients after posthypoxic brain injury traumatic brain injury, (13,14) but the fully recovered. The distribution of GOS authors state, that the evidence was not in patients after traumatic brain injury is sufficient to recommend routine use of shown in figure 2. therapeutic hypothermia for traumatic brain injury outside of research set- Safety tings. (15) Hypothermia affects many A lot of medical problems occurred in intracellular processes. Some of these the MIH patients. The most frequent are directly related to its neuroprotective problem was airways infection. It was Figure 2. Distribution of Glasgow effects. Studies show, that hypothermia Outcome Scale (GOS)in traumatic ascertained in 29 (72.5%) patients brain injury group. tends to decrease protein oxidation and and occurred mostly on the second attenuates oxidative stress after severe day of ventilation. was diag- traumatic brain injury in infants and chil- nosed in 3 (7.5%) patients, but it was infection was not higher than expected dren. (16) But induction of hypothermia confirmed by in only in other ventilated patients. Electrolyte causes a large number of physiological one case. Hypokalemia, defined as a disturbances were not severe and were changes in the circulatory and respira- serum potassium level lower than 3.8 easily correctable. Patients with post- tory systems, coagulation system, drug mmol/l, was observed in 32 (80.06%) hypoxic brain injury had worse PIM2 on metabolism, (17) thus it can increase patients and ranged from 2.4 mmol/l to admission, but the outcome of these bleeding time due to its effect on plate- 3.5 mmol/l. No life threatening compli- patients was better. Of course, the situ- let count, increase risk of arrhythmias cations occurred due to hypokalemia ation following traumatic brain injury as well as impair immune function. The and it was easily correctable. Other is more complicated and outcome physiological and pathophysiological life threatening complications such as depends not only on secondary, but effects of cooling largely depend on the arrhythmia, pancreatitis, coagulative or also on primary brain injury. In the study degree of hypothermia. For example, a renal disorders were not observed. by Berger et al., peak levels of a serum significant risk for severe arrhythmias biomarker of neuronal death, neuron- occurs only at temperatures below 28 – specific enolase, occurred days after 30°C and is very low during mild or mod- Discussion cardiac arrest, whereas they occurred erate hypothermia. Bourdages M et al. Our results show that MIH in pediatric within a few hours of traumatic brain showed that hypothermic patients have patients after posthypoxic brain inju- injury. (10) The only neuroprotective lower heart rates than normothermic ry resulted in a favorable outcome. A therapy used in cardiac arrest is mild patients, but none had severe brady- favorable outcome in posttraumatic hypothermia, while in traumatic brain cardia. The most frequent arrhythmias brain injury was seen in 65% of trauma injury myriad intracranial pressure – were isolated premature atrial contrac- patients. Hypothermia did not cause any directed therapies may confer a variety tions. Most arrhythmias were of short life threatening complications in both of neuroprotective actions, thus raising duration and did not alter hemodynam- groups. The rate of patients with airway the bar for hypothermia to show benefit. ic status. Additionally, the difference in

14 www.signavitae.com the incidence of arrhythmias between improve neurologic outcome and may It is proven that induced hypothermia the hypothermic and normothermic increase mortality. (9) One can ask reduces the risk of death and disability group was not statistically significant. whether hypothermia does more harm in neonates with moderate or severe (18) We did not record any arrhyth- than good in children after severe trau- hypoxic – ischemic encephalopathy, (8) mias, due to cooling itself or electro- matic brain injury. However, there is and there are some case reports about lyte disturbances, in our study and we a big difference in the mechanism of improved neurological outcome while had no bleeding or any platelet count brain injury after trauma or hypoxia. using induced hypothermia in children decrease in our patients. Hypothermia, Peak neuronal death occurs days after who appeared to be near drowning therapeutic or accidental, is usually a hypoxic episode, but hours after trau- victims. (28) In our study, children after accompanied by electrolyte alterations, matic brain