Volume 16 Supplement 2
Hypothermia and advanced neuromonitoring
© Helbok et al.; licensee BioMed Central Ltd. 2012
Published: 7 June 2012
Therapeutic hypothermia (TH) improves short-term neurologic outcome and reduces mortality after cardiac arrest (CA) . Neuroprotective mechanisms comprise reduced cerebral metabolic demand [2, 3], decreased excitotoxicity [4–7], cell membrane stabilization [8, 9], inhibition of spreading depolarizations  and cytokine release , and preservation of cerebral autoregulation. This concept of neuroprotection led to clinical trials using TH for the prevention of secondary brain injury in patients with traumatic brain injury, subarachnoid hemorrhage (SAH) and ischemic stroke; however, they failed to show any benefit in clinical outcomes [12–15]. This may reflect our lack of understanding of the exact pathophysiologic processes induced by TH and the potential harm through hypothermia and rewarming injury .
Advanced neuromonitoring techniques allow online measurement of brain metabolism, cerebral autoregulation, brain tissue oxygenation, and cerebral blood flow (CBF) and provide information about brain function, energy supply and demand [17–19]. Here we will summarize current knowledge about the effects of TH on brain homeostasis after acute brain injury using advanced neuromonitoring techniques and call for more observational trials investigating pathophysiologic mechanisms during TH and rewarming to maximize the benefits of this emerging therapeutic modality.
TH effectively decreases intracranial pressure (ICP) by up to 10 mmHg [12, 20–22], whereby mild hypothermia (35°C) seems to be as effective as 33°C [21, 23]. Mechanisms include the reduction in metabolic demand and the inhibitory effect on inflammation and free radical production stabilizing the blood-brain barrier and decreasing vasogenic edema [20, 24–26].
Cerebral microdialysis allows bedside monitoring of cerebral metabolic changes from the extracellular fluid of the brain . Decreased energy supply, increased demand or mitochondrial dysfunction may result in brain metabolic distress and/or brain hypoglycemia (brain glucose <0.7 mmol/l). Cerebral microdialysis is feasible during TH and sensitive to detect secondary energy failure as indicated by an increase in the lactate-pyruvate ratio (LPR) [28, 29]. Therapeutic hypothermia reduces brain metabolic demand for oxygen and glucose and preserves ATP supply to the brain decreasing the risk of secondary energy failure [29–32]. Moreover, extensive cerebral lactate accumulation is inhibited by TH, which ameliorates the deleterious effects on cell membranes and the blood-brain barrier . Increased brain glucose may be found during TH ; however, an increased blood glucose variability during hypothermia has been reported . This may negatively affect brain glucose as sudden decreases in systemic glucose have been associated with brain metabolic distress and worse outcome . Therefore monitoring of brain glucose is important to detect brain hypoglycemia and prevent further neuronal damage during TH and the rewarming phase. An additional beneficial effect of hypothermia that has been extensively studied in vitro and in animal models is the reduction in excitotoxic neurotransmitter release [4–7, 28], thereby inhibiting nitric oxide synthesis and apoptotic pathways [16, 36]. A decrease of extracellular glutamate was observed during TH after cardiac arrest and in ischemic stroke patients using cerebral microdialysis [28, 37]. In summary, cerebral microdialysis allows monitoring of the metabolic effects of TH after acute brain injury.
Another mechanism how TH may reduce secondary energy failure is a decrease in oxygen consumption through diminished metabolism [2, 3], resulting in increased brain tissue oxygenation [25, 38]. Brain tissue oxygenation reflects the net effect of oxygen delivery, diffusion and consumption and can be assessed by positron emission tomography, magnetic resonance spectroscopy, near-infrared spectroscopy or by invasive PbtO2 probes [39, 40]. Therapeutic hypothermia below 35°C may impair brain tissue oxygenation through a left-shift of the oxygen dissociation curve, therefore enhancing the affinity of oxygen to hemoglobin, or by decreasing delivery of oxygen to the brain [21, 41]. Jugular bulb oxygen saturation (jSvO2) is a global measurement of brain oxygen extraction and is increased during mild TH [31, 41], reflecting a reduction in cerebral metabolic rate of oxygen.
Shivering is frequently observed during TH and may abolish the neuroprotective effect of temperature modulation through increase in metabolic demand and systemic and cerebral energy consumption . A shivering-associated reduction in PbtO2 seems to correlate with the intensity of therapeutic cooling and potentially increases the risk of brain hypoxia . These results imply that the neuroprotective effect of TH may be most beneficial at a temperature not lower than 35°C and shivering should be assessed at the bedside and effectively treated by pharmacological and nonpharmacological means .
