POSTGRAD. MED. J. (1966), 42, 449

HYPERBARIC OXYGENJ. NELSON NORMAN, M.D., Ph.D. GEORGE SMITH, M.B.E., D.Sc., M.D., Ch.M.

Lecturer in Surgical Science Regius Professor of Surgery

Department of Surgery, University of Aberdeen

THE BIOLOGICAL effects of oxygen at increasedatmospheric pressure have been studied sinceboth oxygen and atmospheric pressure werediscovered. Apart from the specialised interestsof compressed air workers and divers, however,careful scientific appraisal of the therapeuticpotentialities of hyperbaric oxygen was not be-gun until the second half of this century. In1955 Churchill-Davidson used hyperbaricoxygen in the oxygenation of the anoxic centreof tumours as an aid to radiotherapy, whileSmith in Scotland and Boerema in Amsterdaminvestigated the possibilities of using oxygen atincreased atmospheric pressure to prolong theperiod during which the circulation may betotally arrested with safety as an aid to cardiacand neuro-surgery. At this time also the Dutchworkers devoted much of their time to anevaluation of the use of oxygen at 3 atmospherespressure in the treatment of anaerobic infectionswhile the Scottish School investigated the use ofoxygen at two atmospheres pressure in resuscita-tion from coal-gas poisoning.

In carbon monoxide poisoning the tissuesare hypoxic since the haemoglobin is no longeravailable for oxygen transport. The advantageof using hyperbaric oxygen in this cond,ition isthat as soon as the patient breathes oxygen attwice atmospheric pressure sufficient oxygen isdissolved in the plasma to oxygenate the tissues,thus by-passing the blocked haemoglobinmechanism. Although the immediate protectionof the tissues from further hypoxic damage isthe most important action of hyperbaric oxygenin carbon monoxide poisoning we have alsoshown that the high arterial Po2 ensures arapid dissociation of carboxyhaemoglobin suchthat when oxygen at two atmospheres oressureis breathed the blood is half cleared of carbonmonoxide twice as quickly as when 7%° carbondioxide in oxygen is breathed (Douglas, Law-son, Ledingham, Norman, Sharp, and Smith,1962). The use of oxygen at twice atmosphericpressure in carbon monoxide noisoning hasproved very satisfactory in clinical practiceand a larpe series of natients have now beentreated with success (Smith and Sharp, 1960;

FIG. 1.- External view of pressure chamber atAberdeen.

..)- ·-- :l| ..._

/;||E g 1 !R ; ,m,3; !5 16,~~~~~

FIG. 2.- Interior of pressure chamber at Aberdeen.

Smith, Ledingham, Norman, Sharp and Bates,1962; Douglas, Lawson, Ledingham, Norman,Sharp and Smith, 1964).Most of these Ipatients have been treated in

large hyperbaric installations such as exiist inAlberdeen and Glasgow. Figs. 1 and 2 showthe hyperbaric chamber at Aberdeen. It con-sists of a cylindrical vessel some 21 feet longand 8½ feet in diameter, divided into a mainchamber, 14 feet long, and an air-lock, 7 feetlong. It is fully air-conditioned and has 8power points. It is compressed with air, by twincompressors, at a maximum rate of 1 atmos-phere in 31 minutes. When the chamber is

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FIG. 3- Mobile pressure chamber.

compressed, the patient breathes oxygen fromany of the 6 oxygen inlet points. Frequent airchanging prevents the accumulation of CO, or

oxygen thus safeguarding the health of the staffand obviating the risk of fire. The air-lockis used for changing staff or equipment withoutdecompressing the main chamber and there isa side-hatch in the 'main chamber which allowsaccess for urgently required equipment in amatter of seconds.

While this type of unit is excellent for patientcare and for research purposes it is very costlyand is not available to the majority of victimsof carbon monoxide poisoning. For this reasonit was suggested (Smith, 1962) that small mobilepressure chambers should be built, capalble ofbeing transported in an amibulance and pres-surised from an oxygen cylinder. Thesechambers should be sufficiently inexpensive toallow their installation in small hospitals andat sites where carbon-monoxide poisoning islikely to occur, such as at mines. To date,the chambers produced have been clumsy andexpensive, but we are developing a model inconjunction with Normatair Ltd. (Smith andNorman, 1966) which is light, versatile and in-expensive. This chamber, Fig. 3, could beused for a variety of purposes, such as thetransport of patients suffering from carbonmonoxide poisoning or traumatic shock tohospital, or for routine use in hospital in thetreatmenit of patients suffering from such con-ditions as peripheral vascular disease, myocar-dial infarction or severe burns. It can also beused for radiotherapy.Open Heart SurgeryThe considerable advances made in the past

10 years in cardiopulmonary by-pass techniqueshave made the use of hyperbaric oxygen in adultopen heart surgery less attractive but it still

