Brain Temperature in Neonates with Hypoxic-Ischemic Encephalopathy during Therapeutic Hypothermia Tai-Wei Wu, MD1, Claire McLean, MD1, Philippe Friedlich, MD, MS Epi, MBA1, Jessica Wisnowski, PhD2, John Grimm, MD2, Ashok Panigrahy, MD2, Stefan Bluml, PhD2, and Istvan Seri, MD, PhD1 Objective To noninvasively determine brain temperature of neonates with hypoxic-ischemic encephalopathy (HIE) during and after therapeutic hypothermia. Study design Using a phantom, we derived a calibration curve to calculate brain temperature based on chemical shift differences in magnetic resonance spectroscopy. We enrolled infants admitted for therapeutic hypothermia and assigned them to a moderate HIE (M-HIE) or severe HIE (S-HIE) group based on Sarnat staging. Rectal (core) temperature and magnetic resonance spectroscopy data used to derive regional brain temperatures (basal ganglia, thalamus, and cortical gray matter) were acquired concomitantly during and after therapeutic hypothermia. We compared brain and rectal temperature in the M-HIE and S-HIE groups during and after therapeutic hypothermia using 2-tailed t-tests. Results Eighteen patients (14 with M-HIE and 4 with S-HIE) were enrolled. As expected, both brain and rectal temperatures were lower during therapeutic hypothermia than after therapeutic hypothermia. Brain temperature in patients with S-HIE was higher than in those with M-HIE both during (35.1 1.3 C vs 33.7 1.2 C; P < .01) and after therapeutic hypothermia (38.1 1.5 C vs 36.8 1.3 C; P < .01). The brain–rectal temperature gradient was also greater in the S-HIE group both during and after therapeutic hypothermia. Conclusion For this analysis of a small number of patients, brain temperature and brain–rectal temperature gradient were higher in neonates with S-HIE than in those with M-HIE during and after therapeutic hypothermia. Further studies are needed to determine whether further decreasing brain temperature in neonates with S-HIE is safe and effective in improving outcome. (J Pediatr 2014;165:1129-34). See editorial, p 1081
H
ypoxic-ischemic encephalopathy (HIE) affects 1-6 per 1000 live term births and continues to be a major cause of newborn morbidity and mortality despite advances in obstetric management.1,2 Adverse outcomes include death, cerebral palsy, intellectual disability, developmental delay, and intractable seizures. Indeed, more than 60% of infants with severe HIE (S-HIE) die, and almost 100% of the survivors suffer from long-term neurologic disabilities.2-4 In animal models of HIE, small increases in brain temperature are associated with increased severity of brain injury, both clinically and histopathologically,5,6 and prevention of hyperthermia or reducing brain temperature decreases neuronal cell damage.7,8 In humans, brain and/or body temperature elevation often accompanies brain injury, as seen in traumatic brain injury, adult stroke, and HIE.9-12 The magnitude of temperature elevation correlates with infarct size and severity and is a risk factor for poor clinical outcome.12-14 In adult patients with acute ischemic stroke, regional brain temperature measurement by magnetic resonance spectroscopy (MRS) thermometry has revealed that regional brain temperature is correlated with the size and location of the lesion, as well as with clinical stroke severity as measured by the National Institutes of Health Stroke Scale score.15 Therapeutic hypothermia has become the standard of care for neonates with HIE, because it reduces overall neurodevelopmental disability and mortality.16-19 Owing to the invasive nature of direct brain temperature measurement, esophageal or rectal temperatures are used to guide therapeutic hypothermia; however, given that brain temperature frequently exceeds systemic temperature in patients with BG GM HIE M-HIE MR MRI MRS NAA S-HIE Thal
Basal ganglia Gray matter Hypoxic-ischemic encephalopathy Moderate hypoxic-ischemic encephalopathy Magnetic resonance Magnetic resonance imaging Magnetic resonance spectroscopy N-acetyl-asparate Severe hypoxic-ischemic encephalopathy Thalamus
From the 1Division of Neonatal Medicine, Department of Pediatrics, Center for Fetal and Neonatal Medicine and 2 Department of Radiology, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA Supported by the Gerber Foundation, United States (507-3217). The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2014.07.022
1129
THE JOURNAL OF PEDIATRICS
www.jpeds.com
acute brain injury, esophageal and rectal temperatures might not be reliable surrogate measures of brain temperature.20,21 In this study, we investigated the effectiveness of therapeutic hypothermia in lowering the brain temperature of infants with HIE. We hypothesized that infants with S-HIE would have higher brain temperatures than those with moderate HIE (M-HIE). In addition, to assess the validity of using rectal temperature as a surrogate for brain temperature, we compared the brain–rectal temperature gradient in infants with M-HIE and those with S-HIE both during and after therapeutic hypothermia.
