Skip to main content

Cool Down the Inflammation: Hypothermia as a Therapeutic Strategy for Acute Brain Injuries

  • Chapter
  • First Online:
Immunological Mechanisms and Therapies in Brain Injuries and Stroke

Part of the book series: Springer Series in Translational Stroke Research ((SSTSR,volume 6))

  • 1276 Accesses

Abstract

While hypothermia has historically been appreciated as a possible cause of injury and mortality, its role as a therapeutic agent of choice in special circumstances has been less delineated in its origins. There are reports of ancient Egyptians, Greeks, and Romans possibly implementing it, including Hippocrates specifically recommending that wounded soldiers be surrounded by snow to improve survival (Polderman, Intensive Care Med 30:757–769, 2004). The first clinical usages of hypothermia for brain injury were conducted by the neurosurgeon Temple Fay in the 1930s with subsequent pioneering reports of its therapeutic usage in various brain disorders (Fay, Ann Surg 101:76–132, 1959; Harris et al., Arch Neurol 59:1077–1083, 2002). Over the last few decades, there have been various animal studies and clinical trials that have investigated the various indications and mechanisms of therapeutic hypothermia, many of which implicate a role in curtailing the inflammatory cascade. Only over the past decade, in the setting of adult and pediatric post-anoxic encephalopathy, has hypothermia become an evidence-based therapy. Indications for treatment as well as mitigation of the inflammatory processes in other acute brain injuries such as ischemic and hemorrhagic strokes, traumatic brain injury, and status epilepticus remain controversial. This chapter reviews the role of therapeutic hypothermia, how “cooling the inflammation” may or may not be indicated in a variety of acute brain injuries: ischemic stroke, neonatal hypoxia–ischemia, post-cardiac arrest global ischemia, traumatic brain injury, intracerebral hemorrhage, subarachnoid hemorrhage, status epilepticus, meningitis/encephalitis, and acute liver failure.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Polderman KH (2004) Application of therapeutic hypothermia in the intensive care unit. Opportunities and pitfalls of a promising treatment modality–part 2: practical aspects and side effects. Intensive Care Med 30:757–69

    PubMed  Google Scholar 

  2. Fay T (1959) Early experiences refrigeration with local and generalized of the human brain. Ann Surg 101:76–132

    Google Scholar 

  3. Harris OA, Colford JM, Good MC, Matz PG (2002) The role of hypothermia in the management of severe brain injury: a meta-analysis. Arch Neurol 59:1077–83

    PubMed  Google Scholar 

  4. Holzer M (2008) Devices for rapid induction of hypothermia. Eur J Anaesthesiol Suppl 42:31–8

    CAS  PubMed  Google Scholar 

  5. Holzer M (2010) Targeted temperature management for comatose survivors of cardiac arrest. N Engl J Med 363:1256–64

    CAS  PubMed  Google Scholar 

  6. Tømte Ø, Drægni T, Mangschau A, Jacobsen D, Auestad B, Sunde K (2011) A comparison of intravascular and surface cooling techniques in comatose cardiac arrest survivors. Crit Care Med 39:443–9

    PubMed  Google Scholar 

  7. Akbari Y, Geocadin RG (2011) A new generation of therapeutic hypothermia: using a warm syringe to cool. Crit Care Med 39:2558–9

    PubMed  Google Scholar 

  8. Weng Y, Sun S, Song F, Phil Chung S, Park J, Harry Weil M, Tang W (2011) Cholecystokinin octapeptide induces hypothermia and improves outcomes in a rat model of cardiopulmonary resuscitation. Crit Care Med 39:2407–12

    CAS  PubMed  Google Scholar 

  9. Sun S, Tang W, Song F, Chung SP, Weng Y, Yu T, Weil MH (2010) Pharmacologically induced hypothermia with cannabinoid receptor agonist WIN55, 212–2 after cardiopulmonary resuscitation. Crit Care Med 38:2282–6

    CAS  PubMed  Google Scholar 

  10. Castrén M, Nordberg P, Svensson L et al (2010) Intra-arrest transnasal evaporative cooling: a randomized, prehospital, multicenter study (PRINCE: Pre-ROSC IntraNasal Cooling Effectiveness). Circulation 122:729–36

    PubMed  Google Scholar 

  11. Nielsen N, Hovdenes J, Nilsson F, Rubertsson S, Stammet P, Sunde K, Valsson F, Wanscher M, Friberg H (2009) Outcome, timing and adverse events in therapeutic hypothermia after out-of-hospital cardiac arrest. Acta Anaesthesiol Scand 53:926–34

    CAS  PubMed  Google Scholar 

  12. Busto R, Dietrich WD, Globus MY, Valdés I, Scheinberg P, Ginsberg MD (1987) Small differences in intraischemic brain temperature critically determine the extent of ischemic neuronal injury. J Cereb Blood Flow Metab 7:729–38

    CAS  PubMed  Google Scholar 

  13. Busto R, Globus MY, Dietrich WD, Martinez E, Valdés I, Ginsberg MD (1989) Effect of mild hypothermia on ischemia-induced release of neurotransmitters and free fatty acids in rat brain. Stroke 20:904–10

    CAS  PubMed  Google Scholar 

  14. Yenari MA, Han HS (2012) Neuroprotective mechanisms of hypothermia in brain ischaemia. Nat Rev Neurosci 13:267–78

    CAS  PubMed  Google Scholar 

  15. Polderman KH (2008) Induced hypothermia and fever control for prevention and treatment of neurologic injuries. Lancet 371:1955–69

    PubMed  Google Scholar 

  16. Colbourne F, Sutherland GR, Auer RN (1996) An automated system for regulating brain temperature in awake and freely moving rodents. J Neurosci Methods 67:185–90

    CAS  PubMed  Google Scholar 

  17. Van der Worp HB, Sena ES, Donnan GA, Howells DW, Macleod MR (2007) Hypothermia in animal models of acute ischaemic stroke: a systematic review and meta-analysis. Brain 130:3063–74