It is important to note that CO2 reactivity may be preserved during TH . Therapeutic hyperventilation as TH is used as rescue therapy to decrease raised ICP and unintentional hypocapnia is also commonly observed in patients with acute brain injury , which increases the risk of brain tissue hypoxia . Monitoring of brain tissue oxygen or jugular venous oxygen saturation (jSvO2) is recommended for patients with acute traumatic brain injury, where therapeutic hyperventilation is used  and is important especially during TH. Preserved cerebral autoregulation seems not to be disturbed during TH and early induction of hypothermia after SAH led to faster restoration of cerebrovascular reactivity in vivo [6, 47, 48].
The rewarming has been considered as the vulnerable phase following TH [42, 49, 50]. Rapid rewarming and timing in vulnerable phases of the injured brain may abolish the neuroprotective effects of TH through ICP increase, excitotoxicity, increased metabolic demand and derangement of cerebrovascular reactivity [42, 51–53]. A report of four patients treated with TH after CA observed an increase in LPR in all patients during rewarming indicating brain ischemia . Slow and controlled rewarming after moderate hypothermia may prevent ICP increase and glutamate release and stabilize infarct volume . Close monitoring of cerebral metabolism, ICP, CBF and brain tissue oxygenation can help to define the optimal rewarming rate to avoid increases in ICP (recommended rate of 0.1°C) and to early detect an imbalance in energy supply and demand.
In the clinical setting there is still need to further explore the best induction and maintenance method, optimal duration and targeted temperature of therapeutic hypothermia. Due to the complexity of pathophysiologic mechanisms during hypothermia and rewarming, combining different advanced monitoring techniques seems mandatory. Multimodal neuromonitoring guidance may then help to define therapeutic targets and to establish clinical protocols to maximize the benefits of this emerging therapeutic modality.
- Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002, 346: 549-556.Google Scholar
- Rosomoff HL, Holaday DA: Cerebral blood flow and cerebral oxygen consumption during hypothermia. Am J Physiol. 1954, 179: 85-88.PubMedGoogle Scholar
- Chopp M, Knight R, Tidwell CD, Helpern JA, Brown E, Welch KM: The metabolic effects of mild hypothermia on global cerebral ischemia and recirculation in the cat: comparison to normothermia and hyperthermia. J Cereb Blood Flow Metab. 1989, 9: 141-148. 10.1038/jcbfm.1989.21.View ArticlePubMedGoogle Scholar
- Busto R, Globus MY, Dietrich WD, Martinez E, Valdes I, Ginsberg MD: Effect of mild hypothermia on ischemia-induced release of neurotransmitters and free fatty acids in rat brain. Stroke. 1989, 20: 904-910. 10.1161/01.STR.20.7.904.View ArticlePubMedGoogle Scholar
- Winfree CJ, Baker CJ, Connolly ES, Fiore AJ, Solomon RA: Mild hypothermia reduces penumbral glutamate levels in the rat permanent focal cerebral ischemia model. Neurosurgery. 1996, 38: 1216-1222.PubMedGoogle Scholar
- Schubert GA, Poli S, Mendelowitsch A, Schilling L, Thome C: 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. 2008, 25: 539-548. 10.1089/neu.2007.0500.View ArticlePubMedGoogle Scholar
- Shima H, Fujisawa H, Suehiro E, Uetsuka S, Maekawa T, Suzuki M: Mild hypothermia inhibits exogenous glutamate-induced increases in nitric oxide synthesis. J Neurotrauma. 2003, 20: 1179-1187. 10.1089/089771503770802862.View ArticlePubMedGoogle Scholar
- Fischer S, Renz D, Wiesnet M, Schaper W, Karliczek GF: Hypothermia abolishes hypoxia-induced hyperpermeability in brain microvessel endothelial cells. Brain Res Mol Brain Res. 1999, 74: 135-144.View ArticlePubMedGoogle Scholar
