Resuscitation 97 (2015) 88–90
Contents lists available at ScienceDirect
Resuscitation journal homepage: www.elsevier.com/locate/resuscitation
Experimental paper
Animal studies of neonatal hypothermic neuroprotection have translated well in to practice夽 Alistair J. Gunn a , Marianne Thoresen b,c,∗ a b c
Department of Physiology, School of Medical Sciences, University of Auckland, Private Bag, 92019 Auckland, New Zealand Department of Physiology, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway Neonatal Neuroscience, School of Clinical Medicine, University of Bristol, UK
a r t i c l e
i n f o
Article history: Received 12 February 2015 Received in revised form 26 March 2015 Accepted 29 March 2015 Keywords: Therapeutic hypothermia Neonatal hypoxic-ischemic encephalopathy Cardiac arrest Temperature
a b s t r a c t The discovery that mild, induced hypothermia can improve neurological recovery after global moderate to severe hypoxia-ischemia has been a dramatic validation of the strong foundation of preclinical studies that informed current protocols. The major challenge is to find ways to further improve outcomes. As discussed in this review, the findings from large clinical trials of extended cooling are highly concordant with recent animal studies. These findings support the use of precise, carefully selected animal models to refine our strategies to protect babies with moderate to severe encephalopathy before instigating further large trials. © 2015 Elsevier Ireland Ltd. All rights reserved.
There is now compelling evidence that mild induced hypothermia consistently improves neurological outcome after a moderate to severe hypoxic-ischemic (HI) insult in term infants, with reduced death, cerebral palsy and disability, and improved neurocognitive functioning that persists into school age.1–4 Despite this clear benefit, current protocols for therapeutic hypothermia are only partially neuroprotective, with a number needed to treat of approximately eight.1 Given this formidable challenge, the obvious question is whether “more” cooling than recommended by current protocols might further improve outcomes. Drs Shankaran and colleagues have recently completed a controlled trial that aimed to recruit 728 infants with neonatal encephalopathy, who were randomized to cooling to 33.5 ◦ C for 72 h (standard care), 32.0 ◦ C for 72 h, 33.5 ◦ C for 120 h, or 32.0 ◦ C for 120 h. The trial was stopped at the halfway point after 364 patients had been recruited, because the interim analyses showed that the risk ratio for death during intensive care after cooling for 120 h compared to 72 h was 1.37 (95% CI, 0.92–2.04), and for cooling to 32.0 ◦ C compared to 33.5 ◦ C, 1.24 (95% CI, 0.69–2.25).5 These data suggest that longer or deeper cooling for neonatal HI encephalopathy is likely to be futile, and may be deleterious. This
夽 A Spanish translated version of the abstract of this article appears as Appendix in the final online version at http://dx.doi.org/10.1016/j.resuscitation.2015.03.026. ∗ Corresponding author. E-mail addresses: [email protected] (A.J. Gunn), [email protected] (M. Thoresen). http://dx.doi.org/10.1016/j.resuscitation.2015.03.026 0300-9572/© 2015 Elsevier Ireland Ltd. All rights reserved.