'has a useful part to play in neonatal patientssuffering from severe intra-cardiac lesions, whorequire some form of surgery urgently for sur-vival. Hyperbaric oxygen has indeed been usedwith considerable success in such patients byGross and Bernhard (Bernhard and Tank, 1963;Bernhard, 1966) in Boston. Our first work inthis field was in normothermic dogs, where itwas shown that if the animal was given oxygento breathe at atmospheric pressure then it waspossible to arrest the circulation completely for5 minutes with safety, but if the dog was givenoxygen at 2 atmospheres pressure to breathe,then it was possible to arrest the circulation for8 minutes with safety. While an increase of 3minutes may be of little value, clinically itrepresents a considerable percentage increase inthe permissible time of total circulatory arrestand hardly seems consistent with the extraquantity of oxygen stored, before the establish-ment of circulatory arrest, when oxygen wasbreathed at two atmospheres pressure insteadof one. Parallel studies of tissue homogenatesexamined in vitro, however, showed that asthe tension of oxygen to which the tissue wasexposed rose, the consumiption of oxygen fell.Thus the consumption of oxygen 'by these tissuehomogenates was reduced by some 30% whenthe tissue was exposed to oxygen at 2 atmos-pheres pressure comoared to air at atmosphericpressure (Norman, Douglas and Smith, 1966).This helped to explain the in vivo experimentsin dogs: more oxygen was supplied and less wasrequired. It also seemed reasonable to expectthat if hypothermia was now added to thesvstem, 1thait considerable periods of "safe"circulatory arrest might be obtained since moreoxygen would be supplied and two factorstendina to reduce tissue oxygen requirementswould be at play.A further two series of circulatory arrest ex-

periments were then carried out at hypothermia,one at 280C and one at 200C (Smith, Leding-ham, Norman, Douglas, Bates and Lee, 1963;Ledingham and Norman, 1965). In this case itwas shown that at 280C the circulation couldbe arrested with safety for 20 minutes if theanimal breathed oxygen at atmospheric pres-sure and for 30 minutes if the animal breathedoxygen at twice atmospheric pressure. At 200Cit was found that the circulation could be totallyarrested for only 40 minutes whether the animalbreathed oxygen at one or two atmospherespressure. The explanation for the apparentlyparadoxical results was found by further invitro studies of tissue homogenates. It wasobserved that. at 280C, as the oxygen tension

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to which the tissue was exposed rose, thethe oxygen consumption also rose until theexposure Po2 reached aibout 500 mm. Hg.Thereafter the oxygen consumption fell. Theoverall reduction in oxygen consumption whenthe tissue was exposed to 2 atmospheres ofoxygen at this temperature, was, however, only10% compared to exposure of the tissue to air.Again at 150C, as the oxygen tension to whichthe tissue was exposed rose, the oxygen con-sumption also rose until the Po2 reached about1000 mm. Hg.. after which the oxygen con-sumption fell. There was, however, no differ-ence in oxvgen consumption of the tissueexposed at this temperature, to air at atmos-pheric pressure or to oxygen at 2 atmospherespressure.These in vitro results can be interpreted as

suggesting that hypothermic tissues may requireless oxygen than normothermic tissues partlvbecause their requirements are less and partlvbecause they are unable to utilise it unless itis sunplied at a sufficiently high pressure. Theseresults suggest that the ontimum tissue Po.,for tissue maintained at 280C is about 500 mm.Hp-,. and about 1000 mm. THg. for tissues main-tained at 150C. The better metabolic conditionof hypothermic tissues exposed to an adequateoxygen tension is reflected in the biochemicalnarameters measured in the dogs subiected to40 minutes circulatory arrest while breathinvoxy,gen at 1 or 2 atmospheres pressure (Table 1).

Local Ischaemia

One of the main clinical anplications ofhvnerbaric oxvgen is the treatment of localischaemia as it occurs in such sites as theheart, limbs or the bowel. We have treated alarge series of cases suffering from perioheralvascular disease from various causes, and thesecases have been divided into those sufferingfrom some form of degenerative disease suchas atherosclerosis, diabetic arteritis or throm)bo-angiitis obliterans and those suffering fromarterial insufficiency following trauma, due toaccidents or from cold. The assessment of themaiority of the cases has denended largelv unonclinical evaluation and serial photography butthe recent improvements in pollarographic andother micro-analytical techniques have enableda more cr,itical judgement to be made of theeffect of hyperbaric oxygen on the patients.Our general impression has been that hyper-baric oxygen is only of limited value in the

TABLE 1

% INCREASE DURING CIRCULATORY ARREST

PotassiumPhosphateLactateExcess Lactate

1 At. 0258494022

2 At. 023622239

Biochemical measurements made after total circula-tory arrest for 40 min. in dogs cooled to 20(C. Onegroup (breathed oxygen at atmospheric pressure andthe other oxygen at twice atmospheric pressure.

treatment of vascular insufficiency resultingfrom atherosclerosis although it has occasionallybeen possible to heal an ischaemic ulcer andthereby to delay amputation or to carry outmore distal amputation than at first appearedpossible. The exception to this general rule isangii'tis obliterans: six cases have been treatedintermittently with hyperbaric oxygen and infive the ischaemic lesion has healed and amputa-tion averted. Astrup (1964) suggested thatpatients suffering from thrombo-angiitis obliter-ans may have a defect in oxygen carriageresulting in the oxygen dissociation curve beingshifted to the left and thereby rendering theoxygen carried by the haemoglobin less readilyavailable to the tissues. Although this is atemipting hypothesis which would readily ex-plain the successful use of hyperbar,ic oxygenin these cases, we have not been able to confirmAstrup's findings.

