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) . M anga nese may act especially sensitive to oxygen under o ne atmosphere by inhibition of mitochondri al swelling and lipid per­ and equated this exposure to air at 5 atmospheres. ox id e fo rmation in th e mitochondria; that is, an anti­ They surmised oxygen acts through enzyme inhibi­ oxid ant effect. However, simil ar reactions may also ti on and preferentially affects enzy mes possessing SH occur producing an opposite effect ; that is, sensitiza­ groups (NS: the statement made previ ously regard­ ti on of cell s ( see below). ing the transmembrane potentials in frog sk in s ) . The cumulative end results as fa r as the lung Pontoppidan and others have demonstrated sim­ is concerned are: the changes in epitheli al cell popu­ ilar changes, including the postmortem appearance of lati on; the accumulation of both interstiti al and alveo­ hyaline membranes, in patients fo ll owing ve ntilati on lar flu id; and / or protein aceous materi al; the deposi­ with hi gh-oxygen concentrations. A great deal of tion of hyaline membrane materi al; and changes in emphasis in the last three or fo ur years has been "surfactant" and it s properti es. Diffusion is altered, placed on this possible causal factor of patient mor­ an "alveolar-capill ary block" situation develops, bidity and mortalit y. In 1970, this hypothesis was ac­ shuntin g occurs. and the pati ent then has a need for centuated by H amilton and Singer in a study of post­ hi gher-inspired oxygen tensions to achi eve any sati s­ operative cardiac surgery patients. It was their fac tory saturati on, while the "cure" is worsening the conclusion that fear of "toxici ty" should not preclude disease process! the administration of oxygen in those patients who The warning seems fa irl y obvious : A minimum needed it. A general opinion still seems to prevail at oxygen concentrati on ( in spired oxygen tension ) this time that cyanotic heart di sease. and other condi­ should be used to produce an arteri al tension of ap­ tions leading to ventil ation-perfu sion in equalities, p roxim ately 100 mm Hg and/ or a normal hemo­ shunting. venous admixtures. and subsequent low­ globin saturati on dependi ng upon the individual. oxygen tensions (and/ or hemoglobin saturati on). Individual va ri ati ons are ve ry important and have a protective effect for the patient. and that hi gh­ should be taken into consid eration. These factors inspired oxygen tensions can be used with consi der­ include: age, sex. temperature. acid-base balance. ably less concern. This conclusion is not necessaril y type and amount of hemoglobin . MHCH. diet, vita­ valid. as shown by a case report from the M assa­ min levels. and the administrati on of other drugs. chusetts General Hospit al (New England Journal. Aspirin and ascorbic ac id seem to augment toxicity May 1970), where it was disclosed that a patient (Serrill. et al. , 197 1). Tocopherol deficient animals died from pulmonary insufficiency with de monstrated appear less sensitive to lipid peroxidation in the fibrosis fo ll owin g prolonged artifici al ventilation. Fur­ lung until ascorbic acid and ferrous ions are added thermore, a very important study by Hills indicates (R askin, et al., 1971 ). Other factors such as that the creation of an a rtificial shunt producing smoking and resultant carbon monoxide levels cyanosis does not necessaril y protect an animal from ( Rodkey, et al., 197 1) affect the response of pulmonary injury secondary to high-oxygen tension. the lung. Simple immersion to the head greatly inten­ It appears that certain conditions can depri ve si fi es the pulmonary reaction, primarily by promoting the individual of protective mechanisms. Artificially the formation of atelectasis (Balldin, et al ., 1971 ). altered physiology can produce changes in th e reac­ Stress and it s effects, especiall y increased adrenal ti on of molecular oxygen with SH groups and other output, all adversely affect the individual, as does enzyme substrates. This effect in turn upsets electron in creased thyroxin. transfer balance and results in additional effects in Conversely. thyroid blockers seem to have a certain types of cell s and subsequently in certain protective effect , as does the administration of sulf­ organ systems or "target areas ." These effects occur hydryl group donors. Others compounds such as following the administration of such compounds as ANTU (alpha naphthylthiourea) may act by both dipyridylium di chloride (Clements, Fisher, and Ken­ actions; that is, by affectin g thyroid hormone release, neth, 1970); or result from the interaction of other and by providing cellular sulfhydryl enzy mes and compounds