Methods Newborns admitted to the newborn and infant critical care unit at Children’s Hospital Los Angeles for therapeutic hypothermia were prospectively enrolled into this observational study between April 2012 and August 2013. Our eligibility criteria for therapeutic hypothermia are similar to those of the National Institute of Child Health and Human Development’s whole-body hypothermia trial,22 including birth at $36 weeks postmenstrual age, birth weight >1800 g, admission during the first 6 hours of postnatal life, and evidence of severe acidosis. Severe acidosis is defined as cord or postnatal blood gas pH #7.0 or base deficit $16 within the first hour after delivery. Alternatively, if blood gas analysis results are not available, or if the pH is 7.01-7.15 or base deficit is 10-16, the patient must have a documented perinatal event (abruptio placentae, cord prolapse, or variable or late fetal heart rate decelerations) and either a 10-minute Apgar score of #5 or the need for assisted ventilation for $10 minutes. Once the foregoing criteria are met, the patient also must have clinical seizures, an abnormal background pattern on amplitude-integrated electroencephalography, or the presence of moderate to severe encephalopathy confirmed by the attending neonatologist based on the findings of the neurologic examination. Patients who had a major congenital anomaly; required inhaled nitric oxide, high-frequency ventilation, extracorporeal membrane oxygenation support; or had another clinical condition precluding safe in-house transport to the magnetic resonance imaging (MRI) suite were excluded. Demographic data were collected retrospectively using the electronic medical record system. The study was approved by the hospital’s Institutional Review Board, and written consent for each patient to undergo an MRI study during therapeutic hypothermia was provided by a parent or a legal guardian. Whole-body therapeutic hypothermia was achieved using a cooling device equipped with a disposable blanket (Blanketrol III; Cincinnati Sub-Zero, Cincinnati, Ohio) programmed to maintain rectal temperature at 33.5 C for 72 hours. For in-house transport and the MRI studies, a mobile power source and custom extension tubing were added. Using this system, therapeutic hypothermia remained uninterrupted, and rectal temperature was successfully maintained at a mean of 33.3 0.3 C during in-house transport and the MRI studies.23 1130
Vol. 165, No. 6 MRS Thermometry and Phantom Experiment MRS can be used to noninvasively measure absolute brain temperature.24-26 This is based on the principle that temperature affects hydrogen bonding between water molecules, which translates to a shift in spectral position of the water signal relative to a reference metabolite, such as N-acetylasparate (NAA), on MRS. By analyzing the chemical shift differences (Dppm) between the water peak and the metabolite spectrum, brain temperature can be derived with a reported accuracy of 0.5 C and a precision of 0.3 C.15,24,27 A reference phantom was constructed using a 500-mL spherical glass flask containing 5 mM NAA in phosphate buffer and pH adjusted to 7.25. A magnetic resonance (MR)-compatible fiberoptic temperature probe (Invivo Systems, Gainesville, Florida) was inserted into the center of the flask, allowing for continuous temperature measurements during MRS acquisition. The flask was placed into a hot water bath until the solution temperature reached 42 C, and then insulated with linens to minimize rapid cooling within the MR suite. Sequential MR spectra were obtained as the brain phantom slowly cooled to room temperature, using the same MRS method as in the patient examinations (see below). iNMR software (Mestrelab Research, Molfetta, Italy) was used to determine the peak positions of water and NAA, from which the chemical shift difference was calculated. Thereafter, chemical shift differences were plotted against