Abstract
The fundamental clinical obstacle to the use of ketamine for neuroprotection is the historical textbook dogma that ketamine is contraindicated in patients at risk of increases in intracranial pressure (ICP) [1, 2]. Early studies in animals and man revealed an increase in cerebral oxygen consumption (CMRO2), cerebral blood flow (CBF) and ICP after ketamine [3–5]. However, various experimental and clinical data show that these findings lack consistency, which seems to be attributable to different study designs [6, 7], the absence or presence of controlled ventilation [8–11] and background anaesthetics or other medication [12–15]. Apart from practical use in haemorrhagic shock based on stimulatory effects on the cardiovascular system [16, 17], the well-known experimental neuroprotective efficacy of ketamine [18–20] has long remained clinically unexploited, with apparently having few if any implications for use in patients with intracranial lesions. When the classic concept of suppression of brain metabolism as the mainstay of cerebral protection by anaesthetics was questioned in recent years, interest in ketamine increasingly started to revive. The new pathophysiological thinking focused on a key role of glutamate signalling in the injury cascade, suggesting that neuronal death results from toxic concentrations of glutamate in the extracellular space and metabolic imbalances leading to apoptosis or delayed degeneration [21, 22]. Ketamine blocks the activation of excitatory glutamate receptors of the N-methyl-D-aspartate (NMDA) subtype by binding non-competitively to the phencyclidine site in the receptor channel in humans [23] and may have further effects of unknown clinical relevance [24, 25].
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Madson JB, Cold GE (1990) The effects of anaesthetics upon cerebral circulation and metabolism. Experimental and clinical studies. Springer, Vienna New York
Hickey R (1999) Effects of anesthesia on cerebral and spinal cord physiology. In: Newfield P, Cottrell J (eds) Handbook of neuroanesthesia. Lippincott Williams & Wilkins, Philadelphia, pp 20–33
Gardner AE, Olson BE, Lichtiger M (1971) Cerebrospinal-fluid pressure during dissociative anesthesia with ketamine. Anesthesiology 35: 226–228
Takeshita H, Okuda Y, Sari A (1972) The effects of ketamine on cerebral circulation and metabolism in man. Anesthesiology 36: 69–75
Shapiro HM, Wyte SR, Harris AB (1972) Ketamine anesthesia in patients with intracranial pathology. Br J Anaesth 44: 1200–1204
Cavazutti M, Porro CA, Biral GP et al (1987) Ketamine effects on local cerebral blood flow and metabolism in the rat. J Cereb Blood Flow Metabol 7: 806–811
Chi O, Wei HM, Klein SL et al (1994) Effect of ketamine on heterogeneity of cerebral microregional venous 02 saturation in the rat. Anesth Analg 79: 860–866
Sari A, Okuda Y, Takeshita H (1972) The effect of ketamine on cerebrospinal fluid pressure. Anesth Analg 51: 560–565
Schwedler M, Miletich DJ, Albrecht RF (1982) Cerebral blood flow and metabolism following ketamine administration. Can Anaesth Soc J 29: 222–225
Akeson J, Björkman S, Messeter K et al (1993) Cerebral pharmcodynamics of anaesthetic and subanaesthetic doses of ketamine in the normoventilated pig. Acta Anaesthesiol Scand 37:211- -218
Pfenninger E, Grünert A, Bowdler I et al (1985) The effect of ketamine on intracranial pressure during hemorrhagic shock under the conditions of spontaneous breathing and controlled ventilation. Acta Neurochir (Wien) 78: 113–118
Dawson B, Michenfelder J, Theye R (1971) Effects of ketamine on canine cerebral blood flow and metabolism: modification by prior administration of thiopental. Anesth Analg 50: 443–447
Nimkoff L, Quinn C, Silver P et al (1997) The effects of intravenous anesthetics on intracranial pressure and cerebral perfusion pressure in two feline models of brain edema. J Crit Care 12: 132–136
Belopavlovic M, Buchthal A (1982) Modification of ketamine-induced intracranial hypertension in neurosurgical patients by pre-treatment with midazolam. Acta Anaesthesiol Scand 26: 458–462