- Jiang JY, Lyeth BG, Kapasi MZ, Jenkins LW, Povlishock JT: Moderate hypothermia reduces blood-brain barrier disruption following traumatic brain injury in the rat. Acta Neuropathol. 1992, 84: 495-500. 10.1007/BF00304468.View ArticlePubMedGoogle Scholar
- Ueda M, Watanabe N, Ushikubo Y, Kasai K, Tsuzuki T, Aoki K, Yamazaki Y, Samejima H: [The effect of hypothermia on CSD propagation in rats]. No Shinkei Geka. 1997, 25: 523-528.PubMedGoogle Scholar
- Marion DW, Penrod LE, Kelsey SF, Obrist WD, Kochanek PM, Palmer AM, Wisniewski SR, DeKosky ST: Treatment of traumatic brain injury with moderate hypothermia. N Engl J Med. 1997, 336: 540-546. 10.1056/NEJM199702203360803.View ArticlePubMedGoogle Scholar
- Clifton GL, Miller ER, Choi SC, Levin HS, McCauley S, Smith KR, Muizelaar JP, Wagner FC, Marion DW, Luerssen TG, et al: Lack of effect of induction of hypothermia after acute brain injury. N Engl J Med. 2001, 344: 556-563. 10.1056/NEJM200102223440803.View ArticlePubMedGoogle Scholar
- Linares G, Mayer SA: Hypothermia for the treatment of ischemic and hemorrhagic stroke. Crit Care Med. 2009, 37: S243-S249. 10.1097/CCM.0b013e3181aa5de1.View ArticlePubMedGoogle Scholar
- Todd MM, Hindman BJ, Clarke WR, Torner JC: Mild intraoperative hypothermia during surgery for intracranial aneurysm. N Engl J Med. 2005, 352: 135-145. 10.1056/NEJMoa040975.View ArticlePubMedGoogle Scholar
- Hutchison JS, Ward RE, Lacroix J, Hebert PC, Barnes MA, Bohn DJ, Dirks PB, Doucette S, Fergusson D, Gottesman R, et al: Hypothermia therapy after traumatic brain injury in children. N Engl J Med. 2008, 358: 2447-2456. 10.1056/NEJMoa0706930.View ArticlePubMedGoogle Scholar
- Warren DE, Bickler PE, Clark JP, Gregersen M, Brosnan H, McKleroy W, Gabatto P: Hypothermia and rewarming injury in hippocampal neurons involve intracellular Ca2+ and glutamate excitotoxicity. Neuroscience. 2012, 207: 316-325.View ArticlePubMedGoogle Scholar
- Stuart RM, Schmidt M, Kurtz P, Waziri A, Helbok R, Mayer SA, Lee K, Badjatia N, Hirsch LJ, Connolly ES, Claassen J: Intracranial multimodal monitoring for acute brain injury: a single institution review of current practices. Neurocrit Care. 2010, 12: 188-198. 10.1007/s12028-010-9330-9.View ArticlePubMedGoogle Scholar
- Stover JF: Actual evidence for neuromonitoring-guided intensive care following severe traumatic brain injury. Swiss Med Wkly. 2011, 141: w13245-PubMedGoogle Scholar
- Vajkoczy P, Roth H, Horn P, Lucke T, Thome C, Hubner U, Martin GT, Zappletal C, Klar E, Schilling L, Schmiedek P: Continuous monitoring of regional cerebral blood flow: experimental and clinical validation of a novel thermal diffusion microprobe. J Neurosurg. 2000, 93: 265-274. 10.3171/jns.2000.93.2.0265.View ArticlePubMedGoogle Scholar
- Schubert GA, Poli S, Schilling L, Heiland S, Thome C: 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. 2008, 25: 841-852. 10.1089/neu.2007.0443.View ArticlePubMedGoogle Scholar
- Tokutomi T, Morimoto K, Miyagi T, Yamaguchi S, Ishikawa K, Shigemori M: Optimal temperature for the management of severe traumatic brain injury: effect of hypothermia on intracranial pressure, systemic and intracranial hemodynamics, and metabolism. Neurosurgery. 2003, 52: 102-111. discussion 111-112PubMedGoogle Scholar
- Schreckinger M, Marion DW: Contemporary management of traumatic intracranial hypertension: is there a role for therapeutic hypothermia?. Neurocrit Care. 2009, 11: 427-436. 10.1007/s12028-009-9256-2.View ArticlePubMedGoogle Scholar
- Tokutomi T, Miyagi T, Takeuchi Y, Karukaya T, Katsuki H, Shigemori M: Effect of 35°C hypothermia on intracranial pressure and clinical outcome in patients with severe traumatic brain injury. J Trauma. 2009, 66: 166-173. 10.1097/TA.0b013e318157dbec.View ArticlePubMedGoogle Scholar