the actual temperature (Figure 1, A). Using linear regression, the temperature (T, in C) was determined as follows: T ¼ ð102:89 DH2O-NAA Þ þ 308:64; where DH2O-NAA is the chemical shift difference between the water and NAA peaks. The R2 value was 0.99. MRI All enrolled patients were scanned in the same clinical 3-T MR scanner during therapeutic hypothermia within the first 3 days of postnatal life (first scan) and again after rewarming before hospital discharge (second scan). According to our clinical practice, a series of standardized MR images (T1-weighted, T2-weighted, and diffusion-weighted MRI and MRS) were acquired for all newborns with HIE. Single-voxel MR spectra of the right basal ganglia (BG), left thalamus (Thal), and medial cortical gray matter (GM) were obtained by 2 investigators independent of brain injury findings on MRI with guidance from neuroanatomic landmarks, such as the caudate nucleus, thalamus, and splenium of corpus callosum. To ensure consistency in localization and size (3 cm3), the 2 investigators also referenced localization images from a previous scan in a previous patient if the study was performed during therapeutic hypothermia and from a previous scan in the same patient if the study was performed after therapeutic hypothermia (Figure 1, B). MR spectra were obtained using a point-resolved spectroscopy sequence with an echo time of 35 ms and a repetition time of 2 seconds. A reference scan from averaging 16 unsuppressed water Wu et al
ORIGINAL ARTICLES
December 2014
signals was obtained first, followed by a water-suppressed spectrum using 128 averages without changing the receiver frequency. A MR-compatible rectal probe was inserted to a depth of 4-5 cm, and rectal temperatures were recorded at each MR spectrum acquisition. Data Analyses Brain temperature was calculated from chemical shift data by applying the equation derived from the calibration phantom experiment. The investigator who calculated brain temperature was blinded to the clinical severity of encephalopathy and rectal temperature at the time of the MRI scan. Statistical analysis was performed using GraphPad Prism software (GraphPad Software, La Jolla, California). Normality was confirmed by the D’Agostino and Pearson omnibus normality test. A 2-tailed t-test was used to compare brain temperature and brain–rectal temperature difference in the M-HIE and S-HIE groups during and after therapeutic hypothermia. Repeated-measures 1-way ANOVA with GeisserGreenhouse correction was used to test the differences among regional brain temperatures (BG, Thal, and GM) during and after therapeutic hypothermia. Values are reported as mean SD, with a P value or = 1 degree C alter functional neurologic outcome and histopathology in a canine model of complete cerebral ischemia. Anesthesiology 1995;83:325-35. 7. Yager JY, Armstrong EA, Jaharus C, Saucier DM, Wirrell EC. Preventing hyperthermia decreases brain damage following neonatal hypoxicischemic seizures. Brain Res 2004;1011:48-57. 8. Mishima K, Ikeda T, Yoshikawa T, Aoo N, Egashira N, Xia YX, et al. Effects of hypothermia and hyperthermia on attentional and spatial learning deficits following neonatal hypoxia-ischemic insult in rats. Behav Brain Res 2004;151:209-17. 9. Mellerg ard P, Nordstr€ om CH. Intracerebral temperature in neurosurgical patients. Neurosurgery 1991;28:709-13. 10. Karaszewski B, Wardlaw JM, Marshall I, Cvoro V, Wartolowska K, Haga K, et al. Early brain temperature elevation and anaerobic metabolism in human acute ischaemic stroke. Brain 2009;132:955-64. 11. Schwab S, Spranger M, Aschoff A, Steiner T, Hacke W. Brain temperature monitoring and modulation in patients with severe MCA infarction. Neurology 1997;48:762-7. 12. Laptook A, Tyson J, Shankaran S, McDonald S, Ehrenkranz R, Fanaroff A, et al. Elevated temperature after hypoxic-ischemic encephalopathy: risk factor for adverse outcomes. Pediatrics 2008;122:491-9.