producing changes in certain trace metals cofactors in active red uced states ( Mountain , 1963) . and in organic phosphorous. Mn" and Zn" may have If one can logically accept the argument that there 116 DURFEY : OXYGEN TOXICITY AND ANESTHESIA are individuals who are hypersusceptible to certain some compounds which are considered to be toxic noxic or toxic stimuli or compounds, such as those themselves, such as Ozone and N02 (Mountain, individuals whose susceptible target areas are the 1963). Ozone is quite toxic and produces striking red blood cells, which subsequently undergo hemol­ epitheli al changes including hyperchromatism, hyper­ ysis by the interaction with other drugs, then it is just plasia, and inflammatory changes. Central nervous as likely th at certain individuals are "pneumonicall y system effects also result. Some changes may occur sensitive." These individuals may react adversely to after only a few hours of exposure (Suskind, et al. , similar circumstances with th e lung as the "targe t 1970). organ." A number of interes ting concepts have devel­ Opposite circumstances may apply. Certain in­ oped in regard to the pulmonary changes and the dividuals are hyposensi tive. They may react with manifestati ons related to oxygen toxicity. A gre at increased resistance, or decreased susceptibility, to deal of weight has been given to changes in "surfac­ the action of what are usually considered to be tant." Earlier, in 1962, the emphasis was on surfac­ "toxic" concentrations of oxygen. This concept would tant changes, modification, depletion, and interfer­ certainly account for variations from the "usual re­ ence with it s formation. However, with increasing sponse," such as the one reported by Kydd : Mice knowledge in the field , and increasing reli ability of exposed to 550 mm Hg oxygen for 30 days showed investi gative techniques, it is beginning to appear that only a few of the classical pulmonary changes, but surfactant (changes) may ve ry well be another did develop changes in the blood vessels. "target," or, if not a "target," a "system," directly Some individuals are susceptible to the occur­ and indirec tl y involved; resulting from more basic rence of atel ectasis presumabl y due to absorption of biochemical alterations such as those mentioned gas (oxygen) , plus other fac tors yet to be deter­ above. mined (Burger, 1967) . "Nitroge n osmosis" is a term referring to an A good deal of work has been devoted to the effect produced by the "in ert gas" nitrogen, wherein effect of oxygen on succinic dehydrogenase activity it can pull water away from other solutions of in ert in the lung. Until recently it was thought that this gases through certain types of membranes. This is was the most important enzy me system affected. now a popular concept in hyperbaric gas physiology. Howeve r, Bardell and Fowler concluded that other Such biophysical alteration may very well have some dehydrogenases in lung ti ssue seem to be more ad­ bearing on the mechanism of oxygen toxicity, and versely affected. At any rate, return of activity is the narcotic action of certain " inert anesthetic gases" slow compared to exposure tim es; that is, 6 hours ( neon, argon, etc.). During increased-inspired ox­ of exposure to oxygen produced inhibition of the ygen tension ( thus increased arterial oxygen tensions enzy mes which returned to normal only aft er 12 to [pO, J) a gradient develops between the arterial 48 hours. Interestingly enough in one study pento­ tension of p02 and ti ssues. This has been call ed barbital seemed to have a protective effect. This a "steady-state gradient. '' If certain physical cir­ conclusion is in contradistinction to the usual non­ cumstances are prevailing, the movement of water protective effects of anesthetics agai nst damage to molecules may occur ( Hills, 1971). Niinikoski and the CNS (see below): Residual effect s may occur coworkers are under the impression that the pri­ even though convulsions are masked. mary effect of oxygen is on the capillary endothelium, Viral and bacteri al di seases may grossly alter producing an increased capillary permeability and the individual's sensitivity to toxic agents such as a secondary "washout" causing a depletion of sur­ oxygen, and may produce changes in "target areas ." factant and other phospholipids not heretofore con­ (Mountain, 1963 ). Smoking has a marked additive sid ered to be part of normal "surfactants." The effect for atelectasis to occur following oxygen mere presence or increase of lipids in such a "wash­ exposure. One study indicates that smokers had out" does not therefore connote adequate surfactant an in-Hi ght vital capacity loss three times that of activity. It may