- Shiozaki T, Sugimoto H, Taneda M, Yoshida H, Iwai A, Yoshioka T, Sugimoto T: Effect of mild hypothermia on uncontrollable intracranial hypertension after severe head injury. J Neurosurg. 1993, 79: 363-368. 10.3171/jns.1993.79.3.0363.View ArticlePubMedGoogle Scholar
- Soukup J, Zauner A, Doppenberg EM, Menzel M, Gilman C, Young HF, Bullock R: The importance of brain temperature in patients after severe head injury: relationship to intracranial pressure, cerebral perfusion pressure, cerebral blood flow, and outcome. J Neurotrauma. 2002, 19: 559-571. 10.1089/089771502753754046.View ArticlePubMedGoogle Scholar
- Polderman KH: Mechanisms of action, physiological effects, and complications of hypothermia. Crit Care Med. 2009, 37: S186-S202. 10.1097/CCM.0b013e3181aa5241.View ArticlePubMedGoogle Scholar
- Hillered L, Persson L, Nilsson P, Ronne-Engstrom E, Enblad P: Continuous monitoring of cerebral metabolism in traumatic brain injury: a focus on cerebral microdialysis. Curr Opin Crit Care. 2006, 12: 112-118. 10.1097/01.ccx.0000216576.11439.df.View ArticlePubMedGoogle Scholar
- Nordmark J, Rubertsson S, Mortberg E, Nilsson P, Enblad P: Intracerebral monitoring in comatose patients treated with hypothermia after a cardiac arrest. Acta Anaesthesiol Scand. 2009, 53: 289-298. 10.1111/j.1399-6576.2008.01885.x.View ArticlePubMedGoogle Scholar
- Berger C, Kiening K, Schwab S: Neurochemical monitoring of therapeutic effects in large human MCA infarction. Neurocrit Care. 2008, 9: 352-356. 10.1007/s12028-008-9093-8.View ArticlePubMedGoogle Scholar
- Steen PA, Newberg L, Milde JH, Michenfelder JD: Hypothermia and barbiturates: individual and combined effects on canine cerebral oxygen consumption. Anesthesiology. 1983, 58: 527-532. 10.1097/00000542-198306000-00009.View ArticlePubMedGoogle Scholar
- Nordmark J, Enblad P, Rubertsson S: Cerebral energy failure following experimental cardiac arrest Hypothermia treatment reduces secondary lactate/pyruvate-ratio increase. Resuscitation. 2009, 80: 573-579. 10.1016/j.resuscitation.2009.02.003.View ArticlePubMedGoogle Scholar
- Erecinska M, Thoresen M, Silver IA: Effects of hypothermia on energy metabolism in Mammalian central nervous system. J Cereb Blood Flow Metab. 2003, 23: 513-530.View ArticlePubMedGoogle Scholar
- Jiang JY, Liang YM, Luo QZ, Zhu C: Effect of mild hypothermia on brain dialysate lactate after fluid percussion brain injury in rodents. Neurosurgery. 2004, 54: 713-717. 10.1227/01.NEU.0000109535.58429.49. discussion 717-718View ArticlePubMedGoogle Scholar
- Cueni-Villoz N, Devigili A, Delodder F, Cianferoni S, Feihl F, Rossetti AO, Eggimann P, Vincent JL, Taccone FS, Oddo M: Increased blood glucose variability during therapeutic hypothermia and outcome after cardiac arrest. Crit Care Med. 2011, 39: 2225-2231. 10.1097/CCM.0b013e31822572c9.View ArticlePubMedGoogle Scholar
- Helbok R, Schmidt JM, Kurtz P, Hanafy KA, Fernandez L, Stuart RM, Presciutti M, Ostapkovich ND, Connolly ES, Lee K, et al: Systemic glucose and brain energy metabolism after subarachnoid hemorrhage. Neurocrit Care. 2010, 12: 317-323. 10.1007/s12028-009-9327-4.View ArticlePubMedGoogle Scholar
- Tseng EE, Brock MV, Lange MS, Troncoso JC, Blue ME, Lowenstein CJ, Johnston MV, Baumgartner WA: Glutamate excitotoxicity mediates neuronal apoptosis after hypothermic circulatory arrest. Ann Thorac Surg. 2010, 89: 440-445. 10.1016/j.athoracsur.2009.10.059.PubMed CentralView ArticlePubMedGoogle Scholar
- Berger C, Schabitz WR, Georgiadis D, Steiner T, Aschoff A, Schwab S: Effects of hypothermia on excitatory amino acids and metabolism in stroke patients: a microdialysis study. Stroke. 2002, 33: 519-524. 10.1161/hs0102.100878.View ArticlePubMedGoogle Scholar
- Zhang S, Zhi D, Lin X, Shang Y, Niu Y: Effect of mild hypothermia on partial pressure of oxygen in brain tissue and brain temperature in patients with severe head injury. Chin J Traumatol. 2002, 5: 43-45.PubMedGoogle Scholar