Brain Temperature in Neonates with Hypoxic-Ischemic Encephalopathy during Therapeutic Hypothermia
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www.jpeds.com
13. Jørgensen HS, Reith J, Pedersen PM, Nakayama H, Olsen TS. Body temperature and outcome in stroke patients. Lancet 1996;348:193. 14. Reith J, Jørgensen HS, Pedersen PM, Nakayama H, Raaschou HO, Jeppesen LL, et al. Body temperature in acute stroke: relation to stroke severity, infarct size, mortality, and outcome. Lancet 1996; 347:422-5. 15. Marshall I, Karaszewski B, Wardlaw JM, Cvoro V, Wartolowska K, Armitage PA, et al. Measurement of regional brain temperature using proton spectroscopic imaging: validation and application to acute ischemic stroke. Magn Reson Imaging 2006;24:699-706. 16. Pfister RH, Soll RF. Hypothermia for the treatment of infants with hypoxic-ischemic encephalopathy. J Perinatol 2010;30(Suppl):S82-7. 17. Tagin MA, Woolcott CG, Vincer MJ, Whyte RK, Stinson DA. Hypothermia for neonatal hypoxic ischemic encephalopathy: an updated systematic review and meta-analysis. Arch Pediatr Adolesc Med 2012;166:558-66. 18. Shankaran S, Pappas A, McDonald SA, Vohr BR, Hintz SR, Yolton K, et al. Childhood outcomes after hypothermia for neonatal encephalopathy. N Engl J Med 2012;366:2085-92. 19. Guillet R, Edwards AD, Thoresen M, Ferriero DM, Gluckman PD, Whitelaw A, et al. Seven- to eight-year follow-up of the CoolCap trial of head cooling for neonatal encephalopathy. Pediatr Res 2012;71:205-9. 20. Rumana CS, Gopinath SP, Uzura M, Valadka AB, Robertson CS. Brain temperature exceeds systemic temperature in head-injured patients. Crit Care Med 1998;26:562-7. 21. Childs C, Vail A, Protheroe R, King AT, Dark PM. Differences between brain and rectal temperatures during routine critical care of patients with severe traumatic brain injury. Anaesthesia 2005;60:759-65. 22. Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 2005;353:1574-84. 23. Wu TW, McLean C, Friedlich P, Grimm J, Bluml S, Seri I. Maintenance of whole-body therapeutic hypothermia during patient transport and magnetic resonance imaging. Pediatr Radiol 2014;44:613-7.
1134
Vol. 165, No. 6 24. Cady EB, Penrice J, Robertson NJ. Improved reproducibility of MRS regional brain thermometry by “amplitude-weighted combination”. NMR Biomed 2011;24:865-72. 25. Corbett RJ, Laptook AR, Tollefsbol G, Kim B. Validation of a noninvasive method to measure brain temperature in vivo using 1H NMR spectroscopy. J Neurochem 1995;64:1224-30. 26. Corbett R, Laptook A, Weatherall P. Noninvasive measurements of human brain temperature using volume-localized proton magnetic resonance spectroscopy. J Cereb Blood Flow Metab 1997;17:363-9. 27. Weis J, Covaciu L, Rubertsson S, Allers M, Lunderquist A, Ahlstr€ om H. Noninvasive monitoring of brain temperature during mild hypothermia. Magn Reson Imaging 2009;27:923-32. 28. Edwards AD, Yue X, Squier MV, Thoresen M, Cady EB, Penrice J, et al. Specific inhibition of apoptosis after cerebral hypoxia-ischaemia by moderate post-insult hypothermia. Biochem Biophys Res Commun 1995;217:1193-9. 29. Thoresen M, Penrice J, Lorek A, Cady EB, Wylezinska M, Kirkbride V, et al. Mild hypothermia after severe transient hypoxia-ischemia ameliorates delayed cerebral energy failure in the newborn piglet. Pediatr Res 1995;37:667-70. 30. Kiyatkin EA. Brain temperature homeostasis: physiological fluctuations and pathological shifts. Front Biosci (Landmark Ed) 2010;15:73-92. 31. Rango M, Arighi A, Bresolin N. Brain temperature: what do we know? Neuroreport 2012;23:483-7. 32. Bertolizio G, Mason L, Bissonnette B. Brain temperature: heat production, elimination and clinical relevance. Paediatr Anaesth 2011; 21:347-58. 33. Sarkar S, Donn SM, Bhagat I, Dechert RE, Barks JD. Esophageal and rectal temperatures as estimates of core temperature during therapeutic whole-body hypothermia. J Pediatr 2013;162:208-10. 34. Iwata S, Iwata O, Thornton JS, Shanmugalingam S, Bainbridge A, Peebles D, et al. Superficial brain is cooler in small piglets: neonatal hypothermia implications. Ann Neurol 2006;60:578-85.