    PubMed  Google Scholar 

  18. Yenari M, Kitagawa K, Lyden P, Perez-Pinzon M (2008) Metabolic downregulation: a key to successful neuroprotection? Stroke 39:2910–7

    CAS  PubMed  Google Scholar 

  19. Maier CM, Sun GH, Kunis D, Yenari MA, Steinberg GK (2001) Delayed induction and long-term effects of mild hypothermia in a focal model of transient cerebral ischemia: neurological outcome and infarct size. J Neurosurg 94:90–6

    CAS  PubMed  Google Scholar 

  20. Erecinska M, Thoresen M, Silver IA (2003) Effects of hypothermia on energy metabolism in Mammalian central nervous system. J Cereb Blood Flow Metab 23:513–30

    CAS  PubMed  Google Scholar 

  21. Lee JM, Zipfel GJ, Choi DW (1999) The changing landscape of ischaemic brain injury mechanisms. Nature 399:A7–14

    CAS  PubMed  Google Scholar 

  22. Colbourne F, Grooms SY, Zukin RS, Buchan AM, Bennett MVL (2003) Hypothermia rescues hippocampal CA1 neurons and attenuates down-regulation of the AMPA receptor GluR2 subunit after forebrain ischemia. Proc Natl Acad Sci USA 100:2906–10

    CAS  PubMed  Google Scholar 

  23. Terao Y, Miyamoto S, Hirai K, Kamiguchi H, Ohta H, Shimojo M, Kiyota Y, Asahi S, Sakura Y, Shintani Y (2009) Hypothermia enhances heat-shock protein 70 production in ischemic brains. Neuroreport 20:745–9

    CAS  PubMed  Google Scholar 

  24. Kumar K, Wu X, Evans AT, Marcoux F (1995) The effect of hypothermia on induction of heat shock protein (HSP)-72 in ischemic brain. Metab Brain Dis 10:283–91

    CAS  PubMed  Google Scholar 

  25. Truettner JS, Alonso OF, Bramlett HM, Dietrich WD (2011) Therapeutic hypothermia alters microRNA responses to traumatic brain injury in rats. J Cereb Blood Flow Metab 31:1897–907

    CAS  PubMed  Google Scholar 

  26. Lee Y, Johnson KR, Hallenbeck JM (2012) Global protein conjugation by ubiquitin-like-modifiers during ischemic stress is regulated by microRNAs and confers robust tolerance to ischemia. PLoS One 7:e47787

    CAS  PubMed  Google Scholar 

  27. Weiss JB, Eisenhardt SU, Stark GB, Bode C, Moser M, Grundmann S (2012) MicroRNAs in ischemia-reperfusion injury. Am J Cardiovasc Dis 2:237–47

    CAS  PubMed  Google Scholar 

  28. Wang Q, Tang XN, Yenari MA (2007) The inflammatory response in stroke. J Neuroimmunol 184:53–68

    CAS  PubMed  Google Scholar 

  29. Maier CM, Sun GH, Cheng D, Yenari MA, Chan PH, Steinberg GK (2002) Effects of mild hypothermia on superoxide anion production, superoxide dismutase expression, and activity following transient focal cerebral ischemia. Neurobiol Dis 11:28–42

    CAS  PubMed  Google Scholar 

  30. Wang GJ, Deng HY, Maier CM, Sun GH, Yenari MA (2002) Mild hypothermia reduces ICAM-1 expression, neutrophil infiltration and microglia/monocyte accumulation following experimental stroke. Neuroscience 114:1081–90

    CAS  PubMed  Google Scholar 

  31. Han HS, Qiao Y, Karabiyikoglu M, Giffard RG, Yenari MA (2002) Influence of mild hypothermia on inducible nitric oxide synthase expression and reactive nitrogen production in experimental stroke and inflammation. J Neurosci 22:3921–8

    CAS  PubMed  Google Scholar 

  32. Choi JS, Park J, Suk K, Moon C, Park Y-K, Han HS (2011) Mild hypothermia attenuates intercellular adhesion molecule-1 induction via activation of extracellular signal-regulated kinase-1/2 in a focal cerebral ischemia model. Stroke Res Treat 2011:846716

    PubMed  Google Scholar 

  33. Schmitt KRL, Diestel A, Lehnardt S, Schwartlander R, Lange PE, Berger F, Ullrich O, Abdul-Khaliq H (2007) Hypothermia suppresses inflammation via ERK signaling pathway in stimulated microglial cells. J Neuroimmunol 189:7–16

    CAS  PubMed  Google Scholar 

  34. Matsui T, Kakeda T (2008) IL-10 production is reduced by hypothermia but augmented by hyperthermia in rat microglia. J Neurotrauma 25:709–15

    PubMed  Google Scholar 

  35. Reith J, Jørgensen HS, Pedersen PM, Nakayama H, Raaschou HO, Jeppesen LL, Olsen TS (1996) Body temperature in acute stroke: relation to stroke severity, infarct size, mortality, and outcome. Lancet 347:422–5

    CAS  PubMed  Google Scholar 

  36. Schwab S, Schwarz S, Spranger M, Keller E, Bertram M, Hacke W (1998) Moderate hypothermia in the treatment of patients with severe middle cerebral artery infarction. Stroke 29:2461–6

    CAS  PubMed  Google Scholar 

  37. Schwab S, Georgiadis D, Berrouschot J, Schellinger PD, Graffagnino C, Mayer SA (2001) Feasibility and safety of moderate hypothermia after massive hemispheric infarction. Stroke 32:2033–5

    CAS  PubMed  Google Scholar 

  38. Kammersgaard LP, Rasmussen BH, Jørgensen HS, Reith J, Weber U, Olsen TS (2000) Feasibility and safety of inducing modest hypothermia in awake patients with acute stroke through surface cooling: a case–control study: the Copenhagen Stroke Study. Stroke 31:2251–6

    CAS  PubMed  Google Scholar 

  39. Krieger DW, De Georgia MA, Abou-Chebl A, Andrefsky JC, Sila CA, Katzan IL, Mayberg MR, Furlan AJ (2001) Cooling for acute ischemic brain damage (cool aid): an open pilot study of induced hypothermia in acute ischemic stroke. Stroke 32:1847–54

