Skip to main content
NCBI home page
Brain Pathology logoLink to Brain Pathology
. 2006 Apr 5;10(1):61–71. doi: 10.1111/j.1750-3639.2000.tb00243.x

Resuscitative Hypothermia Protects the Neonatal Rat Brain from Hypoxic‐Ischemic Injury

Johann Nedelcu 1,✉, Michael A Klein 2, Adriano Aguzzi 2, Ernst Martin 1
PMCID: PMC8098239  PMID: 10668896

Abstract

The effect of 24h of hypothermic recovery on moderate hypoxic‐ischemic brain damage in P7‐rats was investigated for 42d after the insult, using magnetic resonance and histopathology. Occlusion of right common carotid artery and 90min exposure to 8% O2 at 37°C body temperature produced cytotoxic edema of 51 (±11)% brain volume (BV) and depression of brain energy metabolism (PCr/Pi) from 1.43(±0.21) to 0.14(±0.11). During recovery, the body temperature was reduced to 30°C for 24h in 36 animals, but was kept at 37°C in 34 animals. The edema waned upon reoxygenation leaving only the core lesion at 2h, but reappeared reaching a maximal extent of 11 ±8% BV under hypothermia compared to 45(±10)% under normothermia at around 24h. PCr/Pi recovered transiently within 13h and declined again to 1.07(±0.19) under hypothermia and to 0.48(±0.22) under normothermia at around 24h.

Hypothermia led to significant long term brain protection, leaving permanent tissue damage of 12(±6)% BV compared to 35(±12)% BV under normothermia. However, animals with severe initial injury developed large infarctions, despite hypothermic treatment. Even then, the time to develop infarction was significantly prolonged, leaving the opportunity for additional therapeutic intervention.

Full Text

The Full Text of this article is available as a PDF (293.1 KB).