Wu et al
H
ypoxic-ischemic encephalopathy (HIE) affects 1-6 per 1000 live term births and continues to be a major cause of newborn morbidity and mortality despite advances in obstetric management.1,2 Adverse outcomes include death, cerebral palsy, intellectual disability, developmental delay, and intractable seizures. Indeed, more than 60% of infants with severe HIE (S-HIE) die, and almost 100% of the survivors suffer from long-term neurologic disabilities.2-4 In animal models of HIE, small increases in brain temperature are associated with increased severity of brain injury, both clinically and histopathologically,5,6 and prevention of hyperthermia or reducing brain temperature decreases neuronal cell damage.7,8 In humans, brain and/or body temperature elevation often accompanies brain injury, as seen in traumatic brain injury, adult stroke, and HIE.9-12 The magnitude of temperature elevation correlates with infarct size and severity and is a risk factor for poor clinical outcome.12-14 In adult patients with acute ischemic stroke, regional brain temperature measurement by magnetic resonance spectroscopy (MRS) thermometry has revealed that regional brain temperature is correlated with the size and location of the lesion, as well as with clinical stroke severity as measured by the National Institutes of Health Stroke Scale score.15 Therapeutic hypothermia has become the standard of care for neonates with HIE, because it reduces overall neurodevelopmental disability and mortality.16-19 Owing to the invasive nature of direct brain temperature measurement, esophageal or rectal temperatures are used to guide therapeutic hypothermia; however, given that brain temperature frequently exceeds systemic temperature in patients with BG GM HIE M-HIE MR MRI MRS NAA S-HIE Thal
Basal ganglia Gray matter Hypoxic-ischemic encephalopathy Moderate hypoxic-ischemic encephalopathy Magnetic resonance Magnetic resonance imaging Magnetic resonance spectroscopy N-acetyl-asparate Severe hypoxic-ischemic encephalopathy Thalamus
From the 1Division of Neonatal Medicine, Department of Pediatrics, Center for Fetal and Neonatal Medicine and 2 Department of Radiology, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA Supported by the Gerber Foundation, United States (507-3217). The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2014.07.022
1129
THE JOURNAL OF PEDIATRICS
www.jpeds.com
acute brain injury, esophageal and rectal temperatures might not be reliable surrogate measures of brain temperature.20,21 In this study, we investigated the effectiveness of therapeutic hypothermia in lowering the brain temperature of infants with HIE. We hypothesized that infants with S-HIE would have higher brain temperatures than those with moderate HIE (M-HIE). In addition, to assess the validity of using rectal temperature as a surrogate for brain temperature, we compared the brain–rectal temperature gradient in infants with M-HIE and those with S-HIE both during and after therapeutic hypothermia.