indicate only a "washout," and a de­ nonsmokers ( Browning, 1970). Adrenalectomy, pleti on of alveolar surface tension reducing materials. chlorpromazine, and sympathetic-blocking agents Furthermore, one need not find peroxides of lipids, may have a protective effect, as does hypothermia yet detrimental effects of hi gh oxygen may have (Burrows and Edwards, 1970). altered the structural lipids of cells by peroxidation There seems to be a cross-tolerance between and ox id ation and produced subsequent changes in DURFEY: OXYGEN TOXICITY AND ANESTHESIA 117 cellular membranes. These in turn may lead to the pears to be excell ent correlation between problems in release of proteolytic enzymes and even co nnecti ve diffusing capaci ty and pulmonary membrane damage tissue elements may be released into the alveoli. (etc.). Do the increases in areas of poor V/ 0. which So fin ally having reached a discussion of "surfac­ account for much of th e loss or decrease in diffusing tant" after all of the above, it is with th e reali zati on capacity result from changes in surfactant alone with that every aspect of "oxygen toxicity" is tied up with increased surface tension, or does there occur an in­ the mechanisms and biochemical utilization of the crease in pulmonary vascular resistance secondary transport of oxygen. to the capillary proliferation and "granulation tissue" Let us quickly consider the va rio us aspects of forma ti on noted by Pratt as one of the toxic effects alveolar-capillary diffusion pertinent to this discus­ of oxygen ( not the cl assical effects of hypoxia)? sion ( Rankin, 1969). Diffusion can be defined as Capillary congestion, an earlier manifestation, may the movement of molecules of gas from an area of mask problems of diffusion since it will tend to bal­ high concentration to an area of lower concentration. ance them out. As mentioned above, there is direct bearing in rel a­ What then is "surfac tant," and how does it apply tionship to arterial gas tensions. The movements of to the concept of oxygen toxicity as we know it in gases across the alveolar-capillary membrane is de­ the lung? Many workers have been involved in the termined by : ( I ) the mean difference in partial pres­ fi eld for a number of years: these include Pattie, sures of gas on either side of the membrane; (2) the Clements and Fisher, Morgan, Sutnick, Said, Scar­ surface area of the membrane; and ( 3) the permea­ pelli , Tooley, and others mentioned above. A brief bility of the gas through the membrane. The third is summary of their observati ons and conclusions as it inversely related to the thickness of the membrane. applies to the topic under discussion is now in order. It should be noted at the outset that the total distance Surfactant. It would be more appropriate to use for perfusion through the normal alveolar-capillary the terminology "surfactant systems," "surfactants," membrane and the surface lining layer, etc ., is of very or "alveolar lining materi als." Unfortunately, until small magnitude in the normal lung; that is, in the recently at least, the approach has been mostly an order much less than one micron. The pulmonary anatomical one, utilizing electron microscopy. The diffusi ng capacity of any gas is determined by electron microscope has enabled in vestigators to find the ratio of the quantity of gas transferred per unit vari ous structures not heretofore known and has led time over the mean differences in partial pressure. to certain hypotheses about the ori gin, function, and and is directly proportional to the solubility of the eliminati on of th ese lining materials. At the outset, gas and inversely proportional to the square root of it is very important to reali ze th at the lung is not a the molecular weight (density) of the gas. It is not passive organ responding to filling and emptying, but easy to calculate either the alveolar oxygen tension is a very active one in the body. With a surface area or the pulmonary capillary tensions. Oxygen tension of approximately 70 meters square, and an esti­ differences between the alveolar gas and arteri al, end­ mated 300,000,000 alveoli , this fact is quite signifi­ capillary blood are due to incomplete equilibration cant ( Scarpelli, 1970). between the gas and arterial, end-capill aries, and In 1929, Yon Neergaard noticed the differences due to the effect of venous admixtures from areas of between fluid-filled and air-filled lungs in the forces poor ventilation to perfusion ratios. It should be re­ needed to ventilate, and pressure-volume relation­ membered that pulmonary diffusing capacity must ships. Pattie, in 1955, noted the characteristics of be reduced by ¥3 before normal arterial oxygen pulmonary