trial studied relatively large changes, either a greater reduction in body temperature of 1.5 ◦ C, or an additional 48 h of cooling, or both. Therefore, we still cannot rule out the possibility that current protocols might be able to be improved in smaller incremental steps, to provide greater benefit. For example, the first small randomized hypothermia trial examined the safety of lowering body temperature in successive steps of just 0.5 ◦ C.6 The decision to stop the “cooler and deeper” trial was based on short-term survival. The infants in this trial are still being followed to assess primary outcome but these results are not yet available. Although earlier mortality and disability outcomes after hypothermia have been concordant,1 in principle it may still be possible that survivors from the trial could have improved neural outcomes in the longer term. However, current protocols were based on a remarkable foundation of mechanistic and empirical studies, which strongly suggest that standard cooling care is reasonably close to being the most effective protocol, as discussed next. Moreover, preclinical studies suggest that both depth and duration of cooling show u-shaped dose responses, with no further improvement if core temperature is reduced by more than ∼3.5 ◦ C,7 or when cooling is continued for more than approximately 72 h.8 The key to modern treatment was the finding that HI brain injury progressed over time in human and large animal studies. These showed transient recovery of oxidative metabolism and brain swelling for approximately 6 h, followed by a secondary phase of seizures and cell swelling, and bulk cell death that resolves over approximately 48–72 h after hypoxia-ischemia.9–11 Critically, mild cooling applied early after the initial insult, and continued until
A.J. Gunn, M. Thoresen / Resuscitation 97 (2015) 88–90
resolution of the secondary deterioration phase, improved outcomes without rebound deterioration after rewarming.10,12 Brain cooling in near-term fetal sheep was associated with a steep, sigmoidal relationship between brain cooling and protection, with no further benefit at brain temperatures below approximately 34 ◦ C.10 Similarly, in term piglets, whole body cooling from 38.5 to 35 ◦ C (i.e. a 3.5 ◦ C reduction in core temperature) prevented secondary failure of oxidative metabolism and reduced neuronal loss.12 Consistent with this older literature, more recent studies also found that reducing body temperature by 3.5 ◦ C or 5 ◦ C for 2–26 h after hypoxia-ischemia was associated with equivalent reduction in neuronal death in most brain regions, but increased injury was seen after cooling by 8.5 ◦ C.7 Further, deeper cooling by 8.5 ◦ C was also associated with greater mortality.13 In neonatal rats, deeper cooling is no more effective than mild cooling, and does not overcome the loss of protection by hypothermia seen after more severe injury.14 In part, partial protection with current regimens is likely related to the formidable clinical difficulties involved in starting hypothermia within the optimal window of opportunity.15 For example, after moderate HI in neonatal rats, immediate induction of mild hypothermia was protective, with a progressive loss of efficacy up to 6 h after the insult.16 In contrast, even immediate hypothermia was ineffective after a very severe insult in this paradigm. Other preclinical studies in both adult and immature animals do suggest that some of the loss of efficacy associated with delayed onset of hypothermia can be salvaged with more prolonged cooling. For example, in adult gerbils, 12 h of hypothermia initiated one hour after global ischemia effectively reduced hippocampal injury after 3, but not 5 min, of global ischemia.17 However, if the duration of hypothermia was extended for 24 h, near total preservation of CA1 neurons was seen after 5 min of global ischemia.17 In the near-term fetal sheep, cerebral hypothermia delayed by 5.5 h after ischemia, before the onset of post-ischemic seizures, is partially protective, and is associated with moderate secondary microgliosis.10,18 More recently, studies in term-equivalent fetal sheep have shown that extending the duration of delayed head cooling from 3 to 5 days did not improve any EEG or histological outcomes after severe ischemia, and was associated with reduced neuronal survival in the cerebral cortex and dentate gyrus.8 Thus, it is highly improbable that there will be any material neurological benefit from extended cooling. The International Liaison Committee on Resuscitation guidelines also recommend using therapeutic cooling in adults after out of hospital witnessed cardiac arrest. In this patient group, in contrast to newborns, the exact time of circulatory arrest is often known. The duration of cooling in adults is typically shorter; 12–48 h. It is also more difficult to achieve target temperature rapidly in the larger adult body; typically 4–5 h are required to achieve a core temperature of 33 ◦ C. Moreover, there is some concerning evidence from a recent randomized controlled trial that using intravenous saline to achieve prehospital cooling reduced the time to achieve core temperature but did not improve survival or measures of neurological outcome and was associated with significant complications