    CAS  PubMed  Google Scholar 

  40. Els T, Oehm E, Voigt S, Klisch J, Hetzel A, Kassubek J (2006) Safety and therapeutical benefit of hemicraniectomy combined with mild hypothermia in comparison with hemicraniectomy alone in patients with malignant ischemic stroke. Cerebrovasc Dis 21:79–85

    PubMed  Google Scholar 

  41. De Georgia MA, Krieger DW, Abou-Chebl A, Devlin TG, Jauss M, Davis SM, Koroshetz WJ, Rordorf G, Warach S (2004) Cooling for Acute Ischemic Brain Damage (COOL AID): a feasibility trial of endovascular cooling. Neurology 63:312–7

    PubMed  Google Scholar 

  42. Lyden PD, Allgren RL, Ng K, Akins P, Meyer B, Al-Sanani F, Lutsep H, Dobak J, Matsubara BS, Zivin J (2005) Intravascular cooling in the treatment of stroke (ICTuS): early clinical experience. J Stroke Cerebrovasc Dis 14:107–14

    PubMed  Google Scholar 

  43. Hemmen TM, Raman R, Guluma KZ, Meyer BC, Gomes JA, Cruz-Flores S, Wijman CA, Rapp KS, Grotta JC, Lyden PD (2010) Intravenous thrombolysis plus hypothermia for acute treatment of ischemic stroke (ICTuS-L): final results. Stroke 41:2265–70

    PubMed  Google Scholar 

  44. Winerdal M, Winerdal ME, Kinn J, Urmaliya V, Winqvist O, Adén U (2012) Long lasting local and systemic inflammation after cerebral hypoxic ischemia in newborn mice. PLoS One 7:e36422

    CAS  PubMed  Google Scholar 

  45. Pimentel VC, Pinheiro FV, De Bona KS et al (2011) Hypoxic-ischemic brain injury stimulates inflammatory response and enzymatic activities in the hippocampus of neonatal rats. Brain Res 1388:134–40

    CAS  PubMed  Google Scholar 

  46. Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG (2013) Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev 1, CD003311

    PubMed  Google Scholar 

  47. Shankaran S, Laptook AR, Ehrenkranz RA et al (2005) Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 353:1574–84

    CAS  PubMed  Google Scholar 

  48. Gluckman PD, Wyatt JS, Azzopardi D et al (2005) Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 365:663–70

    PubMed  Google Scholar 

  49. Jenkins DD, Rollins LG, Perkel JK et al (2012) Serum cytokines in a clinical trial of hypothermia for neonatal hypoxic-ischemic encephalopathy. J Cereb Blood Flow Metab 32:1888–96

    CAS  PubMed  Google Scholar 

  50. Higgins RD, Raju T, Edwards AD et al (2011) Hypothermia and other treatment options for neonatal encephalopathy: an executive summary of the Eunice Kennedy Shriver NICHD workshop. J Pediatr 159:851.e1–858.e1

    Google Scholar 

  51. Xiong M, Chen L-X, Ma S-M, Yang Y, Zhou W-H (2013) Short-term effects of hypothermia on axonal injury, preoligodendrocyte accumulation and oligodendrocyte myelination after hypoxia-ischemia in the hippocampus of immature rat brain. Dev Neurosci 35:17–27. doi:10.1159/000346324

    CAS  PubMed  Google Scholar 

  52. Lakhan SE, Kirchgessner A, Hofer M (2009) Inflammatory mechanisms in ischemic stroke: therapeutic approaches. J Transl Med 7:97

    PubMed  Google Scholar 

  53. Callaway CW, Rittenberger JC, Logue ES, McMichael MJ (2008) Hypothermia after cardiac arrest does not alter serum inflammatory markers. Crit Care Med 36:2607–12

    CAS  PubMed  Google Scholar 

  54. Meybohm P, Gruenewald M, Zacharowski KD, Albrecht M, Lucius R, Fösel N, Hensler J, Zitta K, Bein B (2010) Mild hypothermia alone or in combination with anesthetic post-conditioning reduces expression of inflammatory cytokines in the cerebral cortex of pigs after cardiopulmonary resuscitation. Crit Care 14:R21

    PubMed  Google Scholar 

  55. Fries M, Stoppe C, Brücken D, Rossaint R, Kuhlen R (2009) Influence of mild therapeutic hypothermia on the inflammatory response after successful resuscitation from cardiac arrest. J Crit Care 24:453–7

    PubMed  Google Scholar 

  56. Fairchild KD, Singh IS, Patel S, Drysdale BE, Viscardi RM, Hester L, Lazusky HM, Hasday JD (2004) Hypothermia prolongs activation of NF-kappaB and augments generation of inflammatory cytokines. Am J Physiol Cell Physiol 287:C422–31

    CAS  PubMed  Google Scholar 

  57. Bisschops LLA, Hoedemaekers CWE, Mollnes TE, Van der Hoeven JG (2012) Rewarming after hypothermia after cardiac arrest shifts the inflammatory balance. Crit Care Med 40:1136–42

    PubMed  Google Scholar 

  58. Sarcia PJ, Scumpia PO, Moldawer LL, DeMarco VG, Skimming JW (2003) Hypothermia induces interleukin-10 and attenuates injury in the lungs of endotoxemic rats. Shock 20:41–5

    CAS  PubMed  Google Scholar 

  59. Meybohm P, Gruenewald M, Albrecht M, Zacharowski KD, Lucius R, Zitta K, Koch A, Tran N, Scholz J, Bein B (2009) Hypothermia and postconditioning after cardiopulmonary resuscitation reduce cardiac dysfunction by modulating inflammation, apoptosis and remodeling. PLoS One 4:e7588

    PubMed  Google Scholar 

  60. Huet O, Kinirons B, Dupic L, Lajeunie E, Mazoit JX, Benhamou D, Vicaut E, Duranteau J (2007) Induced mild hypothermia reduces mortality during acute inflammation in rats. Acta Anaesthesiol Scand 51:1211–6