edema foam were such as to indicate saturation will be affected. This fact should be kept lowered surface tension. This was followed by the in mind in considering the so called "latent periods" work of Clements and others which showed that a involved in oxygen toxicity in regard to the lung surface-tension-lowering substance was present in as well as other organs. Diffusi ng capacity varies lung tissue. Since then, biochemical analysis has in­ with whole body size, metabolic rate, age, levels of dicated that the material is made up of a complex lung inflation, alveolar ventilation, intrathoracic pres­ mixture of lipids, protein, and carbohydrates, chief sure, body position, and distribution of inspired gas. among which is dipalmitoyl phosphatidyl choline The H amman-Rich syndrome is a classical example (DPL) (palmitic acid) . DPL makes up about 50% of the unfortunate patient who requires increasing of the lipid fraction of the layer. This named lipid amounts of oxygen to his own detriment. There ap- has been used interchangeably with "lecithin." It is 118 DURFE Y: OXYGEN TOXICITY AND ANESTHESIA

import ant to note that the surface-tension-lowering T o summari ze briefl y: The activity and struc­ properties depend upon the presence of two .rn1u­ ture of surfactants is affected by a number of factors, ra1 ed fatty acid residues. Included in the complex are including : (I) heat, which will reversibly inactivate albumin and carbohydrates (polysaccharides). In the it; (2) changes in pH; (3) the presence of blood; lung. or alveoli as the case may be. a surface inte r­ ( 4 ) electrolyte concentrati ons. face exists between air and a li quid or hypophase. It is ge nerall y thought th at surfactants are pro­ lining the alveoli . The surface tension along the duced by " type II " alveolar cell s and are secreted alveolar lining results primaril y from molecul ar into the alveoli where they become incorporated into cohesive forces whi ch produce a tendency toward the lining layer. These are presumed by some to be collapse. This force is related to La Pl ace's theorem found as cytoplasmic inclusion bodies, or osmiophilic which in turn relates surface tension (T) in versely lamell ar inclusions. The inclusions are found in much to the radii of spheres and proportionately to lower numbers in those species (non-mammali an ) the pressure of gas within the spheres or, as in lacking or having decreased surfa ctant levels. T wo this case. the alveoli . ( P = 2T / R ). The result is main theori es exist: (I ) th at the giant alveolar cell s a tendency fo r liquid to form increasingly small er form and secrete these organell es or inclusion bodies ; spheres, leading to an ever-increasin g tendency for or ( 2) th at the opposite is true, the giant cells are coll apse. This fo rce is counteracted by the effects of responsible for the phagocytosis and breakdown of the "surfac tant groups." so that a new end-surface­ th e surfactants, production bei ng elsewh ere-the /e nsion, in ac tu alit y a surface pressure. results. This nonciliated bronchiolar cell for example. surface pressure force opposes the fo rces of plasma Nonetheless. synthesis turnover is rapid, C 14 and other ti ssue fluids which have a surface tension of labeled phosph olipids appear in pulmonary phos­ about 50 dynes per cm. Consid erable elasti c recoil pholipids within 5 minutes aft er intravenous injec­ results for the lungs. Fortunately, the tendency of th e tion, and a half-life of 14 hours is estimated fo r the larger alveoli to become larger and larger as the surface acti ve lecithins. It is possible that the entire small er alveoli empty into them (foll owing the above lipid synthesis of lecithin occurs within the lung itself. physical laws) is offset. Theoreti call y, at least, there The mechani sms of lecithin synthesis can take sev­ is some unifo rmity to alveolar confi guration and size, eral paths, as has been nicely described by Morgan. although there is now some doubt as to whether or Of import, in regard to the possibl e effect of oxygen not alveoli ac tu all y exist as true spheres. Max imum on the system, is the rapidity of metabolism. equating intra-alveolar pressures probably ex ist at the precise the lung to the li ve r in some respects. This could moment when th e developing hemi sphere at the end produce a result so th at any occurrence. phys ical or of the respiratory bronchiole has a diameter equal to chemical. interfering with metaboli c generation of that of the terminal respiratory bronchiole. Follow­ either the lipids and / or carbohydrate and protein ing this point, some in stability and dec rease in pres­ moieti es mi ght throw a natural " monkey wrench" sure occurs, with