Methods Newborns admitted to the newborn and infant critical care unit at Children’s Hospital Los Angeles for therapeutic hypothermia were prospectively enrolled into this observational study between April 2012 and August 2013. Our eligibility criteria for therapeutic hypothermia are similar to those of the National Institute of Child Health and Human Development’s whole-body hypothermia trial,22 including birth at $36 weeks postmenstrual age, birth weight >1800 g, admission during the first 6 hours of postnatal life, and evidence of severe acidosis. Severe acidosis is defined as cord or postnatal blood gas pH #7.0 or base deficit $16 within the first hour after delivery. Alternatively, if blood gas analysis results are not available, or if the pH is 7.01-7.15 or base deficit is 10-16, the patient must have a documented perinatal event (abruptio placentae, cord prolapse, or variable or late fetal heart rate decelerations) and either a 10-minute Apgar score of #5 or the need for assisted ventilation for $10 minutes. Once the foregoing criteria are met, the patient also must have clinical seizures, an abnormal background pattern on amplitude-integrated electroencephalography, or the presence of moderate to severe encephalopathy confirmed by the attending neonatologist based on the findings of the neurologic examination. Patients who had a major congenital anomaly; required inhaled nitric oxide, high-frequency ventilation, extracorporeal membrane oxygenation support; or had another clinical condition precluding safe in-house transport to the magnetic resonance imaging (MRI) suite were excluded. Demographic data were collected retrospectively using the electronic medical record system. The study was approved by the hospital’s Institutional Review Board, and written consent for each patient to undergo an MRI study during therapeutic hypothermia was provided by a parent or a legal guardian. Whole-body therapeutic hypothermia was achieved using a cooling device equipped with a disposable blanket (Blanketrol III; Cincinnati Sub-Zero, Cincinnati, Ohio) programmed to maintain rectal temperature at 33.5 C for 72 hours. For in-house transport and the MRI studies, a mobile power source and custom extension tubing were added. Using this system, therapeutic hypothermia remained uninterrupted, and rectal temperature was successfully maintained at a mean of 33.3 0.3 C during in-house transport and the MRI studies.23 1130
Vol. 165, No. 6 MRS Thermometry and Phantom Experiment MRS can be used to noninvasively measure absolute brain temperature.24-26 This is based on the principle that temperature affects hydrogen bonding between water molecules, which translates to a shift in spectral position of the water signal relative to a reference metabolite, such as N-acetylasparate (NAA), on MRS. By analyzing the chemical shift differences (Dppm) between the water peak and the metabolite spectrum, brain temperature can be derived with a reported accuracy of 0.5 C and a precision of 0.3 C.15,24,27 A reference phantom was constructed using a 500-mL spherical glass flask containing 5 mM NAA in phosphate buffer and pH adjusted to 7.25. A magnetic resonance (MR)-compatible fiberoptic temperature probe (Invivo Systems, Gainesville, Florida) was inserted into the center of the flask, allowing for continuous temperature measurements during MRS acquisition. The flask was placed into a hot water bath until the solution temperature reached 42 C, and then insulated with linens to minimize rapid cooling within the MR suite. Sequential MR spectra were obtained as the brain phantom slowly cooled to room temperature, using the same MRS method as in the patient examinations (see below). iNMR software (Mestrelab Research, Molfetta, Italy) was used to determine the peak positions of water and NAA, from which the chemical shift difference was calculated. Thereafter, chemical shift differences were plotted against