Oxygen Toxicity and Anesthesia: A Ten-Year Review and Overview* JOHN Q. DURFEY, M.D. Professor of Anesthesiology, Medical College of Virginia , Richmond, Virginia The awareness of anesthesia personnel in the on the continuing study of oxygen effects by anes­ entity of "oxygen toxicit y" has bee n in creased in the thesia laboratories and the possibl e interaction of the last ten years by the greater in volve ment in pro­ gas with other drugs as related to li ve r and kidney longed respiratory care, and concomitantly in creased function, enzy me acti vity, membrane function, and complexity of operati ve management. The reali zatio n electron transport. The info rmati on obtained will th at cyanotic heart disease and primary pulmonary have broad ramificati ons in our total understanding insuffi ciency does not necessaril y protect the indi­ of uptake and distribution, rate, a nd excreti on of the vidual against the occurrence of the pulmonary mani­ anesth etic agents currently utilized, and hopefully fe stati ons of the disease, and that further realistic will lead the way to the introduction of less nox ious delineati on of the parameters of control is necessary, and more easil y cont roll ed agents and a more careful has fo cused an intense beam of critical reevaluati on and logical phys iological approach to pati ent man­ on present methods of anesthetic management and agement. postoperati ve care. It is important to note that "oxy­ Historical Review. The concept of "oxygen tox­ gen toxicity" as commonl y di scussed. that is. th e ic ity" is anything but new, dating back to the time of CNS, pulmonary, and eye manifestati ons, represents Lavoisier, and fo ll owed in 1849 by Smith's descrip­ advanced stages of the body's adve rse responses. ti on of a fa tal pulmonary " inflammation" after ex­ More frequent and subtle changes are present . but posu re to o xygen at 3-5 atm fo r approximately 24 often overlooked. This is particularl y true in the less hours. easily discernible effects upon electron transport sys­ Insofar as the impact on anesthesia is con­ tems, and interference with basic membrane and cerned, in the last 15 years, during which time the enzymatic function. problems began to affect the care of pati ents, the As individuals trained in the management of primary consideration was the pulmonary manifesta­ cardio-respiratory emergencies, anesthesia personnel ti ons of the "disease." Perh aps, " iatrogenically may expect to be call ed upon professionall y regard­ induced disease" would be a more appropriate ex­ ing problems related to the management of dysbari sm pression. This concentrati on on the pulmonary mani ­ and oxygen toxicit y; particularl y in view of the cur­ festati ons was natural in a nonhyperbaric environ­ rently developing underwater industrial and agricul­ ment, particul arl y since anesthesiologists had been tural interests producing greater numbers of exposed more intimately in volved with suffici ent oxygenati on individuals and radically different environmental of the patient during surgery, and the maintenance of conditions co mplicating acute medical care. The a proper a irway. fe asibility of returning individuals to the surfa ce Although equa ll y concerned about acid-base is poor. This wo uld necessitate prolonged peri ods of balance, carbon di oxide retention, prevention of at­ decompression and would introduce seri ous prob­ electasis, and a reasonably reactive and phys iologi­ lems of logistics. ca ll y intact postoperati ve pati ent, it was not until A good deal more emphasis should be pl aced fo ur major alterati ons occurred in patterns of pati ent care th at the dynami c characteristics of oxygen tox­ ,:, Presented at the 25 th Annual Stoneburne r Lecture icit y and it s relati onship to this particular speci alt y Series, Februa ry 26, I 972, at the Medical Coll ege of Vir­ became more obvious. These changes were: ( I ) The gin ia, Richmond. advent of o pen heart surgery, using the pump-oxy- MCV QUARTERLY 8(2): 11 3- 122, 1972 113 114 DURFEY: OXYGEN TOXICITY AND ANESTHESIA genator, with the special problems resulting there­ University and previously associated with the Ohio from, (hemolysis, air emboli sm, and marked aci­ Tuberculosis H ospital in Columbus, was one of the dosis). (2) The use of hyperbaric facilities for the first clinicians to fully appreciate the early onset and surgical and medical treatment of pati ents with surgi­ progressive course of pulmonary changes in patients cal, medical, infectious, and cardiovascular diseases, exposed to relati ve ly " innocuous" amounts of oxygen and their attendant acute threat of oxygen toxicity; for a period of time. In 1958, he pointed out the simi­ that is, central nervous system oxygen toxicity ( as larity of morphological findings in a seri es of pati ents, well as pulmonary toxicity) . ( 3) The progressive