limits of expansion set by the elasti c into the system, thus accounting for the so-called ti ssue of the lung. and so fo rth. " /a1 en1 period" said to ex ist in the development of Surfac tant s are considered to be bipolar in na­ oxygen toxicity. The term " latent peri od" has very ture and to assume th is confi gurati on anatomi call y in little compatibility with basic tox icologic al hypoth­ the hypoph ase boundary area. The choline, or h vdro­ eses. The presence of packets of surfactant mi ght phi/ic, group is ass umed to associate with the p~otein slow down the depletion rates and subsequent altera­ area of the hypophase: and the two hydrophobi c ti ons in activity until such lack of activity produced fa tty acid sid e chain s become ori ented toward the a fairly rapid onset of symptoms and signs. There alveolar air side. fo rming a compressible film or is no doubt th at the situation is complex. Even the surface-tension-lowering film . Increased compres­ simple concept of a single laye r of surfactant is sion, such as would res ult fr om coll apse of alveoli , under scrutiny and revision at this time. actuall y produces a decrease in surface tension. The Thus indirectly, oxygen may affect organ sys­ result is an equi li bration of tensions between th e tems such as the lung through direct acti on at large r and small er alveoli . The choline group, stated a very basic metabolic level. Surfactant changes to be associated with protein , contains an ioni zed are related to other clinical conditions such as the quarternary ammonium group which is stabilized by Respiratory Distress Syndrome of the newborn, the presence of both calcium and sodium ions. changes fo ll owing pulmonary arterial occlusion with DURFEY : OXYGEN TOXICITY AND ANESTHESIA 119 decrease in surfactant activity; and an ex cess of sur­ dividuals. Furthermore, consid ering the basic nature fac tant has been postulated in the di sease of pul­ of the processes of oxyge n toxicity, one must have monary alveolar protein osis. One must bear in mind some reservations about the poss ible adverse effects th at multi-causal factors operate in th ese di seases, of oxyge n on the CNS at 760 mm or less, other than and th at the inappropriate adminis tration of " hi gher the well-known vasoconstrictive effects upon cerebral th an needed" concentrations of oxygen ( a somewh at vasculature, and the tendency fo r hyperventilation ambiguous phrase ) may contribute to the problems which is commonly seen. developing in vari ous organs through the mechani sms Classicall y, the CNS ex pression appears as a discussed above. convulsion, usually beginning with more foc al signs Toxic Effects on Other Systems. Although the such as twitching about the mouth and eyes, and primary toxic effects of oxygen at less than one at­ perhaps the small muscles of the hand. It is im­ mosphere (760 mm H g) seem to be primarily mani­ portant to remember that mentati on may be quite fested by changes in the lungs, or at least appear clear until th e abrupt onset of the convulsion, which to be so orientated from the standpoint of an­ proceeds through usual tonic-cloni c stages. Attempts esthesiology, it is rather illogical to assume th at all at decompression during periods of glottic spasm systems and organs in the body are not involved. may result in rupture of the lungs . Unlike the usual The appearance of signs and symptoms is related seizure, blood arteri al oxyge n tends to remain at to a time-dose factor, that is, related to exposure normal or higher than usual levels if the patient is and/ or circulation. under OHP ( oxyge n-high pressure ) . Central nervous Two fundamental fa ctors pertain regarding system toxic reactions are intimately involved with oxyge n toxicity: (I) The metabolic consequences pC02 levels and acid-base balance, including lac­ occur at the most basic levels of cellular and mito­ tate/ pyruvate levels and ratios. Factors other than chondrial or membrane ac ti vit y, and, consequently, metaboli c ones also pert ain, such as circadian must involve all areas of physiology and bi ochemi stry rhythms, which may alter the susceptibility to con­ within the body. (2) The "latency" of reaction vul sions ( Hof, et al., 197 1) . At three atmospheres should more appropriately be call ed the " time" of (OHP) , animals treated with acetylsalicylic acid reaction. These considerations are certainly more in and/ or ascorbic acid, and tocopherol defici ent an­ keeping with the basic toxicological principles of imals, began seizures earli er and di ed sooner than time-dose response. The intensity, durati on, suscepti­ oth ers (Serrill, et al., 197 1) . The protective effect bility of the subject, type of