the actual temperature (Figure 1, A). Using linear regression, the temperature (T, in C) was determined as follows: T ¼ ð102:89 DH2O-NAA Þ þ 308:64; where DH2O-NAA is the chemical shift difference between the water and NAA peaks. The R2 value was 0.99. MRI All enrolled patients were scanned in the same clinical 3-T MR scanner during therapeutic hypothermia within the first 3 days of postnatal life (first scan) and again after rewarming before hospital discharge (second scan). According to our clinical practice, a series of standardized MR images (T1-weighted, T2-weighted, and diffusion-weighted MRI and MRS) were acquired for all newborns with HIE. Single-voxel MR spectra of the right basal ganglia (BG), left thalamus (Thal), and medial cortical gray matter (GM) were obtained by 2 investigators independent of brain injury findings on MRI with guidance from neuroanatomic landmarks, such as the caudate nucleus, thalamus, and splenium of corpus callosum. To ensure consistency in localization and size (3 cm3), the 2 investigators also referenced localization images from a previous scan in a previous patient if the study was performed during therapeutic hypothermia and from a previous scan in the same patient if the study was performed after therapeutic hypothermia (Figure 1, B). MR spectra were obtained using a point-resolved spectroscopy sequence with an echo time of 35 ms and a repetition time of 2 seconds. A reference scan from averaging 16 unsuppressed water Wu et al
ORIGINAL ARTICLES
December 2014
signals was obtained first, followed by a water-suppressed spectrum using 128 averages without changing the receiver frequency. A MR-compatible rectal probe was inserted to a depth of 4-5 cm, and rectal temperatures were recorded at each MR spectrum acquisition. Data Analyses Brain temperature was calculated from chemical shift data by applying the equation derived from the calibration phantom experiment. The investigator who calculated brain temperature was blinded to the clinical severity of encephalopathy and rectal temperature at the time of the MRI scan. Statistical analysis was performed using GraphPad Prism software (GraphPad Software, La Jolla, California). Normality was confirmed by the D’Agostino and Pearson omnibus normality test. A 2-tailed t-test was used to compare brain temperature and brain–rectal temperature difference in the M-HIE and S-HIE groups during and after therapeutic hypothermia. Repeated-measures 1-way ANOVA with GeisserGreenhouse correction was used to test the differences among regional brain temperatures (BG, Thal, and GM) during and after therapeutic hypothermia. Values are reported as mean SD, with a P value or = 1 degree C alter functional neurologic outcome and histopathology in a canine model of complete cerebral ischemia. Anesthesiology 1995;83:325-35. 7. Yager JY, Armstrong EA, Jaharus C, Saucier DM, Wirrell EC. Preventing hyperthermia decreases brain damage following neonatal hypoxicischemic seizures. Brain Res 2004;1011:48-57. 8. Mishima K, Ikeda T, Yoshikawa T, Aoo N, Egashira N, Xia YX, et al. Effects of hypothermia and hyperthermia on attentional and spatial learning deficits following neonatal hypoxia-ischemic insult in rats. Behav Brain Res 2004;151:209-17. 9. Mellerg ard P, Nordstr€ om CH. Intracerebral temperature in neurosurgical patients. Neurosurgery 1991;28:709-13. 10. Karaszewski B, Wardlaw JM, Marshall I, Cvoro V, Wartolowska K, Haga K, et al. Early brain temperature elevation and anaerobic metabolism in human acute ischaemic stroke. Brain 2009;132:955-64. 11. Schwab S, Spranger M, Aschoff A, Steiner T, Hacke W. Brain temperature monitoring and modulation in patients with severe MCA infarction. Neurology 1997;48:762-7. 12. Laptook A, Tyson J, Shankaran S, McDonald S, Ehrenkranz R, Fanaroff A, et al. Elevated temperature after hypoxic-ischemic encephalopathy: risk factor for adverse outcomes. Pediatrics 2008;122:491-9.