in­ some of whom had received oxygen, fo r as little as volvement in prolonged postoperative ve ntilatory care, two and one-half days, administered via nasal cathe­ using continuously assisted and/ or controlled respira­ ter-not ventilators. H e demonstrated capillary con­ tion by ventilators equipped with onl y limited con­ gestion and proliferation, followed by the appearance trols governing inspired oxygen tensions; and th e of diffuse fibrosis after a period of about two weeks. nonconcomitant realization th at such care was induc­ Other changes previously noted in experimentally ing or producing toxic pulmonary and/ or other mani­ induced pulmonary manifestati ons were hyperemia, festations, or at least it was increasing the risk of such hemorrhage, edema, atelectasis, and "inflammation." problems. ( 4) The current interest in " halothane These changes had to be differentiated from atelec­ hepatitis," enzymatic acti va tion and inactivati on, and tasis, intrapulmonary hemorrhage, infection, and the bas ic metaboli c consequences produced by anes­ postmortem alt erati ons due to absorption of gas. A thetic agents. Some of the biophysical-electro-chemi­ brief experiment followed wherein mice were ex­ cal-enzymatic and substrate actions may indeed be posed to I 00% oxygen for 4 8 hours at approximately simil ar, as will be di scussed further. The fa scinating. 740 mm Hg, controlling humidity and temperature. multifaceted, and increasingly complex interwoven Some of these mice were sacrificed, then autopsied nature of the spectrum of oxygen toxicity is now only immediately while still in oxygen; others were au­ barely apprec iated. It seems obvious, and reasonable, topsied aft er 3 hours in oxygen. There was a signifi­ that the answers li e in the most bas ic bi ochemical cant difference in the appearance of the lungs at processes. The comments in this paper wi ll be ori­ postmortem. Air control groups were also used. The ented primarily toward the clinical aspects of oxygen lungs of the mice exposed to oxygen, killed in oxy­ tox icity as it relates to the practice of anesthesia. gen, and delayed 3 hours before postmortem were To continue historicall y, in 1927 the observa­ hemorrhagic and li ver-like in consistency and did ti on was made th at cold-blooded animals were much not flo at, thus simulating the characteristic, classical less susceptible to the toxic effects of oxygen unless changes of advanced oxygen toxici ty, usually thought they were warmed to 37.5 °C. At that temperature. to occur after more prolonged exposures. Pratt pre­ even turtles developed fulmin ating pulmonary man i­ sented the above info rmati on at the hyperbaric con­ fe stations after exposure. ference in New York in 1964. and it is particularly It is known that increased oxygen tension pro­ noteworthy that he made the following ve ry pertinent duces ch anges in the transmembrane potenti al of comment: "Since this occurs in hospitalized pati ents frog skin, as contrasted to frog sc iatic nerve, and receiving oxygen by standard methods such as oxy­ that th ese changes are irreversible ( Gottli eb and ge n tents and nasal catheters, it is apparent that the Cymerman, 1970). These in vestigators postulate pulmonary response can result from exposure to that the membrane changes are produced by ad­ atmospheres containing well below I 00% oxygen va nced oxidation of the SH groups; th at membrane and probably in the range of onl y 50% oxygen." lipids and lipid complexes may have been alt ered; Pratt went on to discuss the relevant points in mak­ and that ATP synthesis was in activated. In a monu­ ing th e morphological differentiation between capil­ mentall y informative experiment carried out by lary proliferati on and the opening of previously " un­ Chapin and Hohl , one lung of a dog was infl ated recognized" capill aries . (Author's note: " Unused" with l 00% oxygen for seven days. The other lung capillaries. High-oxyge n tensions seem to decrease was infl ated wit h air. Only the lung infl ated with the size and number of capillaries utilized, at least in oxygen showed th e characteri stic pulmonary changes myocardial perfusion and in th e bra in , as will be of oxygen toxicity which shall be described in more discussed later). Pratt felt that vasodilation leading detail below. to capill ary proliferati on was the probable chain Dr. Phillip C. Pratt, a path ologist, now at Duke of events; that continuous exposure for 24 hours at a DURFEY: OXYGEN TOXICITY AND ANESTHESIA 115 time was necessary; and that intermittent exposures some effect in preventing the occurence of lung were not cumulative in nature. edema. Mg" seems to have a protective effect against In 1964, Heppl eston and Simnett found that seizures resulting from high-oxygen pressures OHP tissue cultures of pulmonary alveolar epithelium were (Radomski and Wood, 1970) .