exposure, temperature, of magnesium has already been mentioned. th yroid activity, presence or absence of other drugs, Anesthetic agents may mask the convulsions of elements, and trace metals, the condition of the oxygen toxicity, but do not appear to prevent the acid-base status, carbon dioxid e elimination, 2-3 C NS damage produced by it which commonly re­ DPG levels, hemoglobin levels and types. sex, in­ sults in spastic paralysis, and so forth. In fact, a teraction and state of the adrenal-pituitary system recent and disturbing study by Lassiter has indi­ and the sympathetic nervous system, perfusion, and cated that in the presence of only 5 psi, exposure other factors all determine which organ system will to oxygen for two weeks (233 mm H g) greatly re­ be affected and at what time. duced levels of acetylated and unacetylated co­ Central Nervous System Toxicity. The toxic enzyme A in the brains of the animals. This occurred effect of oxyge n at higher than ambient ( 760mm) in the absence of overt signs of CNS toxicity. Ap­ pressures on the CNS ordinaril y does not concern parentl y, nitroge n seems to have a " masking" or anesthesiologists unless they are operating under "quenching" effect, casting further doubt about its specific conditions of OHP in speci al chambers. pres umed " inertness." Coenzyme inactivati on is post­ However, the entrance of industry, agriculture, and ul ated to result fr om : (a) direct oxidati on of th e other interests into underwater living and working sulhydryl groups; (b) from a block in sy nthesis, conditions will produce a much larger populati on produced by oxygen itself through fo rmation of of individuals exposed to dysbarism and oxygen oxygen-metal ion complexes; and ( c) by the form a­ toxicity. It is logic al to assume that medical per­ ti on of free radicals elsewhere. These changes sonnel speci ally trained in cardio-pulmonary re­ produce interference with th e transfer of two-carbon suscitati on, and so forth , will be call ed upon to units, with a subsequent bl ock of glycolysis, and mal­ assist in the di agnosis and therapy of such in- functioning of the tricarboxylic acid cycle. 120 DURFEY : OXYGEN TOXICITY AND ANESTHESIA

A recent paper by Kuperman has shown that and changes which occur under one set of circum­ the administration of oxygen fo ll owin g bilateral stances may va ry considerably under a slightly dif­ cordotomy may produce sleep-ind uced apnea, or ferent set of parameters, adding to the complexity " Ondine's curse," possibly through effects on the of response and interaction. aortic-carotid reflex mechani sms. It can be seen fro m Toxic Effects of Oxygen on Liver and Kidney. th e above that the effect of oxygen o n the CNS is With the current interest in " halothane hepatiti s," quite complex and onl y now becoming mo re fully and the renal effects of Penthrane :!D, more emphasis appreciated. sho uld be given to the possibl e toxic effects of other Effect of Oxygen on Red Blood Cells. As pre­ drugs and agents, and th eir possible interaction. The viously mentioned, o ne of the keys to understanding multiplicity of facto rs operating have been discussed oxygen toxicity is a clear comprehensio n of the very above. In 1965, Feli g reviewed the literature avail­ complex and. up to now, not entirely clear mech­ abl e on oxygen toxicity at that time and, supported a ni sms of oxygen transport and it s relat ionship to by experiments in Wright Patterson Aeromedical membrane function. Research L aboratories, came to the co nclusio n that If one acknowledges the fact that hypoxia per evidence indicated the fo ll owin g : Exposures to only se is a mark ed st imulant to erythropoeisis. o ne would 258 mm H g of oxygen fo r one week produced sub­ assume depression of bone marrow function upo n cellular hepatic and renal alteratio ns, visible on exposure to hi gh concentrations of oxygen. This is electron mi croscopy, in the absence of pulmonary not necessarily the case, and the effect of hi gh­ hi stopathology. These changes included mitochon­ oxygen tensions o n DPG levels is not entirely clear. drial enl argement, clumping, and degeneratio n of