Mayberg TS, Lam AM, Matta BF et al (1995) Ketamine does not increase blood flow velocity or intracranial pressure during isoflurane/nitrous oxide anesthesia in patients undergoing craniotomy. Anesth Analg 81: 84–89
White PF, Way WL, Trevor AJ (1982) Ketamine–its pharmacology and therapeutic uses. Anesthesiology 56: 119–136
Himmelseher S, Pfenninger E (2000) Anaesthetic techniques and agents in neuroanesthesia — a comparison of German surveys in 1991 and 1997. Anaesthesiol lntensivmed 41: 126–136
Choi DW (1990) Ketamine reduces NMDA receptor mediated neurotoxicity in cortical cultures. In: Domino EF (ed) Status of ketamine in anaesthesiology. NPP Books, Ann Arbor, Mich, pp 549–555
Hoffman WE, Pelligrino D, Werner C et al (1992) Ketamine decreases plasma catecholamines and improves outcome from incomplete cerebral ischemia in rats. Anesthesiology 76: 755–762
Shapira Y, Lam AM, Eng CC et al (1994) Therapeutic time window and dose response of the beneficial effects of ketamine in experimental head injury. Stroke 25: 1637–1643
Sattler R, Tymianski M (2001) Molecular mechanisms of glutamate receptor-mediated excitotoxic neuronal cell death. Mol Neurobiol 24: 107–129
Sahuquillo J, Poca MA, Amoros S (2001) Current aspects of pathophysiology and cell dysfunction after severe head injury. Curr Pharm Des 15: 1475–1483
Qye I, Paulsen O, Maurset A (1992) Effects of ketamine on sensory perception: evidence for a role of N-methyl-D-aspartate receptors. J Pharmacol Exp Ther 260: 1209–1213
Orser BA, Pennefather PS, MacDonald JF (1997) Multiple mechanisms of ketamine blockade of N-methyl-D-aspartate receptors. Anesthesiology 86: 903–917
Kohrs R, Durieux ME (1998) Ketamine: teaching an old drug new tricks. Anesth Analg 87: 1186–1193
Schüttler J, Zsigmond E, White PF (1997) Ketamine and its isomers. In: White PF (ed) Textbook of intravenous anesthesia. Williams & Wilkins, Baltimore, pp 171–188
Mathews KS, Toner CC, McLaughlin DP et al (2001) Comparison of ketamine stereoisomers on tissue metabolic activity in an vitro model of global cerebral ischaemia. Neurochemistry Int 38: 367–372
Himmelseher S, Pfenninger E, Georgieff M (1996) The effects of ketamine-isomers on neuronal injury and regeneration in rat hippocampal neurons. Anesth Analg 83: 505–512
Himmelseher S, Pfenninger E, Kochs E et al (2000) S(+)-Ketamine up-regulates neuronal regeneration associated proteins following glutamate injury in cultured rat hippocampal neurons. J Neurosurg Anesthesiol 12: 84–94
Akeson J, Björkman S, Messeter K et al (1993) Low-dose midazolam antagonizes cerebral metabolic stimulation by ketamine in the pig. Acta Anaesthesiol Scand 37: 525–531
Sakai K, Cho S, Fukusaki M et al (2000) The effects of propofol with and without ketamine on human cerebral blood flow velocity and response. Anesth Analg 90: 377–382
Nagase K, Ida H, Dohi S (2002) L-Arginine and nitroglycerin restore hypercapnia-induced cerebral vasodilation in rabbits after its attenuation by ketamine. Anesth Analg 94: 954–958
Friesen RH, Honda At (1987) Changes in anterior fontanel pressure in preterm neonates receiving isoflurane, halothane, fentanyl or ketamine. Anesth Analg 66: 431–434
Oren RE, Rasool NA, Rubinstein EH (1987) Effect of ketamine on cerebral cortical blood flow and metabolism in rabbits. Stroke 1987: 441–444
Wendling WW, Daniels FB, Chen D et al (1994) Ketamine directly dilates bovine cerebral arteries by acting as a calcium entry blocker. J Neurosurg 6: 186–192
Shakunaga K, Kojima S, Jomura K et al (1998) Ketamine suppresses the production and release of endothelin 1 from cultured bovine endothelial cells. Anesth Analg 86: 1098–1102
Engelhard K, Werner C, Möllenberg O et al (2001) S(+)-ketamine/propofol maintain dynamic cerebrovascular autoregulation in humans. Can J Anaesth 48: 1034–1039
Vollenweider FX, Leenders KL, Oyc I et al (1997) Differential psychopathology and patterns of cerebral glucose utilisation produced by (S)- and (R)-ketamine in healthy volunteers using positron emission tomography. Eur Neuropsychopharmacol 7: 25–38