    CAS  PubMed  Google Scholar 

  61. Amiry-Moghaddam M, Otsuka T, Hurn PD et al (2003) An alpha-syntrophin-dependent pool of AQP4 in astroglial end-feet confers bidirectional water flow between blood and brain. Proc Natl Acad Sci USA 100:2106–11

    CAS  PubMed  Google Scholar 

  62. Xiao F, Arnold TC, Zhang S, Brown C, Alexander JS, Carden DL, Conrad SA (2004) Cerebral cortical aquaporin-4 expression in brain edema following cardiac arrest in rats. Acad Emerg Med 11:1001–7

    PubMed  Google Scholar 

  63. Weng Y, Sun S (2012) Therapeutic hypothermia after cardiac arrest in adults: mechanism of neuroprotection, phases of hypothermia, and methods of cooling. Crit Care Clin 28:231–43

    PubMed  Google Scholar 

  64. Hypothermia after Cardiac Arrest Study Group (2002) Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 346:549–56

    Google Scholar 

  65. Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, Smith K (2002) Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 346:557–63

    PubMed  Google Scholar 

  66. Arrich J, Holzer M, Havel C, Müllner M, Herkner H (2012) Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation. Cochrane Database Syst Rev 9, CD004128

    PubMed  Google Scholar 

  67. Rothman SM, Olney JW (1986) Glutamate and the pathophysiology of hypoxic–ischemic brain damage. Ann Neurol 19:105–11

    CAS  PubMed  Google Scholar 

  68. Vaagenes P, Ginsberg M, Ebmeyer U et al (1996) Cerebral resuscitation from cardiac arrest: pathophysiologic mechanisms. Crit Care Med 24:S57–68

    CAS  PubMed  Google Scholar 

  69. Belousov AB (2012) Novel model for the mechanisms of glutamate-dependent excitotoxicity: role of neuronal gap junctions. Brain Res 1487:123–30

    CAS  PubMed  Google Scholar 

  70. Lipton SA, Rosenberg PA (1994) Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med 330:613–22

    CAS  PubMed  Google Scholar 

  71. Gundersen RY, Vaagenes P, Breivik T, Fonnum F, Opstad PK (2005) Glycine—an important neurotransmitter and cytoprotective agent. Acta Anaesthesiol Scand 49:1108–16

    CAS  PubMed  Google Scholar 

  72. Globus M, Ginsberg M, Busto R (1991) Excitotoxic index—a biochemical marker of selective vulnerability. Neurosci Lett 127:39–42

    CAS  PubMed  Google Scholar 

  73. Kaindl AM, Degos V, Peineau S et al (2012) Activation of microglial N-methyl-D-aspartate receptors triggers inflammation and neuronal cell death in the developing and mature brain. Ann Neurol 72:536–49

    CAS  PubMed  Google Scholar 

  74. Zipfel G, Babcock J, Lee J, Choi D (2000) Neuronal apoptosis after CNS injury: the roles of glutamate and calcium. J Neurotrauma 17:857–69

    CAS  PubMed  Google Scholar 

  75. Choi D (1994) Calcium and excitotoxic neuronal injury. Ann N Y Acad Sci 747:162–71

    CAS  PubMed  Google Scholar 

  76. Moore LE, Traystman RJ (1994) Role of oxygen free radicals and lipid peroxidation in cerebral reperfusion injury. Adv Pharmacol 31:565–76

    CAS  PubMed  Google Scholar 

  77. Yang J, Ahn H-N, Chang M, Narasimhan P, Chan PH, Song YS (2013) Complement component 3 inhibition by an antioxidant is neuroprotective after cerebral ischemia and reperfusion in mice. J Neurochem 124(4):523–35

    CAS  PubMed  Google Scholar 

  78. Van Beek J, Elward K, Gasque P (2003) Activation of complement in the central nervous system: roles in neurodegeneration and neuroprotection. Ann N Y Acad Sci 992:56–71

    PubMed  Google Scholar 

  79. Donadello K, Favory R, Salgado-Ribeiro D, Vincent J-L, Gottin L, Scolletta S, Creteur J, De Backer D, Taccone FS (2011) Sublingual and muscular microcirculatory alterations after cardiac arrest: a pilot study. Resuscitation 82:690–5

    PubMed  Google Scholar 

  80. Lo Pizzo M, Schiera G, Di Liegro I, Di Liegro CM, Pál J, Czeiter E, Sulyok E, Dóczi T (2012) Aquaporin-4 distribution in control and stressed astrocytes in culture and in the cerebrospinal fluid of patients with traumatic brain injuries. Neurol Sci. doi:10.1007/s10072-012-1233-4

    PubMed  Google Scholar 

  81. Suehiro E, Fujisawa H, Akimura T, Ishihara H, Kajiwara K, Kato S, Fujii M, Yamashita S, Maekawa T, Suzuki M (2004) Increased matrix metalloproteinase-9 in blood in association with activation of interleukin-6 after traumatic brain injury: influence of hypothermic therapy. J Neurotrauma 21:1706–11

    PubMed  Google Scholar 

  82. Soukup J, Zauner A, Doppenberg EMR, Menzel M, Gilman C, Bullock R, Young HF (2002) Relationship between brain temperature, brain chemistry and oxygen delivery after severe human head injury: the effect of mild hypothermia. Neurol Res 24:161–8

    CAS  PubMed  Google Scholar 

  83. Vespa P, Bergsneider M, Hattori N, Wu H-M, Huang S-C, Martin NA, Glenn TC, McArthur DL, Hovda DA (2005) Metabolic crisis without brain ischemia is common after traumatic brain injury: a combined microdialysis and positron emission tomography study. J Cereb Blood Flow Metab 25:763–74

    CAS  PubMed  Google Scholar 

  84. Glenn TC, Kelly DF, Boscardin WJ, McArthur DL, Vespa P, Oertel M, Hovda DA, Bergsneider M, Hillered L, Martin NA (2003) Energy dysfunction as a predictor of outcome after moderate or severe head injury: indices of oxygen, glucose, and lactate metabolism. J Cereb Blood Flow Metab 23:1239–50