such as rearrest and pulmonary edema.19 Such cold infusions are not needed to rapidly cool newborn infants and so have never been tested. It is not known whether the lack of benefit in adult cardiac arrest was related to the change in temperature per se, or to adverse effects of fast volume loading. Although data are limited, in African children with septic shock, the Fluid Expansion as a Supportive Treatment trial found that rapid fluid resuscitation increased mortality.20 Conversely, rewarming in adult studies has been slower, 33 ◦ C–37 ◦ C over 12–24 h, compared to 33.5◦ –37◦ over 4 h in newborn infants. In the first adult hypothermia studies the standard care group had temperatures close to 38 ◦ C after 24 h.21,22 It could therefore be that relative protection with hypothermia
89
was influenced by increased injury due increased brain temperatures in the control group. In line with this theory, a subsequent randomized trial where the cooling temperature was either 33 ◦ C or 36 ◦ C for 24 h, followed by slow rewarming and controlled normothermia, found similar rates of death or severe disability after 6 months in the two groups.23 However, interpretation of this study is difficult, as it included comatose patients with initial non-shockable rhythm, who had a high rate of adverse outcomes.24 Despite the overwhelming preclinical evidence from both newborn and adult animal studies,15,25 supported by observational data,26 that starting cooling earlier dramatically improves neuroprotection, there have been no formal controlled trials. In terms of directions that are most likely to inform the development of more robust protocols, we strongly suggest finding ways to start cooling earlier should be a key focus of future research. The recent findings from Shankaran and colleagues involving deeper and longer cooling provide a unique validation of the findings from many preclinical paradigms. Importantly, more recent findings from animal studies are highly concordant with the outcome of the ‘Cooler and Deeper’ trial. We therefore strongly support the use of precise, carefully selected animal models to refine our strategies to protect babies with moderate to severe encephalopathy before instigating further large trials. Conflict of interest statement The authors declare that they have no conflict of interest. References 1. Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev 2013;1:CD003311. 2. Azzopardi D, Strohm B, Marlow N, et al. Effects of hypothermia for perinatal asphyxia on childhood outcomes. N Engl J Med 2014;371:140–9. 3. Shankaran S, Pappas A, McDonald SA, et al. Childhood outcomes after hypothermia for neonatal encephalopathy. N Engl J Med 2012;366:2085–92. 4. Guillet R, Edwards AD, Thoresen M, et al. Seven- to eight-year follow-up of the CoolCap trial of head cooling for neonatal encephalopathy. Pediatr Res 2012;71:205–9. 5. Shankaran S, Laptook AR, Pappas A, et al. Effect of depth and duration of cooling on deaths in the NICU among neonates with hypoxic ischemic encephalopathy: a randomized clinical trial. JAMA 2014;312:2629–39. 6. Gunn AJ, Gluckman PD, Gunn TR. Selective head cooling in newborn infants after perinatal asphyxia: a safety study. Pediatrics 1998;102:885–92. 7. Alonso-Alconada D, Broad KD, Bainbridge A, et al. Brain cell death is reduced with cooling by 3.5 degrees C to 5 degrees C but increased with cooling by 8.5 degrees C in a piglet asphyxia model. Stroke 2015;46:275–8. 8. Davidson JO, Wassink G, Yuill CA, Zhang FG, Bennet L, Gunn AJ. How long is too long for cerebral cooling after ischemia in fetal sheep? J Cereb Blood Flow Metab 2015. Epub January 21. 9. Tan WK, Williams CE, During MJ, et al. Accumulation of cytotoxins during the development of seizures and edema after hypoxic-ischemic injury in late gestation fetal sheep. Pediatr Res 1996;39:791–7. 10. Gunn AJ, Gunn TR, de Haan HH, Williams CE, Gluckman PD. Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs. J Clin Invest 1997;99:248–56. 11. Azzopardi D, Wyatt JS, Cady EB, et al. Prognosis of newborn infants with hypoxic-ischemic brain injury assessed by phosphorus magnetic resonance spectroscopy. Pediatr Res 1989;25:445–51. 12. Thoresen M, Penrice J, Lorek A, et al. Mild hypothermia after severe transient hypoxia-ischemia ameliorates delayed cerebral energy failure in the newborn piglet. Pediatr Res 1995;37:667–70. 13. Kerenyi A, Kelen D, Faulkner SD, et al. Systemic effects of whole-body cooling to 35 degrees C, 33.5 degrees C, and 30 degrees C in a piglet model of perinatal asphyxia: implications for therapeutic hypothermia. Pediatr Res 2012;71:573–82. 14. Wood T, Osredkar D, Sabir H, Falck M, Maes E, Thoresen M. Cooler isn’t better – hypothermia at three different temperatures does not provide neuroprotection in a rat model of severe neonatal hypoxic-ischaemic encephalopathy. E-PAS2014 2014;4650:4658. 15. Gunn AJ, Thoresen M. Hypothermic neuroprotection. NeuroRx 2006;3:154–69. 16. Sabir H, Scull-Brown E, Liu X, Thoresen M. Immediate hypothermia is not neuroprotective after severe hypoxia-ischemia and is deleterious when delayed by 12 hours in neonatal rats. Stroke 2012;43:3364–70. 17. Colbourne F, Corbett D. Delayed and prolonged post-ischemic hypothermia is neuroprotective in the gerbil. Brain Res 1994;654:265–72.