References

  • 1. Amess PN, Penrice J, Lorek A, Kirkbride V, Wylezinska M, Cooper CE, D'Souza P, Tyszczuk L, Thoresen M, Edwards AD, Wyatt JS, Reynolds OR (1997) Mild hypothermia after severe transient hypoxia‐ischemia reduces the delayed rise in cerebral lactate in the piglet. Pediatr Res 41:803–808. [DOI] [PubMed] [Google Scholar]
  • 2. Azzopardi D, Wyatt JS, Cady EB, Delpy DT, Baudin J, Stewart AL, Hope PL, Hamilton PA, Reynolds OR (1989) Prognosis of newborn infants with hypoxic‐ischemic brain injury assessed by phosphorus magnetic resonance spectroscopy. Pediatr Res 25:445–451. [DOI] [PubMed] [Google Scholar]
  • 3. Bona E, Hagberg H, Loberg EM, Baagenholm R, Thoresen M (1998) Protective effects of moderate hypothermia after hypoxia‐ischemia in a neonatal rat model: short and long‐term outcome. Pediatr Res 43:738–745. [DOI] [PubMed] [Google Scholar]
  • 4. Burger C, McKinnon G, Buchli R, Boesiger P (1991) Toward fully automatic estimation of in vivo 31P spectra. Magn Reson Med 21:216–21. [DOI] [PubMed] [Google Scholar]
  • 5. Busto R, Globus MYT, Dietrich WD, Martinez E, Valdez I (1989) Effect of mild hypothermia on ischemia‐induced release of neurotransmitters and free fatty acids. Stroke 20:904–910. [DOI] [PubMed] [Google Scholar]
  • 6. Caroll M, Beek O (1992) Protection against hippocampal CA1 cell loss by post‐ischemic hypothermia is dependent on delay of initiation and duration. Metab Brain Dis 7:45–50. [DOI] [PubMed] [Google Scholar]
  • 7. Coimbra C, Wieloch T (1994) Moderate hypothermia mitigates neuronal damage in the rat brain when initiated several hours following transient cerebral ischemia. Acta Neuropathol 87:325–331. [DOI] [PubMed] [Google Scholar]
  • 8. Chopp M, Chen H, Dereski MO, Garcia JH (1991) Mild hypothermic intervention after graded ischemic stress in rats. Stroke 22:37–43. [DOI] [PubMed] [Google Scholar]
  • 9. Colbourne F, Corbett D (1994) Delayed and prolonged post‐ischemic hypothermia is neuroprotective in the gerbil. Brain Res 654:265–272. [DOI] [PubMed] [Google Scholar]
  • 10. Colbourne F, Corbett D (1995) Delayed postischemic hypthermia: A six month survival study using behavioral and histological assessments of neuroprotection. J Neurosci 15:7250–7256. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. Cordey R (1964) Hypothermia in resuscitating newborns in white asphyxia. Obstet Gynecol 24:760–767. [PubMed] [Google Scholar]
  • 12. Cordey R, Chiolero R, Miller JA (1973) Resuscitation of neonates by hypothermia: report on 20 cases with acid‐base determination on 10 cases and the long‐term development of 33 cases. Resuscitation 2:169–181. [DOI] [PubMed] [Google Scholar]
  • 13. Dietrich WD, Busto R, Alonso O, Globus MY, Ginsberg MD (1993) Intraischemic but not postischemic brain hypothermia protects chronically following forebrain ischemia in rats. J Cereb Blood Flow Metab 13:541–549. [DOI] [PubMed] [Google Scholar]
  • 14. Dietrich DW, Busto R, Globus MYT, Ginsberg MD (1996) Brain damage and temperature: cellular and molecular mechanisms. Advances in Neurology 71:177–194. [PubMed] [Google Scholar]
  • 15. Dunn JM, Miller JNJ (1969) Hypothermia combined with positive pressure ventilation in resuscitation of the asphyxiated neonate. Am J Obstet Gynecol 104:58–67. [DOI] [PubMed] [Google Scholar]
  • 16. Edwards AD, Yue X, Squier MV, Thoresen M, Cady EB, Penrice J, Cooper CE, Wyatt JS, Reynolds EOR, Mehmet H (1995) Specific inhibition of apoptosis after cerebral hypoxia‐ischemia by moderate post‐insult hypothermia. Biochem Biophys Res Com 217:1193–1199. [DOI] [PubMed] [Google Scholar]
  • 17. Ehrström J, Hirvensalo M, Donner M, Hietalathi J (1969) Hypothermia in the resuscitation of severely asphyctic newborn infants. Ann Clin Res 1:40–49. [PubMed] [Google Scholar]
  • 18. Ginsberg MD, Sternau LL, Globus MYT, Dietrich WD, Busto R (1992) Therapeutic modulation of brain temperature: relevance to ischemic brain injury. Cerebrovasc Brain Metab Rev 4:189–225. [PubMed] [Google Scholar]
  • 19. Ginsberg MD (1997) The new language of cerebral ischemia. AJNR 18(8):1435–1445. [PMC free article] [PubMed] [Google Scholar]