    CAS  PubMed  Google Scholar 

  85. Bacher A, Illievich UM, Fitzgerald R, Ihra G, Spiss CK (1997) Changes in oxygenation variables during progressive hypothermia in anesthetized patients. J Neurosurg Anesthesiol 9:205–10

    CAS  PubMed  Google Scholar 

  86. Sydenham E, Roberts I, Alderson P (2009) Hypothermia for traumatic head injury (2009 review). Cochrane Database Syst Rev 1–48

    Google Scholar 

  87. Rivera-Lara L, Zhang J, Muehlschlegel S (2012) Therapeutic hypothermia for acute neurological injuries. Neurotherapeutics 9:73–86

    CAS  PubMed  Google Scholar 

  88. Choi HA, Badjatia N, Mayer SA (2012) Hypothermia for acute brain injury—mechanisms and practical aspects. Nat Rev Neurol 8:214–22

    CAS  PubMed  Google Scholar 

  89. Sadaka F, Veremakis C (2012) Therapeutic hypothermia for the management of intracranial hypertension in severe traumatic brain injury: a systematic review. Brain Inj 26:899–908

    PubMed  Google Scholar 

  90. Jiang J-Y, Xu W, Li W-P, Gao G-Y, Bao Y-H, Liang Y-M, Luo Q-Z (2006) Effect of long-term mild hypothermia or short-term mild hypothermia on outcome of patients with severe traumatic brain injury. J Cereb Blood Flow Metab 26:771–6

    PubMed  Google Scholar 

  91. Bratton SL, Chestnut RM, Ghajar J et al (2007) Guidelines for the management of severe traumatic brain injury. III. Prophylactic hypothermia. J Neurotrauma 24(Suppl 1):S21–5

    PubMed  Google Scholar 

  92. Nunnally ME, Jaeschke R, Bellingan GJ et al (2011) Targeted temperature management in critical care: a report and recommendations from five professional societies. Crit Care Med 39:1113–25

    PubMed  Google Scholar 

  93. Andrews PJ, Sinclair HL, Battison CG et al (2011) European society of intensive care medicine study of therapeutic hypothermia (32–35 °C) for intracranial pressure reduction after traumatic brain injury (the Eurotherm3235Trial). Trials 12:8

    PubMed  Google Scholar 

  94. Greenhalgh AD, Brough D, Robinson EM, Girard S, Rothwell NJ, Allan SM (2012) Interleukin-1 receptor antagonist is beneficial after subarachnoid haemorrhage in rat by blocking haem-driven inflammatory pathology. Dis Model Mech 5:823–33

    CAS  PubMed  Google Scholar 

  95. Chou SH-Y, Feske SK, Atherton J, Konigsberg RG, De Jager PL, Du R, Ogilvy CS, Lo EH, Ning M (2012) Early elevation of serum tumor necrosis factor-α is associated with poor outcome in subarachnoid hemorrhage. J Investig Med 60:1054–8

    CAS  PubMed  Google Scholar 

  96. Maddahi A, Povlsen G, Edvinsson L (2012) Regulation of enhanced cerebrovascular expression of proinflammatory mediators in experimental subarachnoid hemorrhage via the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathway. J Neuroinflammation 9:274

    CAS  PubMed  Google Scholar 

  97. Rodling-Wahlström M, Olivecrona M, Koskinen L-OD, Naredi S, Hultin M (2012) Subarachnoid haemorrhage induces an inflammatory response followed by a delayed persisting increase in asymmetric dimethylarginine. Scand J Clin Lab Invest 72:484–9

    PubMed  Google Scholar 

  98. Török E, Klopotowski M, Trabold R, Thal SC, Plesnila N, Schöller K (2009) Mild hypothermia (33 degrees C) reduces intracranial hypertension and improves functional outcome after subarachnoid hemorrhage in rats. Neurosurgery 65:352–9, discussion 359

    PubMed  Google Scholar 

  99. Kawamura Y, Yamada K, Masago A, Katano H, Matsumoto T, Mase M (2000) Hypothermia modulates induction of hsp70 and c-jun mRNA in the rat brain after subarachnoid hemorrhage. J Neurotrauma 17:243–50

    CAS  PubMed  Google Scholar 

  100. Wang Z, Chen H, Wang F-X (2011) Influence of plasma and cerebrospinal fluid levels of endothelin-1 and NO in reducing cerebral vasospasm after subarachnoid hemorrhage during treatment with mild hypothermia, in a dog model. Cell Biochem Biophys 61:137–43

    CAS  PubMed  Google Scholar 

  101. Schubert GA, Poli S, Schilling L, Heiland S, Thomé C (2008) Hypothermia reduces cytotoxic edema and metabolic alterations during the acute phase of massive SAH: a diffusion-weighted imaging and spectroscopy study in rats. J Neurotrauma 25:841–52

    PubMed  Google Scholar 

  102. Schubert GA, Poli S, Mendelowitsch A, Schilling L, Thomé C (2008) Hypothermia reduces early hypoperfusion and metabolic alterations during the acute phase of massive subarachnoid hemorrhage: a laser-Doppler-flowmetry and microdialysis study in rats. J Neurotrauma 25:539–48

    PubMed  Google Scholar 

  103. Todd MM, Hindman BJ, Clarke WR, Torner JC (2005) Mild intraoperative hypothermia during surgery for intracranial aneurysm. N Engl J Med 352:135–45

    CAS  PubMed  Google Scholar 

  104. Anderson SW, Todd MM, Hindman BJ, Clarke WR, Torner JC, Tranel D, Yoo B, Weeks J, Manzel KW, Samra S (2006) Effects of intraoperative hypothermia on neuropsychological outcomes after intracranial aneurysm surgery. Ann Neurol 60:518–27

    PubMed  Google Scholar 

  105. Hindman BJ, Bayman EO, Pfisterer WK, Torner JC, Todd MM (2010) No association between intraoperative hypothermia or supplemental protective drug and neurologic outcomes in patients undergoing temporary clipping during cerebral aneurysm surgery. Anesthesiology 112:86–101