Brain Trauma Foundation, American Association of Neurological Surgeons, Joint Section on Neurotrauma and Critical Care (2000) Management and prognosis of severe traumatic brain injury. Brain Trauma Foundation, New York
Robertson CS (2001) Management of cerebral perfusion pressure after traumatic brain injury. Anesthesiology 95: 2086–2095
Chesnut RM (1997) Avoidance of hypotension: condition sine qua non of successful severe head-injury management. J Trauma 42 (5 Suppl): S4 - S9
Jeremitsky E, Omert L, Dunham CM et al (2003) Harbingers of poor outcome the day after severe head injury: hypothermia, hypoxia, and hypoperfusion. J Trauma 54: 312–319
Doenicke A, Angster R, Mayer Metal (1992) The action of S-(+)-ketamine on serum catecholamine and cortisol. A comparison with ketamine racemate. Anaesthesist 41: 585–587
Kunst G, Martin E, Graf BM et al (1999) Actions of ketamine and its isomers on contractility and calcium transients in human myocardium. Anesthesiology 90: 1363–1371
Kanellopoulos A, Lenz G, Mühlbauer B (1998) Stereoselective differences in the vasorelaxing effects of S(+) and R(-) ketamine on rat isolated aorta. Anesthesiology 88: 718–724
Müllenheim J, Rulands R, Wietschorke T et al (2001) Late preconditioning is blocked by racemic ketamine, but not by S(+)-ketamine. Anesth Analg 93: 265–270
Kienbaum P, Heuter T, Pavlakovic G et al (2001) S(+)-Ketamine increases muscle sympathetic activity and maintains the neural response to hypotensive challenges in humans. Anesthesiology 94: 252–256
Strebel S, Kaufman M, Maitre L et al (1995) Effects of ketamine on cerebral blood flow velocity in humans. Influence of pre-treatment with midazolam or esmolol. Anaesthesia 50: 223–228
Adams HA (1997) S(+)-Ketamine. Circulatory interactions during total intravenous anesthesia and analgo-sedation Anaesthesist 46: 1081–1087
Adams HA, Brausch M, Schmitz CS et al (2001) Analgosedation with (S)-ketamine/propofol vs. (S)-ketamine/midazolam: control and quality of sedation, stress response and haemodynamic reactions. Anaesthesiol Intensivmed Notfallmed Schmerzther 36: 417–424
Albanese J, Arnaud S, Rey M, Thomachot L et al (1997) Ketamine decreases intracranial pressure and electroencephalographic activity in traumatic brain injury patients during propofol sedation. Anesthesiology 87: 1328–1334
Weiss J, Goldberg MP, Choi DW (1986) Ketamine protects cultured neurons from hypoxic injury. Brain Res 380: 186–190
Chan PH, Chu L (1989) Ketamine protects cultured astrocytes from glutamate-induced swelling. Brain Res 487: 380–383
Lucas JH, Wolf A (1991) In vitro studies of multiple impact injury to mammalian CNS neurons: prevention of perikaryal damage and death by ketamine. Brain Res 543: 181–193
Gonzalez JM, Loeb AL, Reichard PS, et al (1995) Ketamine inhibits glutamate-, N-methlyl-Daspartate-, and quisqualate-stimulated cGMP production in cultured cerebral neurons. Anesthesiology 82: 205–213
Church J, Zeman S, Lodge D (1988) The neuroprotective action of ketamine and MK-801 after transient cerebral ischaemia in rats. Anesthesiology 69: 702–709
Smith DH, Okiyama TA, Gennarelli TA et al (1993) Magnesium and ketamine attenuate cognitive dysfunction following experimental head injury. Neurosci Lett 157: 211–214
Fujikawa DG (1995) Neuroprotective effect of ketamine administered after status epilepticus onset. Epilepsia 36: 186–195
Lin SZ, Chiou AL, Wang Y (1996) Ketamine antagonizes nitric oxide release from cerebral cortex after middle cerebral artery ligation in rats. Stroke 27: 747–752
Spandou E, Karkavelas G, Soubasi V et al (1999) Effect of ketamine on hypoxic-ischemic brain damage in newborn rats. Brain Res 819: 1–7
Chang ML, Yang J, Kem S et al (2002) Nicotinamide and ketamine reduce infarct volume and DNA fragmentation in rats after brain ischemia and reperfusion. Neurosci Lett 322: 137–140
Zhang C, Shen W, Zhang G (2002) N-Methyl-D-aspartate receptor and L-type voltage-gated Ca channel antagonists suppress the release of cytochrome c and the expression of procaspase-3 in rat hippocampus after global brain ischemia. Neurosci Lett 328: 265–268
Shen WH, Zhang CY, Zhang GY (2003) Modulation of IkB kinase autophosphorylation and activity following brain ischemia. Acta Pharmacol Sin 24: 311–315
Engelhard K, Werner C, Eberspächer E et al (2003) The effect of the az-agonist dexmedetomidine and the N-methyl-D-aspartate antagonist S(+)-ketamine on the expression of apoptosis-regulating proteins after incomplete cerebral ischemia and reperfusion in rats. Anesth Analg 96: 524–531
Proescholdt M, Heimann A, Kempski 0 (2001) Neuroprotection of S(+) ketamine isomer in global forebrain ischemia. Brain Res 904: 245–251
Reeker W, Werner C, Möllenberg O et al (2000) High-dose S(+)-ketamine improves neurological outcome following incomplete cerebral ischemia. Can J Anaesth 47: 572–578
Ikonomidou C, Bosch F, Miksa M et al (1999) Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 283: 70–74
Pohl D, Bittigau P, Ishimaru MJ et al (1999) N-Methyl-D-aspartate antagonists and apoptotic cell death triggered by head trauma in developing rat brain. Proc Natl Acad Sci 96: 2508–2513
Zafra F, Hengerer B, Leibrock (1990) Activity dependent regulation of BDNF and NGF mRNAs in the rat hippocampus is mediated by non-NMDA glutamta receptors. EMBO J 9: 3545–3550
Hardingham GE, Fukunaga Y, Bading H (2002) Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat Neurosci 5: 405–414
Adams HA, Claussen E, Gebhardt B et al (1991) The use of ketamine and midazolam for analgesia and sedation in ventilated patients subject to obligatory treatment with catecholamines. Anaesthesist 40: 238–244
Kolbel CB, Rippel K, Klar H et al (2000) Esophageal motility disorders in critically ill patients: a 24-hour manometric study. Intensive Care Med 26: 1421–1427
Ostermann ME, Keenan SP, Seiferling RA et al (2000) Sedation in the intensive care unit. JAMA 283: 1451–1459
Koppel C, Arndt I, lbe K (1990) Effects of enzyme induction, renal and cardiac function on ketamine plasma kinetics in patients with ketamine long-term analgosedation. Eur J Drug Metab Pharmacokinet 15: 259–263
Tsubo T, Sakai I, Okawa H et al (2001) Ketamine and midazolam kinetics during continuous hemodiafiltration in patients with multiple organ dysfunction syndrome. Intensive Care Med 27: 1087–1090
Kolenda H, Gremmelt A, Rading S et al (1996) Ketamine for analgosedative therapy in intensive care treatment of head-injured patients. Acta Neurochir (Wien) 138: 1193–1199
Bourgin A, Albanese J, Wereszcynski N et al (2003) Safety of sedation with ketamine in severe head injury patients: comparison with sufentanil. Crit Care Med 31: 711–717
Hijazi Y, Bodoni an C, Bolon Metal (2003) Pharmacokinetics and haemodynamics of ketamine in intensive care patients with brain or spinal cord injury. Br J Anaesth 90: 155–160
Bullock R, Zauner A, Woodward JJ et al (1998) Factors affecting excitatory amino acid release following severe head injury. J Neurosurg 89: 507–518
Narayan RK, Michel ME, and the Clinical Trials in Head Injury Study Group (2002) Clinical Trials in Head Injury. J Neurotrauma 19: 503–518
Arrowsmith JE, Harrison Mi, Newman SP et al (1998) Neuroprotection of the brain during cardiopulmonary bypass: randomized trial of remacemide during coronary artery bypass in 171 patients. Stroke 29: 2357–2362
Morris GF, Bullock R. Marshall SB et al (1999) Failure of the competitive N-methyl-D-aspartate antagonist selfotel (CGS 19755) in the treatment of severe head inury: results of two phase III clinical trials. The selfotel investigators. J Neurosurg 91: 737–743
Albers GW, Goldstein LB. Hall D et al (2001) Aptiganel hydrochloride in acute ischemic stroke: a randomized controlled trial. JAMA 286:2673–2682
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2004 Springer-Verlag Italia, Milano
About this paper
Cite this paper
Himmelseher, S., Kochs, E. (2004). Neuroprotection by ketamine. In: Gullo, A. (eds) Anaesthesia, Pain, Intensive Care and Emergency Medicine — A.P.I.C.E.. Springer, Milano. https://doi.org/10.1007/978-88-470-2189-1_19
Download citation
DOI: https://doi.org/10.1007/978-88-470-2189-1_19
Publisher Name: Springer, Milano
Print ISBN: 978-88-470-0235-7
Online ISBN: 978-88-470-2189-1
eBook Packages: Springer Book Archive