  • 20. Gunn AJ, Gunn TR, De Haan HH, Williams CE, Gluckman P (1997) Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs. J Clin Invest 99:248–256. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21. Gunn AJ, Gunn TR, Gunning MI, Williams CE, Gluckman PD (1998) Neuroprotection with prolonged head cooling started before postischemic seizures in fetal sheep. Pediatrics 102(5):1098–106. [DOI] [PubMed] [Google Scholar]
  • 22. Haaland K, Loeberg EM, Steen PA, Satas S, Thoresen M (1997) Posthypoxic hypothermia in newborn piglets. Pediatr Res 41:505–512. [DOI] [PubMed] [Google Scholar]
  • 23. Hennig J, Nauerth A, Friedburg H (1986) RARE‐imaging: A fast imaging method for clinical MR. Magn Reson Med 3(6):823–833. [DOI] [PubMed] [Google Scholar]
  • 24. Yasow K II, Hennig J (1998) Single‐shot diffusion‐weighted RARE sequence: Application for temperature monitoring during hyperthermia session. JMRI 8:1296–1305. [DOI] [PubMed] [Google Scholar]
  • 25. Krokfors E, Pitkänen H, Hirvensalo M, Rhen K (1961) The use of hypothermia in severe neonatal asphyxia. Finlands Läkartidning 17:987–1004. [PubMed] [Google Scholar]
  • 26. Laptook AR, Corbett RJ, Sterett R, Burns DK, Garcia D, Tollefsbol G (1997) Modest hypothermia provides partial neuroprotection when used for immediate resuscitation afte brain ischemia. Pediatr Res 42:17–23. [DOI] [PubMed] [Google Scholar]
  • 27. Levine S (1960) Anoxic‐ischemic encephalopathy in rats. Am J Pathol 36:1–17. [PMC free article] [PubMed] [Google Scholar]
  • 28. Lorek A, Takei Y, Cady EB, Wyatt JS, Penrice J, Edwards AD, Peebles D, Wylezinska M, Owen‐Reece H, Kirkbride V, Cooper CE, Aldrige RF, Roth SC, Brown G, Delpy DT, Reynolds EOR (1994) Delayed (“secondary”) energy failure following acute hypoxia‐ischemia in the newborn piglet: Continuous 48‐hour studies by 31P magnetic resonance spectroscopy. Pediatr Res 36:699–706. [DOI] [PubMed] [Google Scholar]
  • 29. Marion DW, Leonov Y, Ginsberg MD, Katz LM, Kochanek PM, Lechleuthner A, Nemoto EM, Obrist W, Safar P, Sterz F, Tisherman SA, White RJ, Xiao F, Zar H (1996) Resuscitative hypothermia. Crit Care Med 24:S81–89. [PubMed] [Google Scholar]
  • 30. Martin E, Buchli R, Ritter S, Schmid R, Largo RH, Boltshauser E, Fanconi S, Duc G, Rumpel H (1996) Diagnostic and prognostic value of cerebral 31P magnetic resonance spectroscopy in neonates with perinatal asphyxia. Pediatr Res 40:749–758. [DOI] [PubMed] [Google Scholar]
  • 31. Moseley ME, Cohen Y, Mintorovich J, Chileuitt L, Shimizu H, Kucharczyk J, Wendland MF, Weinstein PR (1990) Early detection of regional cerebral ischemia in cats: Comparison of diffusion‐ and T2‐weighted MRI and spectroscopy. Magn Reson Med 14:330–346. [DOI] [PubMed] [Google Scholar]
  • 32. Nedelcu J, Klein M, Aguzzi A, Martin E (1999) Biphasic edema after hypoxic‐ischemic brain injury in neonatal rats reflects early neuronal and late glial damage. Pediatr Res 46: 297–304. [DOI] [PubMed] [Google Scholar]
  • 33. Patel J, Edwards AD (1997) Prediction of neurological outcome after perinatal asphyxia. Curr Opin Pediatr 9:128–132. [DOI] [PubMed] [Google Scholar]
  • 34. Paxinos G, Tork I, Tesott LH, Valentino KL (1991) Atlas of the developing rat brain, Academic Press, San Diego . [Google Scholar]
  • 35. Pierpaoli C, Righini A, Linfante I, Tao‐Cheng JH, Alger JR, Di Chiro G (1993) Histopathologic correlates of abnormal water diffusion in cerebral ischemia: Diffusion‐weighted MR imaging and light microscopic study. Radiology 189:439–448. [DOI] [PubMed] [Google Scholar]
  • 36. Rice JE, Vannucci RC, Brierley JV 1981. The influence of immaturity on hypoxic‐ischemic brain damage in the rat. Ann Neurol 9: 131–141. [DOI] [PubMed] [Google Scholar]
  • 37. Roth SC, Edwards AD, Cady EV, Delpy DT, Wyatt JS, Azzopardi D, Baudin J, Townsend J, Stewart AL, Reynolds EO (1992) Relation between cerebral oxidative metabolism following birth asphyxia and neurodevelopmental outcome and brain growth at one year. Dev Med Cild Neurol 34: 285–295. [DOI] [PubMed] [Google Scholar]
  • 38. Rumpel H, Buchli R, Gehrmann J, Aguzzi A, IIIi O, Martin E (1995) Magnetic resonance imaging of brain edema in the neonatal rat: a comparison of short and long term hypoxia‐ischemia. Pediatr Res 38:113–118. [DOI] [PubMed] [Google Scholar]
  • 39. Sirimane ES, Blumberg RM, Bossamo D, Gunning MI, Edwards AD, Gluckman PD, Williams CD (1996) The effect of prolonged modification of cerebral temperature on outcome following hypoxic ischemic injury in the infant rat. Pediatr Res 39:591–598. [DOI] [PubMed] [Google Scholar]
  • 40. Speck O, II'yasov K, Hennig J (1996) Correction of artifacts in DWI and BOLD single shot RARE images with centered phase encoding (abstract). In: Proceedings of the 13th annual meeting of European Society of Magnetic Resonance in Medicine and Biology. Prague : European Society of Mangetic Resonance in Medicine and Biology; 1996:71. [Google Scholar]
  • 41. Thoresen M, Penrice J, Lorek A, Cady EG, Wylezinska M, Kirkbride V, Cooper CE, Brown GC, Edwards AD, Wyatt JS, Reynolds EOR (1995) Mild hypothermia after severe transient hypoxia‐ischemia ameliorates delayed cerebral energy failure in the newborn piglet. Pediatr Res 37:667–676. [DOI] [PubMed] [Google Scholar]
  • 42. Thoresen M, Haaland K, Loberg EM, Whitelaw A, Apricena F, Hanko E, Stehen PA (1996) A piglet survival model of posthypoxic encephalopathy. Pediatr Res 40:738–748. [DOI] [PubMed] [Google Scholar]
  • 43. Thoresen M, Bagenholm R, Loberg EM, Apricena F, Kjellmer I (1996) Posthypoxic cooling of neonatal rats provides protection against injury. Arch Dis Child 74:F3–F9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44. Thoresen M, Wyatt J (1997) Keeping a cool head, posthypoxic hypothermia‐ an old idea revisited. Acta Pediatr 86:1029–1033. [DOI] [PubMed] [Google Scholar]
  • 45. Todd NV, Picozzi P, Crockhard HA, Russell RRW (1986) Duration of ischemia influences the development and resolution of ischemic brain edema. Stroke 17:466–471. [DOI] [PubMed] [Google Scholar]
  • 46. Trescher WH, Ishiwa S, Johnston MV (1997) Brief post‐hypoxic‐ischemic hypothermia markedly delays neonatal brain injury. Brain & Development. 19(5):326–38, 1997. [DOI] [PubMed] [Google Scholar]
  • 47. Towfighi J, Yager JY, Housman C, Vannucci RC (1991) Neuropathology of remote hypoxic‐ischemic damage in the immature rat. Acta neuropathol 81:578–587. [DOI] [PubMed] [Google Scholar]
  • 48. van der Toorn A, Sykova E, Dijkhuizen RM, Vorisek I, Vargova L, Skobisova E, Van Lookeren Campagne, Reese T, Nicolay C (1996) Dynamic changes of water ADC, energy metabolism, extracellular space volume, and tortuosity in neonatal rat brain during global ischemia. Magn Reson Med 36:52–56. [DOI] [PubMed] [Google Scholar]
  • 49. Vannucci RC (1990) Experimental biology of cerebral hypoxia‐ischemia: relation to perinatal brain damage. Pediatr Res 27:317–326. [DOI] [PubMed] [Google Scholar]
  • 50. Vannucci RC, Perlman JM (1997) Interventions for perinatal hypoxic‐ischemic encephalopathy. Pediatrics 100:1004–1014. [DOI] [PubMed] [Google Scholar]
  • 51. Vorisek I, Sykova E (1997) Ischemia‐induced changes in the extracellular space diffusion parameters, K+, and pH in the developing rat cortex and corpus callosum. J Cereb Blood Flow Metab 17:191–203. [DOI] [PubMed] [Google Scholar]
  • 52. Westin B, Miller JA, Nyberg R, Wendenberg E (1959) Neonatal asphyxia pallida treated with hypothermia alone of with hypothermia and transfusion of oxygenated blood. Surgery 45:868–879. [PubMed] [Google Scholar]
  • 53. Westin B, Nyberg R, Miller JA, Wendenberg E (1962) Hypothermia and transfusion with oxygenated blood in the treatment of asphyxia neonatorum. Acta Ped Scand 51:1–80. [PubMed] [Google Scholar]
  • 54. Yager J, Towfighi J, Vannucci RC (1993) Influence of mild hypothermia on hypoxic‐ischemic brain damage in the immature rat. Pediatr Res 34:525–529. [DOI] [PubMed] [Google Scholar]
  • 55. Yanamoto H, Hong SC, Soleau S, Dassell N, Lee KS (1996) Mild postischemic hypothermia limits cerebral injury following transient focal ischemia in rat neocortex. Brain Research 718:207–21138. [DOI] [PubMed] [Google Scholar]

Articles from Brain Pathology are provided here courtesy of Wiley

RESOURCES