injury, (13) so the neuropro- posthypoxic injury had significantly especially hypokalemia. The plasma tective effect of hypothermia in case of worse admission scores, but their out- potassium level corresponds to chang- traumatic brain injury depends on the come was significantly better (all five es in plasma phosphate (P) level and time at which the cooling protocol is children had GOS of 5 on discharge) that may have a role in the physiological started and the aimed core temperature than children with severe head trauma. derangements that occur during mod- reached as well as on the duration of One of the points to note is that in two erate hypothermia, because P is impor- treatment and the rewarming speed. cases of submersion cold water, the tant for energy metabolism or blood (15,23) In Hutchinson’s study, core children’s body temperature was low- pressure regulation. (19) Arrhythmias temperature at a mean of 32.5°C was ered so we can say that cooling began may be the result of hypomagnesae- maintained for 24 hours. It is possible, at the time of the accident. On the other mia, induced by cooling patients, that’s that starting the cooling protocol earlier, hand, posthypoxic brain injury has why prophylactic electrolyte supple- maintaining the aimed temperature for other pathophysiological mechanisms mentation should be considered and longer and rewarming at a slower rate compared to severe head trauma, and electrolyte levels should be monitored may have improved outcomes. Recent that also affects outcomes. frequently. (20) Serum electrolytes were studies show that even pre-hospital In conclusion we want to state, that measured every four hours according induction of therapeutic hypothermia MIH is a safe and feasible treatment in to our protocol. Though hypokalemia using infusions of 4°C normal saline children with traumatic or posthypoxic was observed in 80% of patients, it was during advanced is fea- brain injury and it has a potential ben- easily correctable and no life threaten- sible, effective and safe. (24,25) Some efit on outcomes. Further studies are ing complications occurred. authors are raising the question of local required for determining the optimal Studies show, that mild induced hypo- cooling of the traumatized brain, (26) time of onset, duration and temperature thermia is likely a safe therapeutic inter- which is quite effective in neonates, (27) of hypothermia, as well as for produc- vention for children after severe trau- but is not as effective in adults and are ing proper protocols for its manage- matic brain injury up to 24 hours after is not available for general clinical use. ment, because sometimes potentially injury. (21) In our study we provided (26) Our study suggests that it may beneficial treatments are under used cooling for 48 hours in trauma patients be beneficial starting the cooling pro- for various reasons, such as the with- and 24 hours in posthypoxic patients. tocol within six hours and maintaining drawal of active treatment due to poor After a pretrial study (22) in which the MIH protocol for 48 hours in traumatic prognosis, a long delay in reaching ability of the investigators to adhere to brain injury patients and for 24 hours in target temperature, or thinking, that it the clinical protocols of care, including posthypoxic brain injury patients. We will prolong the intensive care unit (ICU) the cooling and rewarming procedures think that longer periods of cooling do stay and thus cause a potential burden as well as management guidelines in not cause more complications if the on resources. (29) pediatric patients with severe traumatic protocol is used with great attention brain injury, was evaluated, a multi- to the prevention of side effects. Con- Conclusions center, international trial of 225 children tinuous hemodynamic and intracranial Efforts to improve outcomes in children after severe traumatic brain injury was pressure in head trauma after brain injury are extremely impor- initiated. The results of this study show, patients and frequent monitoring of tant. Mild induced hypothermia can be that in children with severe traumatic electrolyte levels are essential. safely used in pediatric patents after brain injury, hypothermia therapy that There are no randomized trials concern- severe traumatic or posthypoxic brain is initiated within 8 hours after injury ing the efficacy of induced hypothermia injury. This method may be of benefit and continued for 24 hours does not after posthypoxic brain injury in children. while improving outcomes in children.