    PubMed  Google Scholar 

  106. Gasser S, Khan N, Yonekawa Y, Imhof H-G, Keller E (2003) Long-term hypothermia in patients with severe brain edema after poor-grade subarachnoid hemorrhage: feasibility and intensive care complications. J Neurosurg Anesthesiol 15:240–8

    PubMed  Google Scholar 

  107. Connolly ES, Rabinstein AA, Carhuapoma JR et al (2012) Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/american Stroke Association. Stroke 43:1711–37

    PubMed  Google Scholar 

  108. Nguyen H, Zaroff J, Bayman E, Gelb A, Todd M, Hindman B (2010) Perioperative hypothermia (33 °C) does not increase the occurrence of cardiovascular events in patients undergoing cerebral aneurysm surgery: findings. Anesthesiology 113:327–42

    PubMed  Google Scholar 

  109. Badjatia N, Fernandez L, Schmidt JM, Lee K, Claassen J, Connolly ES, Mayer SA (2010) Impact of induced normothermia on outcome after subarachnoid hemorrhage: a case–control study. Neurosurgery 66:696–700, discussion 700–701

    PubMed  Google Scholar 

  110. Kawanishi M, Kawai N, Nakamura T, Luo C, Tamiya T, Nagao S (2008) Effect of delayed mild brain hypothermia on edema formation after intracerebral hemorrhage in rats. J Stroke Cerebrovasc Dis 17:187–95

    PubMed  Google Scholar 

  111. Fingas M, Penner M, Silasi G, Colbourne F (2009) Treatment of intracerebral hemorrhage in rats with 12 h, 3 days and 6 days of selective brain hypothermia. Exp Neurol 219:156–62

    PubMed  Google Scholar 

  112. MacLellan CL, Davies LM, Fingas MS, Colbourne F (2006) The influence of hypothermia on outcome after intracerebral hemorrhage in rats. Stroke 37:1266–70

    PubMed  Google Scholar 

  113. Morgenstern LB, Hemphill JC, Anderson C et al (2010) Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 41:2108–29

    PubMed  Google Scholar 

  114. Staykov D, Wagner I, Volbers B, Doerfler A, Schwab S, Kollmar R (2013) Mild prolonged hypothermia for large intracerebral hemorrhage. Neurocrit Care 18:178–83. doi:10.1007/s12028-012-9762-5

    PubMed  Google Scholar 

  115. Kollmar R, Juettler E, Huttner HB, Dörfler A, Staykov D, Kallmuenzer B, Schmutzhard E, Schwab S, Broessner G (2012) Cooling in intracerebral hemorrhage (CINCH) trial: protocol of a randomized German-Austrian clinical trial. Int J Stroke 7:168–72

    PubMed  Google Scholar 

  116. Vezzani A, Moneta D, Richichi C, Aliprandi M, Burrows SJ, Ravizza T, Perego C, De Simoni MG (2002) Functional role of inflammatory cytokines and antiinflammatory molecules in seizures and epileptogenesis. Epilepsia 43(Suppl 5):30–5

    CAS  PubMed  Google Scholar 

  117. Marchi N, Fan Q, Ghosh C et al (2009) Antagonism of peripheral inflammation reduces the severity of status epilepticus. Neurobiol Dis 33:171–81

    CAS  PubMed  Google Scholar 

  118. Hsieh PF, Hou C-W, Yao P-W, Wu S-P, Peng Y-F, Shen M-L, Lin C-H, Chao Y-Y, Chang M-H, Jeng K-C (2011) Sesamin ameliorates oxidative stress and mortality in kainic acid-induced status epilepticus by inhibition of MAPK and COX-2 activation. J Neuroinflammation 8:57

    PubMed  Google Scholar 

  119. Zhou Y, Wang Y, Shao X, Chen L (2012) Effects of hypothermia on brain injury induced by status epilepticus. Front Biosci 17:1882–90

    CAS  Google Scholar 

  120. Wang Y, Liu P-P, Li L-Y, Zhang H-M, Li T (2011) Hypothermia reduces brain edema, spontaneous recurrent seizure attack, and learning memory deficits in the kainic acid treated rats. CNS Neurosci Ther 17:271–80

    CAS  PubMed  Google Scholar 

  121. Shorvon S, Ferlisi M (2012) The outcome of therapies in refractory and super-refractory convulsive status epilepticus and recommendations for therapy. Brain 135:2314–28

    PubMed  Google Scholar 

  122. Orlowski J, Erenberg G, Lueders H, Cruse R (1984) Hypothermia and barbiturate coma for refractory status epilepticus. Crit Care Med 12:367–72

    CAS  PubMed  Google Scholar 

  123. Robakis T, Hirsch L (2006) Literature review, case report, and expert discussion of prolonged refractory status epilepticus. Neurocrit Care 04:35–46

    CAS  Google Scholar 

  124. Fernandez A, Claassen J (2012) Refractory status epilepticus. Curr Opin Crit Care 18:127–31

    PubMed  Google Scholar 

  125. Fisher A, Wang X, Cock HR, Thom M, Patsalos PN, Walker MC (2004) Synergism between topiramate and budipine in refractory status epilepticus in the rat. Epilepsia 45:1300–7

    CAS  PubMed  Google Scholar 

  126. Turtle L, Griffiths MJ, Solomon T (2012) Encephalitis caused by flaviviruses. QJM 105:219–23

    CAS  PubMed  Google Scholar 

  127. Wang T, Rumbaugh JA, Nath A (2006) Viruses and the brain: from inflammation to dementia. Clin Sci (Lond) 110:393–407

    CAS  Google Scholar 

  128. Scheld WM, Koedel U, Nathan B, Pfister H-W (2002) Pathophysiology of bacterial meningitis: mechanism(s) of neuronal injury. J Infect Dis 186(Suppl):S225–33

    CAS  PubMed  Google Scholar 

  129. Rowin M, Xue V, Irazuzta J (2001) Hypothermia attenuates beta 1 integrin expression on extravasated neutrophils in an animal model of meningitis. Inflammation 25:137–44

    CAS  PubMed  Google Scholar 

  130. Koedel U, Paul R, Winkler F, Kastenbauer S, Huang P, Pfister W (2001) Lack of endothelial nitric oxide synthase aggravates murine pneumococcal meningitis. J Neuropathol Exp Neurol 60:1041–50