There are combined effects of increased pC02 membranes. Sodium lactate seemed to have a pro­ levels, difficulties in " unsaturating" oxyhemoglobin, tective effect; lactate metabolism occurs through and resultant decreased pH levels (Astrup. 1970). oxidation and th e transfer of electrons to DPN. Further influences of the pituitary and th yroid must Oxygen at tensions higher than one atmosphere be considered (Rodriquez and Sh ahidi . 1971) . increases lipid biosynthesis (Adams and Norton, Ascorbic acid and ASA may se nsitize the red 1971). On the other hand, oxygen may indirectl y blood cells to lysis (Serrill, et al. , 197 1) . Vitamin E affect protein synthesis by altering dietary habits defi cient animals are markedly sensitive to the rapid ( L eon. et al. , 197 1). This could be considered a destruction of rbcs, wh ich in part is caused by the subtle form of oxygen toxicity. actual peroxidation of lipids in the rbc membrane. Insofar as the kidney is concerned. important There appears to be a selective effect o n older rbcs findings relevant to kidney structure and function (Sabine and Leon. 1971) . In certain susceptible were reported by Hess and Menzel in 1971 . In animals, such lytic activity may occur at less than animals subjected to di etary de pl eti on. particularl y one atmosphere, manifesting itself by immediate Vitamin A , a 35-day exposure to I 00% oxygen effects o n old cell s. and delayed effects on the produced changes in the proximal convoluted tu­ younge r cells which demonstrate decreased mean bules, leading to an increase in lipid levels. These potential life spans. A diet of alpha tocopherol, an changes were presumed secondary to decreased antagonist to lipid peroxid ati on will aboli sh o r pre­ fatty acid metaboli sm. vent thi s lyti c activity. Several areas are involved, Conclusion. The adverse effect of overexposure including anerobic glycol ysis, hexokinase acti vit y, to oxygen, that is, "oxygen toxicity," involves vir­ glucose 6-phosphate dehydrogenase activity, acetyl­ tually every organ system in th e body, including the cholinesterasc acti vi ty, and specific gravit y. It ap­ lung. eye, kidney, liver. and erythropoetic systems. pears to be a membrane phenomeno n. T o confuse The effect follows classic toxicologic al principles, for the issue even more, one study of angin a pcctoris the most part relating to time and dose of ex posure, and oxygen transpo rt has indicated that it s occur­ which in turn alt ered by the relati ve proximity of rence may actually decrease oxygen aflinity of the any particular organ to hi gh-oxygen tensio ns. Ob­ hemoglobin without changes in DPG levels, possibl y viously, the lung has the greatest exposure directly. secondary to " humeral factors" (Shappell, et al., The effect o n other organ systems is primarily deter­ 1970) . One thing is certain , the vario us metabolic mined by the circulation and oxygen carrying and activities invo lved in oxygen tra nsport and mem­ transport systems ( Skinner. 1972; Siekevitz. 1970). brane function are no t always predictable nor finite, Most of the emphasis in this paper has been DURFEY: OXYGEN TOXICITY AND ANESTHESIA 121

upon the basic effects of high-oxygen tensions on CLEMENTS, J. A. Smoking and pulmonary surfactant. New enzymatic membrane and substrate systems. since Eni. !. Med. 286:261, 1972. it appears that altered biochemistry at these levels determines the ultimate manifestations of the toxic CLEMENTS. J. A. AND F1sHER, H. K. The oxygen dilemma. New Eng. J. Med. 282:976, 1970. response. be it pulmonary, hepatic. ophthalmologic. and so forth. CYMERMAN, A. AND GOTTLIEB, S. F. Effects of increased More definitive criteria for controlling inspired oxygen tensions on bioelectric properties of frog sciatic and transported oxygen are needed. Even the pres­ nerve. Aero.,pacc Med. 36. 1970. ence of cyanotic heart disease with shunting and desaturation, or primary pulmonary failure per se, FELIG. P. Oxygen toxicity: ultrastructural and metabolic do not necessarily protect the individual against th e aspects. Aerospace Med. 658, 1965. deleterious effects of over-oxygenation. Thus a paradoxical situation develops wherein the admin­ GOTTLIEB, S. AND CYMERMAN, A. Effects of increased oxy­ gen tensions on sod ium active transport through frog sk in, istration of oxygen as a lifesaving measure eventually Aerospace Med. 661, 1970. may produce fatal consequences. Anesthesia personnel will become increasingly H ESS, R. T. AND MENZ EL, D. B. Effect of dietary antioxidant involved in situations related to such exposures to level and oxygen exposure on the fine structure of the proxi­ oxygen at high pressure (OHP) such as will be mal convoluted tubules. Aerospace Med. 646, 1971. found in the new fields of industry and agriculture now being developed underwater, sometimes at great HILLS, B. A. Osmosis induced by nitrogen. Aerospace Med. depths. It is the responsibility of the specialty to 664, 1971. continue basic and clinical research in these areas and to expand clinical teaching to encompass the HOF, D. G .. DEXTER, J. D .. AND MENGEL , C. E. Effect of circadian rhythm on CNS oxygen toxicit y. A erospace Med. management of related problems. 1293 , 1971.

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