www.signavitae.com 15 REFERENCES

1. Verive, MJ. Near Drowning [Internet]. 2009 [updated 2009 Apr 29]. Available from: http://www.scribd.com/doc/48799917/Near-Drowning- eMedicine-Specialties 2. Wang H, Olivero W, Wang D, Lanzino G. Cold as a therapeutic agent. Acta Neurochir 2006;148:565-70. 3. Foster K, Stocker C, Schibler A. Controversies of prophylactic hypothermia and the emerging use of brain tissue oxygen tension monitoring and decompressive craniectomy in traumatic brain - injured children. Aust Crit Care 2010;23:4-11. 4. Vincent A. Therapeutic hypothermia for brain injury: the clinical evidence. Anaesthesia 2004;6(3):116-21. 5. Sookplung P, Vavilala MS. What is new in pediatric traumatic brain injury? Curr Opin Anaesthesiol 2009;22:572-8. 6. Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, et al. Treatment of comatose survivors of out – of – hospital cardiac arrest with induced hypothermia. N Engl J Med 2002;346(8):557-63. 7. Holzer M. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002;346(8):549-56. 8. Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan ER, et al. Whole - body hypothermia for neonates with hypo- xic - ischemic encephalopathy. N Engl J Med 2005;535:1574-84. 9. Hutchinson JS, Ward RE, Lacroix J, Hebert PC, Barnes M, Bohn DJ, et al. Hypothermia therapy after traumatic brain injury in children. N Engl J Med 2008;358(23):2447-56. 10. Berger RP, Adelson PD, Richichi R, Kochanek PM. Serum biomarkers after traumatic and hypoxemic brain injuries: insight into the bioche- mical response of the pediatric brain to inflicted brain injury. Dev Neurosci 2006;28:327-35. 11. Kochanek PM. The brain, the heart, and therapeutic hypothermia. Cleve Clin J Med 2009;76(2):8-12. 12. Adelson PD. Hypothermia following pediatric traumatic brain injury. J Neurotrauma 2009;26:429-36. 13. Marion DW, Penrod LE, Kelsey SF, Obrist WD, Kochanek PM, Palmer AM, et al. Treatment of traumatic brain injury with moderate hypo- thermia. N Engl J Med 1997;336(8):540-6. 14. Polderman KH, Joe RTT, Peederman SM, Vandertop WP, Girbes ARJ. Effects of therapeutic hypothermia on intracranial pressure and outcome in patients with severe head injury. Intensive Care Med 2002;28:1563-73. 15. McIntyre LA, Fergusson DA, Hebert PC, Moher D, Hutchinson JS. Prolonged therapeutic hypothermia after traumatic brain injury in adults. JAMA 2003;289(22):2992-9. 16. Bayir H, Adelson PD, Wisniewski SR, Shore P, Lai MY, Brown D, et al. Therapeutic hypothermia preserves antioxidant defenses after severe traumatic brain injury in infants and children. Crit Care Med 2009;37(2):689-95. 17. Polderman KH. Application of therapeutic hypothermia in the intensive care unit. Opportunities and pitfalls of promising treatment modality – Part 2: Practical aspects and side effects. Intensive Care Med 2004;30:757-69. 18. Bourdages M, Bigras JL, Farrel CA, Hutchinson J, Lacroix J. Cardiac arrhythmias associated with severe traumatic brain injury and hypo- thermia therapy. Pediatr Crit Care 2010;11(3):408-14. 19. Aibiki M, Kawaguchi S, Maekawa N. Reversible hypophosphatemia during moderate hypothermia therapy for brain – injured patients. Crit Care Med 2001;29(9):1726-30. 20. Polderman KH, Peederman SM, Girbes ARJ. Hypophosphatemia and hypomagnesemia induced by cooling in patients with severe head injury. J Neurosurg 2001;94(5):697-705. 21. Adelson PD, Ragheb J, Kaney P, Brockmeyer D, Beers SR, Brown SD, et al. Phase II clinical trial of moderate hypothermia after severe traumatic brain injury in children. Neurosurgery 2005;56(4):740-54. 22. Hutchinson J, Ward R, Lacroix J, Hebert P, Skippen P, Barnes M, et al. Hypothermia pediatric head injury trial: the value of a pretrial clinical evaluation phase. Dev Neurosci 2006;28(4-5):291-301. 23. Polderman KH. Induced hypothermia and fever control for prevention and treatment of neurological injuries. Lancet 2008;371:1955-69. 24. Bruel C, Parienti JJ, Marie W, Arrot X, Daubin C, Du Cheiron D, et al. Mild hypothermia during advanced life support: a preliminary study in out – of – hospital cardiac arrest. Crit Care 2008;12(1):R31(doi:10.1186/cc6809). 25. Kim F, Olsufka M, Longstreth WTMJC, Carlbom D, Deem S, Kudenchuk P. Pilot randomized clinical trial of prehospital induction of mild hypothermia in out-of-hospital cardiac arrest patients with a rapid infusion of 4oC normal saline. Circulation 2007;115:3064-70. 26. Grande PO, Reinstrup P, Romner B. Active cooling in traumatic brain - injured patients: a questionable therapy? Acta Anesthesiol Scand 2009;53:1233-8. 27. Gluckman PD, Wyatt JS, Azzopardi D, ballard R, Edwards AD, Ferriero DM. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomized trial. Lancet 2005;365:663-70. 28. Hein OV, Triltsch A, Buch C, Kox WJ, Spies C. Mild hypothermia after near drowning twin toddlers. Crit Care 2004;8(5):R353-R357. 29. Hay AW, Swann DG, Bell K, Walsh TS, Cook B. Therapeutic hypothermia in comatose patients after out – of hospital cardiac arrest. Ana- esthesia 2008;63:15-9.

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