    CAS  PubMed  Google Scholar 

  131. Humphries HE, Triantafilou M, Makepeace BL, Heckels JE, Triantafilou K, Christodoulides M (2005) Activation of human meningeal cells is modulated by lipopolysaccharide (LPS) and non-LPS components of Neisseria meningitidis and is independent of Toll-like receptor (TLR)4 and TLR2 signalling. Cell Microbiol 7:415–30

    CAS  PubMed  Google Scholar 

  132. Stevens NT, Sadovskaya I, Jabbouri S, Sattar T, O’Gara JP, Humphreys H, Greene CM (2009) Staphylococcus epidermidis polysaccharide intercellular adhesin induces IL-8 expression in human astrocytes via a mechanism involving TLR2. Cell Microbiol 11:421–32

    CAS  PubMed  Google Scholar 

  133. Irazuzta JE, Pretzlaff R, Rowin M, Milam K, Zemlan FP, Zingarelli B (2000) Hypothermia as an adjunctive treatment for severe bacterial meningitis. Brain Res 881:88–97

    CAS  PubMed  Google Scholar 

  134. Mpabanzi L, Jalan R (2012) Neurological complications of acute liver failure: pathophysiological basis of current management and emerging therapies. Neurochem Int 60:736–42

    CAS  PubMed  Google Scholar 

  135. Stravitz RT, Larsen FS (2009) Therapeutic hypothermia for acute liver failure. Crit Care Med 37:S258–64

    PubMed  Google Scholar 

  136. Jiang W, Desjardins P, Butterworth RF (2009) Hypothermia attenuates oxidative/nitrosative stress, encephalopathy and brain edema in acute (ischemic) liver failure. Neurochem Int 55:124–8

    CAS  PubMed  Google Scholar 

  137. Gregorios JB, Mozes LW, Norenberg LO, Norenberg MD (1985) Morphologic effects of ammonia on primary astrocyte cultures. I. Light microscopic studies. J Neuropathol Exp Neurol 44:397–403

    CAS  PubMed  Google Scholar 

  138. Lavoie J, Giguère JF, Layrargues GP, Butterworth RF (1987) Amino acid changes in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy. J Neurochem 49:692–7

    CAS  PubMed  Google Scholar 

  139. Lavoie J, Giguère JF, Layrargues GP, Butterworth RF (1987) Activities of neuronal and astrocytic marker enzymes in autopsied brain tissue from patients with hepatic encephalopathy. Metab Brain Dis 2:283–90

    CAS  PubMed  Google Scholar 

  140. Clemmesen JO, Larsen FS, Kondrup J, Hansen BA, Ott P (1999) Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration. Hepatology 29:648–53

    CAS  PubMed  Google Scholar 

  141. Hindfelt B, Plum F, Duffy TE (1977) Effect of acute ammonia intoxication on cerebral metabolism in rats with portacaval shunts. J Clin Invest 59:386–96

    CAS  PubMed  Google Scholar 

  142. Lai JC, Cooper AJ (1986) Brain a-ketoglutarate dehydrogenase complex: kinetic properties, regional distribution, and effects of inhibitors. J Neurochem 47:1376–86

    CAS  PubMed  Google Scholar 

  143. Zwingmann C, Chatauret N, Leibfritz D, Butterworth RF (2003) Selective increase of brain lactate synthesis in experimental acute liver failure: results of a [H-C] nuclear magnetic resonance study. Hepatology 37:420–8

    CAS  PubMed  Google Scholar 

  144. Chatauret N, Zwingmann C, Rose C, Leibfritz D, Butterworth RF (2003) Effects of hypothermia on brain glucose metabolism in acute liver failure: a 1H/13C-nuclear magnetic resonance study. Gastroenterology 125:815–24

    CAS  PubMed  Google Scholar 

  145. Murthy C, Rama Rao K, Bai G, Norenberg MD (2001) Ammonia-induced production of free radicals in primary cultures of rat astrocytes. J Neurosci Res 288:282–8

    Google Scholar 

  146. Rao VL, Audet RM, Butterworth RF (1997) Increased neuronal nitric oxide synthase expression in brain following portacaval anastomosis. Brain Res 765:169–72

    CAS  PubMed  Google Scholar 

  147. Schliess F, Görg B, Fischer R, Desjardins P, Bidmon HJ, Herrmann A, Butterworth RF, Zilles K, Häussinger D (2002) Ammonia induces MK-801-sensitive nitration and phosphorylation of protein tyrosine residues in rat astrocytes. FASEB J 16:739–41

    CAS  PubMed  Google Scholar 

  148. Horowitz ME, Schafer DF, Molnar P, Jones EA, Blasberg RG, Patlak CS, Waggoner J, Fenstermacher JD (1983) Increased blood–brain transfer in a rabbit model of acute liver failure. Gastroenterology 84:1003–11

    CAS  PubMed  Google Scholar 

  149. Skowrońska M, Zielińska M, Wójcik-Stanaszek L, Ruszkiewicz J, Milatovic D, Aschner M, Albrecht J (2012) Ammonia increases paracellular permeability of rat brain endothelial cells by a mechanism encompassing oxidative/nitrosative stress and activation of matrix metalloproteinases. J Neurochem 121:125–34

    PubMed  Google Scholar 

  150. Wright G, Shawcross D, Olde Damink SWM, Jalan R (2007) Brain cytokine flux in acute liver failure and its relationship with intracranial hypertension. Metab Brain Dis 22:375–88

    CAS  PubMed  Google Scholar 

  151. Sawara K, Desjardins P, Chatauret N, Kato A, Suzuki K, Butterworth RF (2009) Alterations in expression of genes coding for proteins of the neurovascular unit in ischemic liver failure. Neurochem Int 55:119–23

    CAS  PubMed  Google Scholar 

  152. Butterworth RF (2011) Neuroinflammation in acute liver failure: mechanisms and novel therapeutic targets. Neurochem Int 59:830–6