90
A.J. Gunn, M. Thoresen / Resuscitation 97 (2015) 88–90
18. Gunn AJ, Gunn TR, Gunning MI, Williams CE, Gluckman PD. Neuroprotection with prolonged head cooling started before postischemic seizures in fetal sheep. Pediatrics 1998;102:1098–106. 19. Kim F, Nichol G, Maynard C, et al. Effect of prehospital induction of mild hypothermia on survival and neurological status among adults with cardiac arrest: a randomized clinical trial. JAMA 2014;311:45–52. 20. Maitland K, Kiguli S, Opoka RO, et al. Mortality after fluid bolus in African children with severe infection. N Engl J Med 2011;364:2483–95. 21. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002;346:557–63. 22. The Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002;346:549–56.
23. Nielsen N, Wetterslev J, Cronberg T, et al. Targeted temperature management at 33 degrees C versus 36 degrees C after cardiac arrest. N Engl J Med 2013;369:2197–206. 24. Frydland M, Kjaergaard J, Erlinge D, et al. Target temperature management of 33 ◦ C and 36 ◦ C in patients with out-of-hospital cardiac arrest with initial non-shockable rhythm – a TTM sub-study. Resuscitation 2015;89: 142–8. 25. Colbourne F, Sutherland G, Corbett D. Postischemic hypothermia. A critical appraisal with implications for clinical treatment. Mol Neurobiol 1997;14:171–201. 26. Thoresen M, Tooley J, Liu X, et al. Time is brain: starting therapeutic hypothermia within three hours after birth improves motor outcome in asphyxiated newborns. Neonatology 2013;104:228–33.
Contents lists available at ScienceDirect
Resuscitation journal homepage: www.elsevier.com/locate/resuscitation
Experimental paper
Animal studies of neonatal hypothermic neuroprotection have translated well in to practice夽 Alistair J. Gunn a , Marianne Thoresen b,c,∗ a b c
Department of Physiology, School of Medical Sciences, University of Auckland, Private Bag, 92019 Auckland, New Zealand Department of Physiology, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway Neonatal Neuroscience, School of Clinical Medicine, University of Bristol, UK
a r t i c l e
i n f o
Article history: Received 12 February 2015 Received in revised form 26 March 2015 Accepted 29 March 2015 Keywords: Therapeutic hypothermia Neonatal hypoxic-ischemic encephalopathy Cardiac arrest Temperature
a b s t r a c t The discovery that mild, induced hypothermia can improve neurological recovery after global moderate to severe hypoxia-ischemia has been a dramatic validation of the strong foundation of preclinical studies that informed current protocols. The major challenge is to find ways to further improve outcomes. As discussed in this review, the findings from large clinical trials of extended cooling are highly concordant with recent animal studies. These findings support the use of precise, carefully selected animal models to refine our strategies to protect babies with moderate to severe encephalopathy before instigating further large trials. © 2015 Elsevier Ireland Ltd. All rights reserved.
There is now compelling evidence that mild induced hypothermia consistently improves neurological outcome after a moderate to severe hypoxic-ischemic (HI) insult in term infants, with reduced death, cerebral palsy and disability, and improved neurocognitive functioning that persists into school age.1–4 Despite this clear benefit, current protocols for therapeutic hypothermia are only partially neuroprotective, with a number needed to treat of approximately eight.1 Given this formidable challenge, the obvious question is whether “more” cooling than recommended by current protocols might further improve outcomes. Drs Shankaran and colleagues have recently completed a controlled trial that aimed to recruit 728 infants with neonatal encephalopathy, who were randomized to cooling to 33.5 ◦ C for 72 h (standard care), 32.0 ◦ C for 72 h, 33.5 ◦ C for 120 h, or 32.0 ◦ C for 120 h. The trial was stopped at the halfway point after 364 patients had been recruited, because the interim analyses showed that the risk ratio for death during intensive care after cooling for 120 h compared to 72 h was 1.37 (95% CI, 0.92–2.04), and for cooling to 32.0 ◦ C compared to 33.5 ◦ C, 1.24 (95% CI, 0.69–2.25).5 These data suggest that longer or deeper cooling for neonatal HI encephalopathy is likely to be futile, and may be deleterious. This
夽 A Spanish translated version of the abstract of this article appears as Appendix in the final online version at http://dx.doi.org/10.1016/j.resuscitation.2015.03.026. ∗ Corresponding author. E-mail addresses: [email protected] (A.J. Gunn), [email protected] (M. Thoresen). http://dx.doi.org/10.1016/j.resuscitation.2015.03.026 0300-9572/© 2015 Elsevier Ireland Ltd. All rights reserved.
trial studied relatively large changes, either a greater reduction in body temperature of 1.5 ◦ C, or an additional 48 h of cooling, or both. Therefore, we still cannot rule out the possibility that current protocols might be able to be improved in smaller incremental steps, to provide greater benefit. For example, the first small randomized hypothermia trial examined the safety of lowering body temperature in successive steps of just 0.5 ◦ C.6 The decision to stop the “cooler and deeper” trial was based on short-term survival. The infants in this trial are still being followed to assess primary outcome but these results are not yet available. Although earlier mortality and disability outcomes after hypothermia have been concordant,1 in principle it may still be possible that survivors from the trial could have improved neural outcomes in the longer term. However, current protocols were based on a remarkable foundation of mechanistic and empirical studies, which strongly suggest that standard cooling care is reasonably close to being the most effective protocol, as discussed next. Moreover, preclinical studies suggest that both depth and duration of cooling show u-shaped dose responses, with no further improvement if core temperature is reduced by more than ∼3.5 ◦ C,7 or when cooling is continued for more than approximately 72 h.8 The key to modern treatment was the finding that HI brain injury progressed over time in human and large animal studies. These showed transient recovery of oxidative metabolism and brain swelling for approximately 6 h, followed by a secondary phase of seizures and cell swelling, and bulk cell death that resolves over approximately 48–72 h after hypoxia-ischemia.9–11 Critically, mild cooling applied early after the initial insult, and continued until
A.J. Gunn, M. Thoresen / Resuscitation 97 (2015) 88–90
resolution of the secondary deterioration phase, improved outcomes without rebound deterioration after rewarming.10,12 Brain cooling in near-term fetal sheep was associated with a steep, sigmoidal relationship between brain cooling and protection, with no further benefit at brain temperatures below approximately 34 ◦ C.10 Similarly, in term piglets, whole body cooling from 38.5 to 35 ◦ C (i.e. a 3.5 ◦ C reduction in core temperature) prevented secondary failure of oxidative metabolism and reduced neuronal loss.12 Consistent with this older literature, more recent studies also found that reducing body temperature by 3.5 ◦ C or 5 ◦ C for 2–26 h after hypoxia-ischemia was associated with equivalent reduction in neuronal death in most brain regions, but increased injury was seen after cooling by 8.5 ◦ C.7 Further, deeper cooling by 8.5 ◦ C was also associated with greater mortality.13 In neonatal rats, deeper cooling is no more effective than mild cooling, and does not overcome the loss of protection by hypothermia seen after more severe injury.14 In part, partial protection with current regimens is likely related to the formidable clinical difficulties involved in starting hypothermia within the optimal window of opportunity.15 For example, after moderate HI in neonatal rats, immediate induction of mild hypothermia was protective, with a progressive loss of efficacy up to 6 h after the insult.16 In contrast, even immediate hypothermia was ineffective after a very severe insult in this paradigm. Other preclinical studies in both adult and immature animals do suggest that some of the loss of efficacy associated with delayed onset of hypothermia can be salvaged with more prolonged cooling. For example, in adult gerbils, 12 h of hypothermia initiated one hour after global ischemia effectively reduced hippocampal injury after 3, but not 5 min, of global ischemia.17 However, if the duration of hypothermia was extended for 24 h, near total preservation of CA1 neurons was seen after 5 min of global ischemia.17 In the near-term fetal sheep, cerebral hypothermia delayed by 5.5 h after ischemia, before the onset of post-ischemic seizures, is partially protective, and is associated with moderate secondary microgliosis.10,18 More recently, studies in term-equivalent fetal sheep have shown that extending the duration of delayed head cooling from 3 to 5 days did not improve any EEG or histological outcomes after severe ischemia, and was associated with reduced neuronal survival in the cerebral cortex and dentate gyrus.8 Thus, it is highly improbable that there will be any material neurological benefit from extended cooling. The International Liaison Committee on Resuscitation guidelines also recommend using therapeutic cooling in adults after out of hospital witnessed cardiac arrest. In this patient group, in contrast to newborns, the exact time of circulatory arrest is often known. The duration of cooling in adults is typically shorter; 12–48 h. It is also more difficult to achieve target temperature rapidly in the larger adult body; typically 4–5 h are required to achieve a core temperature of 33 ◦ C. Moreover, there is some concerning evidence from a recent randomized controlled trial that using intravenous saline to achieve prehospital cooling reduced the time to achieve core temperature but did not improve survival or measures of neurological outcome and was associated with significant complications such as rearrest and pulmonary edema.19 Such cold infusions are not needed to rapidly cool newborn infants and so have never been tested. It is not known whether the lack of benefit in adult cardiac arrest was related to the change in temperature per se, or to adverse effects of fast volume loading. Although data are limited, in African children with septic shock, the Fluid Expansion as a Supportive Treatment trial found that rapid fluid resuscitation increased mortality.20 Conversely, rewarming in adult studies has been slower, 33 ◦ C–37 ◦ C over 12–24 h, compared to 33.5◦ –37◦ over 4 h in newborn infants. In the first adult hypothermia studies the standard care group had temperatures close to 38 ◦ C after 24 h.21,22 It could therefore be that relative protection with hypothermia
89
was influenced by increased injury due increased brain temperatures in the control group. In line with this theory, a subsequent randomized trial where the cooling temperature was either 33 ◦ C or 36 ◦ C for 24 h, followed by slow rewarming and controlled normothermia, found similar rates of death or severe disability after 6 months in the two groups.23 However, interpretation of this study is difficult, as it included comatose patients with initial non-shockable rhythm, who had a high rate of adverse outcomes.24 Despite the overwhelming preclinical evidence from both newborn and adult animal studies,15,25 supported by observational data,26 that starting cooling earlier dramatically improves neuroprotection, there have been no formal controlled trials. In terms of directions that are most likely to inform the development of more robust protocols, we strongly suggest finding ways to start cooling earlier should be a key focus of future research. The recent findings from Shankaran and colleagues involving deeper and longer cooling provide a unique validation of the findings from many preclinical paradigms. Importantly, more recent findings from animal studies are highly concordant with the outcome of the ‘Cooler and Deeper’ trial. We therefore strongly support the use of precise, carefully selected animal models to refine our strategies to protect babies with moderate to severe encephalopathy before instigating further large trials. Conflict of interest statement The authors declare that they have no conflict of interest. References 1. Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev 2013;1:CD003311. 2. Azzopardi D, Strohm B, Marlow N, et al. Effects of hypothermia for perinatal asphyxia on childhood outcomes. N Engl J Med 2014;371:140–9. 3. Shankaran S, Pappas A, McDonald SA, et al. Childhood outcomes after hypothermia for neonatal encephalopathy. N Engl J Med 2012;366:2085–92. 4. Guillet R, Edwards AD, Thoresen M, et al. Seven- to eight-year follow-up of the CoolCap trial of head cooling for neonatal encephalopathy. Pediatr Res 2012;71:205–9. 5. Shankaran S, Laptook AR, Pappas A, et al. Effect of depth and duration of cooling on deaths in the NICU among neonates with hypoxic ischemic encephalopathy: a randomized clinical trial. JAMA 2014;312:2629–39. 6. Gunn AJ, Gluckman PD, Gunn TR. Selective head cooling in newborn infants after perinatal asphyxia: a safety study. Pediatrics 1998;102:885–92. 7. Alonso-Alconada D, Broad KD, Bainbridge A, et al. Brain cell death is reduced with cooling by 3.5 degrees C to 5 degrees C but increased with cooling by 8.5 degrees C in a piglet asphyxia model. Stroke 2015;46:275–8. 8. Davidson JO, Wassink G, Yuill CA, Zhang FG, Bennet L, Gunn AJ. How long is too long for cerebral cooling after ischemia in fetal sheep? J Cereb Blood Flow Metab 2015. Epub January 21. 9. Tan WK, Williams CE, During MJ, et al. Accumulation of cytotoxins during the development of seizures and edema after hypoxic-ischemic injury in late gestation fetal sheep. Pediatr Res 1996;39:791–7. 10. Gunn AJ, Gunn TR, de Haan HH, Williams CE, Gluckman PD. Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs. J Clin Invest 1997;99:248–56. 11. Azzopardi D, Wyatt JS, Cady EB, et al. Prognosis of newborn infants with hypoxic-ischemic brain injury assessed by phosphorus magnetic resonance spectroscopy. Pediatr Res 1989;25:445–51. 12. Thoresen M, Penrice J, Lorek A, et al. Mild hypothermia after severe transient hypoxia-ischemia ameliorates delayed cerebral energy failure in the newborn piglet. Pediatr Res 1995;37:667–70. 13. Kerenyi A, Kelen D, Faulkner SD, et al. Systemic effects of whole-body cooling to 35 degrees C, 33.5 degrees C, and 30 degrees C in a piglet model of perinatal asphyxia: implications for therapeutic hypothermia. Pediatr Res 2012;71:573–82. 14. Wood T, Osredkar D, Sabir H, Falck M, Maes E, Thoresen M. Cooler isn’t better – hypothermia at three different temperatures does not provide neuroprotection in a rat model of severe neonatal hypoxic-ischaemic encephalopathy. E-PAS2014 2014;4650:4658. 15. Gunn AJ, Thoresen M. Hypothermic neuroprotection. NeuroRx 2006;3:154–69. 16. Sabir H, Scull-Brown E, Liu X, Thoresen M. Immediate hypothermia is not neuroprotective after severe hypoxia-ischemia and is deleterious when delayed by 12 hours in neonatal rats. Stroke 2012;43:3364–70. 17. Colbourne F, Corbett D. Delayed and prolonged post-ischemic hypothermia is neuroprotective in the gerbil. Brain Res 1994;654:265–72.
90
A.J. Gunn, M. Thoresen / Resuscitation 97 (2015) 88–90
18. Gunn AJ, Gunn TR, Gunning MI, Williams CE, Gluckman PD. Neuroprotection with prolonged head cooling started before postischemic seizures in fetal sheep. Pediatrics 1998;102:1098–106. 19. Kim F, Nichol G, Maynard C, et al. Effect of prehospital induction of mild hypothermia on survival and neurological status among adults with cardiac arrest: a randomized clinical trial. JAMA 2014;311:45–52. 20. Maitland K, Kiguli S, Opoka RO, et al. Mortality after fluid bolus in African children with severe infection. N Engl J Med 2011;364:2483–95. 21. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002;346:557–63. 22. The Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002;346:549–56.
23. Nielsen N, Wetterslev J, Cronberg T, et al. Targeted temperature management at 33 degrees C versus 36 degrees C after cardiac arrest. N Engl J Med 2013;369:2197–206. 24. Frydland M, Kjaergaard J, Erlinge D, et al. Target temperature management of 33 ◦ C and 36 ◦ C in patients with out-of-hospital cardiac arrest with initial non-shockable rhythm – a TTM sub-study. Resuscitation 2015;89: 142–8. 25. Colbourne F, Sutherland G, Corbett D. Postischemic hypothermia. A critical appraisal with implications for clinical treatment. Mol Neurobiol 1997;14:171–201. 26. Thoresen M, Tooley J, Liu X, et al. Time is brain: starting therapeutic hypothermia within three hours after birth improves motor outcome in asphyxiated newborns. Neonatology 2013;104:228–33.