- Maloney-Wilensky E, Le Roux P: The physiology behind direct brain oxygen monitors and practical aspects of their use. Childs Nerv Syst. 2010, 26: 419-430. 10.1007/s00381-009-1037-x.View ArticlePubMedGoogle Scholar
- Rosenthal G, Hemphill JC, Sorani M, Martin C, Morabito D, Obrist WD, Manley GT: Brain tissue oxygen tension is more indicative of oxygen diffusion than oxygen delivery and metabolism in patients with traumatic brain injury. Crit Care Med. 2008, 36: 1917-1924. 10.1097/CCM.0b013e3181743d77.View ArticlePubMedGoogle Scholar
- Gupta AK, Al-Rawi PG, Hutchinson PJ, Kirkpatrick PJ: Effect of hypothermia on brain tissue oxygenation in patients with severe head injury. Br J Anaesth. 2002, 88: 188-192. 10.1093/bja/88.2.188.View ArticlePubMedGoogle Scholar
- Choi HA, Badjatia N, Mayer SA: Hypothermia for acute brain injury - mechanisms and practical aspects. Nat Rev Neurol. 2012.Google Scholar
- Oddo M, Frangos S, Maloney-Wilensky E, Andrew Kofke W, Le Roux PD, Levine JM: Effect of shivering on brain tissue oxygenation during induced normothermia in patients with severe brain injury. Neurocrit Care. 2010, 12: 10-16. 10.1007/s12028-009-9280-2.View ArticlePubMedGoogle Scholar
- Bisschops LL, Hoedemaekers CW, Simons KS, van der Hoeven JG: Preserved metabolic coupling and cerebrovascular reactivity during mild hypothermia after cardiac arrest. Crit Care Med. 2010, 38: 1542-1547. 10.1097/CCM.0b013e3181e2cc1e.View ArticlePubMedGoogle Scholar
- Neumann JO, Chambers IR, Citerio G, Enblad P, Gregson BA, Howells T, Mattern J, Nilsson P, Piper I, Ragauskas A, et al: The use of hyperventilation therapy after traumatic brain injury in Europe: an analysis of the BrainIT database. Intensive Care Med. 2008, 34: 1676-1682. 10.1007/s00134-008-1123-7.View ArticlePubMedGoogle Scholar
- Bratton SL, Chestnut RM, Ghajar J, McConnell Hammond FF, Harris OA, Hartl R, Manley GT, Nemecek A, Newell DW, Rosenthal G, et al: Guidelines for the management of severe traumatic brain injury. XIV. Hyperventilation. J Neurotrauma. 2007, 24 (Suppl 1): S87-S90.PubMedGoogle Scholar
- Preisman S, Marks R, Nahtomi-Shick O, Sidi A: Preservation of static and dynamic cerebral autoregulation after mild hypothermic cardiopulmonary bypass. Br J Anaesth. 2005, 95: 207-211. 10.1093/bja/aei147.View ArticlePubMedGoogle Scholar
- Verhaegen MJ, Todd MM, Hindman BJ, Warner DS: Cerebral autoregulation during moderate hypothermia in rats. Stroke. 1993, 24: 407-414. 10.1161/01.STR.24.3.407.View ArticlePubMedGoogle Scholar
- Nakamura T, Miyamoto O, Yamagami S, Hayashida Y, Itano T, Nagao S: Influence of rewarming conditions after hypothermia in gerbils with transient forebrain ischemia. J Neurosurg. 1999, 91: 114-120. 10.3171/jns.1999.91.1.0114.View ArticlePubMedGoogle Scholar
- Jiang JY, Xu W, Li WP, Gao GY, Bao YH, Liang YM, Luo QZ: 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. 2006, 26: 771-776. 10.1038/sj.jcbfm.9600253.View ArticlePubMedGoogle Scholar
- Lavinio A, Timofeev I, Nortje J, Outtrim J, Smielewski P, Gupta A, Hutchinson PJ, Matta BF, Pickard JD, Menon D, Czosnyka M: Cerebrovascular reactivity during hypothermia and rewarming. Br J Anaesth. 2007, 99: 237-244. 10.1093/bja/aem118.View ArticlePubMedGoogle Scholar
- Povlishock JT, Wei EP: Posthypothermic rewarming considerations following traumatic brain injury. J Neurotrauma. 2009, 26: 333-340. 10.1089/neu.2008.0604.PubMed CentralView ArticlePubMedGoogle Scholar
- Berger C, Xia F, Kohrmann M, Schwab S: Hypothermia in acute stroke - slow versus fast rewarming an experimental study in rats. Exp Neurol. 2007, 204: 131-137. 10.1016/j.expneurol.2006.10.002.View ArticlePubMedGoogle Scholar
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