Brain Temperature in Neonates with Hypoxic-Ischemic Encephalopathy during Therapeutic Hypothermia
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www.jpeds.com
13. Jørgensen HS, Reith J, Pedersen PM, Nakayama H, Olsen TS. Body temperature and outcome in stroke patients. Lancet 1996;348:193. 14. Reith J, Jørgensen HS, Pedersen PM, Nakayama H, Raaschou HO, Jeppesen LL, et al. Body temperature in acute stroke: relation to stroke severity, infarct size, mortality, and outcome. Lancet 1996; 347:422-5. 15. Marshall I, Karaszewski B, Wardlaw JM, Cvoro V, Wartolowska K, Armitage PA, et al. Measurement of regional brain temperature using proton spectroscopic imaging: validation and application to acute ischemic stroke. Magn Reson Imaging 2006;24:699-706. 16. Pfister RH, Soll RF. Hypothermia for the treatment of infants with hypoxic-ischemic encephalopathy. J Perinatol 2010;30(Suppl):S82-7. 17. Tagin MA, Woolcott CG, Vincer MJ, Whyte RK, Stinson DA. Hypothermia for neonatal hypoxic ischemic encephalopathy: an updated systematic review and meta-analysis. Arch Pediatr Adolesc Med 2012;166:558-66. 18. Shankaran S, Pappas A, McDonald SA, Vohr BR, Hintz SR, Yolton K, et al. Childhood outcomes after hypothermia for neonatal encephalopathy. N Engl J Med 2012;366:2085-92. 19. Guillet R, Edwards AD, Thoresen M, Ferriero DM, Gluckman PD, Whitelaw A, et al. Seven- to eight-year follow-up of the CoolCap trial of head cooling for neonatal encephalopathy. Pediatr Res 2012;71:205-9. 20. Rumana CS, Gopinath SP, Uzura M, Valadka AB, Robertson CS. Brain temperature exceeds systemic temperature in head-injured patients. Crit Care Med 1998;26:562-7. 21. Childs C, Vail A, Protheroe R, King AT, Dark PM. Differences between brain and rectal temperatures during routine critical care of patients with severe traumatic brain injury. Anaesthesia 2005;60:759-65. 22. Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 2005;353:1574-84. 23. Wu TW, McLean C, Friedlich P, Grimm J, Bluml S, Seri I. Maintenance of whole-body therapeutic hypothermia during patient transport and magnetic resonance imaging. Pediatr Radiol 2014;44:613-7.
1134
Vol. 165, No. 6 24. Cady EB, Penrice J, Robertson NJ. Improved reproducibility of MRS regional brain thermometry by “amplitude-weighted combination”. NMR Biomed 2011;24:865-72. 25. Corbett RJ, Laptook AR, Tollefsbol G, Kim B. Validation of a noninvasive method to measure brain temperature in vivo using 1H NMR spectroscopy. J Neurochem 1995;64:1224-30. 26. Corbett R, Laptook A, Weatherall P. Noninvasive measurements of human brain temperature using volume-localized proton magnetic resonance spectroscopy. J Cereb Blood Flow Metab 1997;17:363-9. 27. Weis J, Covaciu L, Rubertsson S, Allers M, Lunderquist A, Ahlstr€ om H. Noninvasive monitoring of brain temperature during mild hypothermia. Magn Reson Imaging 2009;27:923-32. 28. Edwards AD, Yue X, Squier MV, Thoresen M, Cady EB, Penrice J, et al. Specific inhibition of apoptosis after cerebral hypoxia-ischaemia by moderate post-insult hypothermia. Biochem Biophys Res Commun 1995;217:1193-9. 29. Thoresen M, Penrice J, Lorek A, Cady EB, Wylezinska M, Kirkbride V, et al. Mild hypothermia after severe transient hypoxia-ischemia ameliorates delayed cerebral energy failure in the newborn piglet. Pediatr Res 1995;37:667-70. 30. Kiyatkin EA. Brain temperature homeostasis: physiological fluctuations and pathological shifts. Front Biosci (Landmark Ed) 2010;15:73-92. 31. Rango M, Arighi A, Bresolin N. Brain temperature: what do we know? Neuroreport 2012;23:483-7. 32. Bertolizio G, Mason L, Bissonnette B. Brain temperature: heat production, elimination and clinical relevance. Paediatr Anaesth 2011; 21:347-58. 33. Sarkar S, Donn SM, Bhagat I, Dechert RE, Barks JD. Esophageal and rectal temperatures as estimates of core temperature during therapeutic whole-body hypothermia. J Pediatr 2013;162:208-10. 34. Iwata S, Iwata O, Thornton JS, Shanmugalingam S, Bainbridge A, Peebles D, et al. Superficial brain is cooler in small piglets: neonatal hypothermia implications. Ann Neurol 2006;60:578-85.
Wu et al