    CAS  PubMed  Google Scholar 

  153. Bémeur C, Butterworth RF (2012) Liver-brain proinflammatory signalling in acute liver failure: role in the pathogenesis of hepatic encephalopathy and brain edema. Metab Brain Dis 28:145–50. doi:10.1007/s11011-012-9361-3

    PubMed  Google Scholar 

  154. Chastre A, Bélanger M, Beauchesne E, Nguyen BN, Desjardins P, Butterworth RF (2012) Inflammatory cascades driven by tumor necrosis factor-alpha play a major role in the progression of acute liver failure and its neurological complications. PLoS One 7:e49670

    CAS  PubMed  Google Scholar 

  155. Jiang W, Desjardins P, Butterworth RF (2009) Direct evidence for central proinflammatory mechanisms in rats with experimental acute liver failure: protective effect of hypothermia. J Cereb Blood Flow Metab 29:944–52

    CAS  PubMed  Google Scholar 

  156. Barba I, Chatauret N, García-Dorado D, Córdoba J (2008) A 1H nuclear magnetic resonance-based metabonomic approach for grading hepatic encephalopathy and monitoring the effects of therapeutic hypothermia in rats. Liver Int 28:1141–8

    CAS  PubMed  Google Scholar 

  157. Jalan R, Damink SW, Deutz NE, Lee A, Hayes PC (1999) Early reports moderate hypothermia for uncontrolled intracranial hypertension in acute liver failure. Lancet 354:1164–8

    CAS  PubMed  Google Scholar 

  158. Jalan R, Olde Damink SWM, Deutz NEP, Davies NA, Garden OJ, Madhavan KK, Hayes PC, Lee A (2003) Moderate hypothermia prevents cerebral hyperemia and increase in intracranial pressure in patients undergoing liver transplantation for acute liver failure. Transplantation 75:2034–9

    PubMed  Google Scholar 

  159. Jalan R, Olde Damink SWM, Deutz NEP, Hayes PC, Lee A (2004) Moderate hypothermia in patients with acute liver failure and uncontrolled intracranial hypertension. Gastroenterology 127:1338–46

    CAS  PubMed  Google Scholar 

  160. Vaquero J (2012) Therapeutic hypothermia in the management of acute liver failure. Neurochem Int 60:723–35

    CAS  PubMed  Google Scholar 

  161. Nakamura K (2011) Central circuitries for body temperature regulation and fever. Am J Physiol Regul Integr Comp Physiol 301:R1207–28

    CAS  PubMed  Google Scholar 

  162. Ogoina D (2011) Fever, fever patterns and diseases called “fever”—a review. J Infect Public Health 4:108–24

    PubMed  Google Scholar 

  163. Zhang Y, Calderwood SK (2011) Autophagy, protein aggregation and hyperthermia: a mini-review. Int J Hyperthermia 27:409–14

    CAS  PubMed  Google Scholar 

  164. Bisschops LLA, Van der Hoeven JG, Hoedemaekers CWE, Van Der Hoeven JG (2012) Effects of prolonged mild hypothermia on cerebral blood flow after cardiac arrest. Crit Care Med 40:2362–7

    PubMed  Google Scholar 

  165. Krüger A, Ošťádal P, Vondráková D, Janotka M, Herget J (2012) Nitrotyrosine and nitrate/nitrite levels in cardiac arrest survivors treated with endovascular hypothermia. Physiol Res 61:425–30

    PubMed  Google Scholar 

  166. Matsui T, Motoki Y, Inomoto T, Miura D, Kato Y, Suenaga H, Hino K, Nojima J (2012) Temperature-related effects of adenosine triphosphate-activated microglia on pro-inflammatory factors. Neurocrit Care 17:293–300

    CAS  PubMed  Google Scholar 

  167. Lee H-C, Chuang H-C, Cho D-Y, Cheng K-F, Lin P-H, Chen C-C (2010) Applying cerebral hypothermia and brain oxygen monitoring in treating severe traumatic brain injury. World Neurosurg 74:654–60

    PubMed  Google Scholar 

  168. Baumann E, Preston E, Slinn J, Stanimirovic D (2009) Post-ischemic hypothermia attenuates loss of the vascular basement membrane proteins, agrin and SPARC, and the blood–brain barrier disruption after global cerebral ischemia. Brain Res 1269:185–97

    CAS  PubMed  Google Scholar 

  169. Polderman KH, Herold I (2009) Therapeutic hypothermia and controlled normothermia in the intensive care unit: practical considerations, side effects, and cooling methods. Crit Care Med 37:1101–20

    PubMed  Google Scholar 

  170. Badjatia N (2009) Hyperthermia and fever control in brain injury. Crit Care Med 37:S250–7

    PubMed  Google Scholar 

  171. Axelrod YK, Diringer MN (2008) Temperature management in acute neurologic disorders. Neurol Clin 26:585–603, xi

    PubMed  Google Scholar 

  172. Fernandez A, Schmidt JM, Claassen J et al (2007) Fever after subarachnoid hemorrhage: risk factors and impact on outcome. Neurology 68:1013–9

    CAS  PubMed  Google Scholar 

  173. Todd MM, Hindman BJ, Clarke WR, Torner JC, Weeks JB, Bayman EO, Shi Q, Spofford CM (2009) Perioperative fever and outcome in surgical patients with aneurysmal subarachnoid hemorrhage. Neurosurgery 64:897–908, discussion 908

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Romergryko Geocadin .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media New York

About this chapter

Cite this chapter

Akbari, Y., Mulder, M., Razmara, A., Geocadin, R. (2014). Cool Down the Inflammation: Hypothermia as a Therapeutic Strategy for Acute Brain Injuries. In: Chen, J., Hu, X., Stenzel-Poore, M., Zhang, J. (eds) Immunological Mechanisms and Therapies in Brain Injuries and Stroke. Springer Series in Translational Stroke Research, vol 6. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-8915-3_19

Download citation

  • DOI: https://doi.org/10.1007/978-1-4614-8915-3_19

  • Published:

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-1-4614-8914-6

  • Online ISBN: 978-1-4614-8915-3

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics