Evidence that hypoxia induced in cortical neurons is the mechanism of general anaesthesia
Despite much research the mode of action of gaseous anaesthetic agents has proven elusive since the first, ether, was used in 1842. As anaesthetic gas mixtures contain at least 21% oxygen and the minimum alveolar concentration of an anaesthetic agent producing an effect does not change over a wide range of inspired oxygen concentrations,1 it appears unlikely that hypoxia is involved. However, a significant reduction in the respired oxygen concentration always causes loss of consciousness.
The intrepid balloonists James Glaisher and Henry Coxwell first discovered this on their ascent to the height of Everest over Wolverhampton in 1862: details were published in the Lancet the following year. Normal levels of oxygen in blood cannot ensure adequate oxygen tensions in cells and intracellular oxygen concentrations cannot be measured. However, the discovery of the Hypoxia-inducible transcription factor 1 (HIF-1) provides a unique marker for cellular hypoxia.2 HIF-1 is a heterodimer of alpha and beta components, with the level of HIF-1α controlled by its destruction by the Von Hippel Lindau protein (VHL). A fall in cellular oxygen tension reduces the production of VHL,allowing HIF-1α to persist, which binds to HIF-1β to produce the transcription factor HIF-1.
Anaesthesia can be produced by xenon and oxygen mixtures3 and evidence that xenon produces cellular hypoxia has come from use of the gas by athletes in performance enhancement. HIF-1 and the effector hormone, erythropoietin, are up-regulated by the inhalation of xenon/oxygen mixtures with sufficient oxygen to sustain consciousness4 and the effect lasts many hours longer than a hypoxia exposure induced by breathing a low oxygen partial pressure. As xenon is inert with no known compounds, it would seem unlikely that its action is to lower VHL production as can be achieved chemically, for example, by using cobalt compounds. Cortical neurons are exquisitely sensitive to hypoxia and their activity is abolished at oxygen levels well above that associated with irreversible cell damage.5 Xenon may induce a reversible change in cellular and/or mitochondrial membranes impairing oxygen transport and ATP production.
The loss of consciousness induced by gaseous anaesthetic agents that have a high water/lipid solubility ratio like xenon may, therefore, be due to hypoxia of cortical neurons. This can be tested by determining if HIF-1 is up-regulated in other forms of gaseous anaesthesia and it may be possible to investigate if conformational changes of cell membranes occur and the mechanism by using a physical model.
Philip B. James
Emeritus Professor of Medicine
The University of Dundee
Dundee DD1 4HN
1. Eger EI II. Minimal alveolar concentration. Chapter 1 in: Anesthetic uptake and action. Williams and Williams
Company, Baltimore, Maryland, 1974.
2. Wang GL, Jiang B-H, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS
heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci 1995;92:5510-14.
3. Cullen SC, Gross EG. The anesthetic properties of xenon in animals and human beings with additional
observations on krypton. Science 1951;113:580-82.
4. Ma D, Lim T, Xu J, Tang H, et al. Xenon preconditioning protects against ischemic-reperfusion injury via HIF-
1α activation. J Am Soc Nephrol 2009;20:713-20.
5. Astrup J, Siesjo BK, Symon L. Thresholds in cerebral ischemia – the ischemic penumbra. Stroke 1981;12:723-725.
Submitted to the Lancet 16th September 2015
Chapter 19: Head Injuries – the Curse of Life in the Fast Lane
1. Voss HU, Ulug AM, Dyke JP, et al. Possible axonal regrowth in late recovery from the minimally conscious state. J Clin Invest 2005;116:2005-2011.
2. Shin SS, Verstynen T, Pathak S, et al. High-definition fiber tracking for assessment of neurological deficit in a case of traumatic brain injury: finding, visualizing, and interpreting small sites of damage. J Neurosurg 2012;116:1062-1069.
3. Ghajar J. Traumatic brain injury. Lancet 2000;356:923–929.
5. Diringer MN. Hyperoxia-good or bad for the injured brain. Curr Opin Crit Care 2008;14:167–171.
6. Sukoff MH, Ragatz RE. Hyperbaric oxygenation for the treatment of acute cerebral edema. Neurosurgery 1982;10:29-38.
7. Stamler JS, Jia L, Eu JP, et al. Blood flow regulation by S-nitrosohemoglobin in the physiological oxygen gradient. Science 1997;276:2034-2037.
8. Cramer T, Yamanishi Y, Clausen BE, et al. HIF 1α is essential for myeloid cell-mediated inflammation. Cell 2003;112:645-657.
9. Dai J, Swaab DF, Buijs RM. Recovery of axonal transport in “dead neurons.” Lancet 1998;351:499-500.
10. Zamboni WA, Roth AC, Russell RC, e al. Morphologic analysis of the microcirculation during reperfusion of ischemic skeletal muscle and the effect of hyperbaric oxygen. Plast Reconstr Surg 1993;91:1110-1123.
11. Gandy SE, Snow RB, Zimmerman RD, Deck MDF. Cranial nuclear magnetic resonance imaging in head trauma. Ann Neurol 1984;16:254-257.
12. Faden AI. Neuroprotection and traumatic brain injury: The search continues. Arch Neurol 2001;58:1553-1555.
13. Autti, T, Sipila L, Autti, H, Salonen O. Brain lesions in players of contact sports, Lancet 1997;349:1144.
14. Jones D. Heal thyself. New Scientist 14 August 2010.
15. Singer M. Treating critical illness: The importance of first doing no harm. PLoS Medicine 2005;2:e167.
16. Pintu L, Whitehead T, Evans T, Griffiths M. Ventilator-associated lung injury. Lancet 2003;361:332-340.
17. Sukoff MH, Hollin SA, Espinosa OE, Jacobson JH. The protective effect of hyperbaric oxygenation in experimental cerebral edema. J Neurosurg 1968;29:236-241.
18. Holbach KH, Caroli A, Wassmann H. Cerebral energy metabolism in patients with brain lesions at normo and hyperbaric oxygen pressures. J Neurol 1977;217:17-30.
19. Ingevar DH, Lassen NA. Treatment of focal cerebral ischemia with hyperbaric oxygen: report of 4 cases. Acta Neurol Scand 1965;41;92-95.
20. Kelly DL Jr, Lassiter KRL, Vongsvivut A, Smith JM. Effects of hyperbaric oxygenation and tissue oxygen studies in experimental paraplegia. Neurosurgery 1972;36:425-429.
21. Jacobson I, Harper AM, McDowall DG. Effects of oxygen under pressure on cerebral blood-flow and cerebral venous oxygen tension. Lancet 1963;i:549.
22. Haldane JS. The therapeutic administration of oxygen. Br Med J 1917;1:181-183.
23. Nunn JF. 100% oxygen at normal pressure is an alternative. Br Med J 1994;309:124.
24. Rockswold GL, Ford SE. Preliminary results of a prospective randomized trial for treatment of severely brain-injured patients with hyperbaric oxygen. Min Med 1985;68:533-535.
25. Rockswold GL, Ford SE, Anderson DC, Bergman TA, Sherman RE. Results of a prospective randomised trial for treatment of severely brain injured patients with hyperbaric oxygen. J Neurosurg 1992;76:929-934.
26. Oddo M, Levine JM, Mackenzie L, et al. Brain hypoxia is associated with short-term outcome after severe head injury independently of intracranial hypertension and low cerebral perfusion pressure. Neurosurg 2011;69:1037-1045.
27. Spiotta AM, Stiefel MF, Gracias VH, et al. Brain tissue oxygen-directed management and outcome in patients with severe traumatic brain injury. J Neurosurg 2010;113:571-580.
28. Tolias CM, Reinert M, Seiler R, et al. Normobaric hyperoxia—induced improvement in cerebral metabolism and reduction in intracranial pressure in patients with severe head injury: a prospective historical cohort-matched study. J Neurosurg 2004;101:435-444.
29. Bardt TF, Unterberg AW, Hartl R, et el. Monitoring of brain tissue PO2 in traumatic brain injury: effect of cerebral hypoxia on outcome. Acta Neurochir 1998;71(Suppl):153–156.
30. Neubauer RA, Gottlieb SF, Kagan RL, Enhancing “idling” neurons. Lancet 1990;335:542.
31. Peters BH, Levin HS, Kelly PJ. Neurologic and psychologic manifestations of decompression illness in divers. Neurology 1977;27:125-127.
32. Curley MD, Schwartz HJC, Zwingelberg KM. Neuropsychologic assessment of cerebral decompression sickness and gas embolism. Undersea Biomed Res 1988;15:223-236.
33. Courville CB, Kimball TS. Histologic observations in a case of old gunshot wound of the brain. Am J Pathol 1934;17:10-21.
34. Harch PG, Fogarty EF, Staabl PK, Van Meter K. Low pressure hyperbaric oxygen therapy and SPECT brain imaging in the treatment of blast induced chronic traumatic brain injury (post-concussion syndrome) and post traumatic stress disorder: a case report. Cases Journal 2009;2:6538. (http://www.casesjournal.com/content/2/1/6538)
35. Harch PG, Kriedt C, Van Meter KW, Sutherland RJ. Hyperbaric oxygen therapy improves spatial learning and memory in a rat model of chronic traumatic brain injury. Brain Res 2007;1174:120-129.
36. Mychaskiw G. How many deaths will it take till they know? Monkeys, madmen and the standard of evidence: an editorial perspective. Undersea Hyperb Med 2012;39:795-797.
37. Wright JK, Zant E, Groom K., et al. Case report: Treatment of mild traumatic brain injury with hyperbaric oxygen. Undersea Hyperb Med 2009;36:391-399.
38. Wolf G, Cifu D, Baugh L, Carne W, Profenna L. The effect of hyperbaric oxygen on symptoms following mild traumatic brain injury. J Neurotrauma 2012; 29: 2606-2612.
39. Collet JP, Vanasse M, Marois P, et al. HBO-CP research group. Hyperbaric oxygen for children with cerebral palsy: a randomised multicentre trial. Lancet 2001;357:582-586.
40. Babchin A, Levich E, Melamed Y, Sivashinsky G. Osmotic phenomena in application of hyperbaric oxygen treatment. Colloids Surf B Biointerfaces 2010;83:128-132.
41. Lawrence JH, Tobias CR, Lyons WMR, et al. A study of aero medical problems in a Liberator bomber at high altitude. J Aviat Med 1945;16:286-303.
42. Astrup J, Siesjo BK, Symon L. Thresholds in cerebral ischemia – the ischemic penumbra. Stroke 1981;12:723-725.
43. Ewing, R, McCarthy D, Gronwall D, Wrightson,. Persisting effects of minor head injury observable during hypoxic stress. J Clin Exp Neuropsychol 1980;2:147-155.
44. Lin KC, Niu KC, Tsai KJ, et al. Attenuating inflammation but stimulating both angiogenesis and neurogenesis using hyperbaric oxygen in rats with traumatic brain injury. J Trauma Acute Care Surg 2012;72:650-659.
45. Saunders RL, Harbaugh RE. The second impact in catastrophic contactsports head trauma. JAMA 1984;252:538-539.
46. Weinstein E, Turner M, Kuzma BB, Feuer H. Second impact syndrome in football: new imaging and insights into a rare and devastating condition. J Neurosurg: Pediatrics 2013;11;331-334.
47. Menzel M, Doppenberg MR, Zauner A, et al. Increased inspired oxygen concentration as a factor in improved brain tissue oxygenation and tissue lactate levels after severe human head injury. J Neurosurg 1999;91:1-10.
48. Johnston AJ, Steiner LA, Gupta AK, Menon DK. Cerebral oxygen vasoreactivity and cerebral tissue oxygen reactivity. Br J Anaesth 2003;90:774-786.
49. Erecinska M, Silver IA. Tissue oxygen tension and brain sensitivity to hypoxia. Resp Physiol 2001;128:263–276.
50. MacDonald CL, Johnson AM, Cooper D, et al. Detection of blast related traumatic brain injury in US military personnel. N Engl J Med 2011;364:2091–2100.
51. Boussi-Gross R, Golan H, Fishlev G, et al. Hyperbaric oxygen therapy can improve post concussive syndrome years after mild traumatic brain injury - randomized prospective trial. PLoS ONE 2013;8(11): e79995. doi:10.1371/journal.pone.0079995