Greaiter success has artended the treatmentof vascular insufficiency following trauma,however (Smith, Stevens, Griffiths and Leding-ham, 1961; Donald and Tankel, 1962; Smith,1964). These patients have all been treatedcontinuously with oxygen at 2 atmospherespressure for 2 to 3 days, in the hope that if atrickle of blood is entering a limlb it may bepossible to dissolve sufficient oxygen in it tomaintain the vitality of the limlb until a suffi-cient collateral circulation becomes establisghed.The effect of hyperbaric oxygen on one of thecases may be seen 'in Table 2. This patient hada compound fracture of the ankle, treated byinternal fixation, and the foot subsequentlybecame grossly ischaemic. The greatly improvedmetabolic state of the ischaemic foot followingthe institution of hyperbaric oxygen therapycan be seen from the measurements made onthe venous effluent of the ischaemic foot com-pared to that of the undamaged foot (Table 2).

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452 POSTGRADUATE MEDICAL JOURNAL July, 1966

TABLE 2TRAUMAIIC ISQHAEMIA

1. Before PressurisationPo2 O2Sat. pH p(Oz St. Bic. Base Excess

(a) Inljured leg 43 31.5 7.02 160 14.8 -14.5(b) Normal leg - 57.0 7.27 50 20.5 -A.2

2. Following Pressurisation(a) Injured leg 70 89 7.27 65 22.8 -1.3(b) Normal leg 82 92 7.34 51 23.2 -0.8

(Biochemical measurements made from the venous effluent of both 'feet when the -patient Ibreathed air atatmospheric pressure and then oxygen at two atmospheres pressure. The injured leg was the site of severetraumatic ischaemia.

Myocardial InfarctionSmith and Lawson (1958, 1962) showed a

striking improvement in the survival of dogswhose circumflex coronary artery had beenligated provided the animals breathed oxygenat two atmospheres pressure instead of air.These results have subsequently been confirmed(Chardack, Gage, Federico, Cusick, Matsumotoand Lanphier, 1964) and Trapp and Creighton(1964) have shown that following ligation ofthe left anterior descending coronary arteryin the dog, the mass of the resulting infarctis smaller if the animal breathes hyperbaricoxygen instead of air. Meijne (1965) has alsoshown an increase in the coronary artery back-flow in animals breathing oxygen at 3 atmos-

pheres pressure. Encouraging reports have beenpublished on the use of hyperbaric oxygen inhuman myocardial infarction, but the resultsof a controlled clinical trial are not yet avail-able. It seems reasonable to expect that thepatients who may benefit most from this formof therapy are those whose condition is com-plicated by the development of a marked degreeof cardiogenic shock. The course of such apatient treated by us may (be seen in Figure 4.This patient was given oxygen at two atmos-pheres pressure to breathe for 36 hours.

Oxygen PoisoningThe use of hyperbaric oxygen is considerably

limited by the occurrence of oxygen poisoning

pH 7.295 pH 7 368 pH 7 410pCO2 330 pCO2 31 pCO2 31Std. Bicarb. 170 td. Bicarb. 20 Std.Bicorb.212BASE Xs - 92 BASE Xs-4.4 BASE Xs -2.4

RESP 40RATE(/min) 20

140

120PULSERATE -o100(/min)

80120

BLOODPRESSURE(mmHg)

4020

I 5 10 IS 20 25 30TIME (hrs.)

FIG. 4.- Systemic blood pressure, heart rate and respiration changes occurring in a patient under treat-ment for cardiogenic shock following myocardial infarction. Acid-base measurements are also shown.

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and much of our more recent work has beendirected towards the elucidation of this synd-rome, which has been variously ascribed tochanges in the cerebral circulation, loss of thedual function of haemoglobin or inactivationof thiol-containing enzymes. It is uncertainwhich of these mechanisms is fundamentallyresponsible for oxygen toxicity, but it has be-come apparent that high pressures of oxygencause numerous changes in the metabolism andblood flow of certain tissues.

It has been known for some time that hyper-baric oxygen causes cerebral vasoconstriction(Kety and Schmidt, 1946; Lambertson, Kough,Cooper, Emmel, Loeschoke and Schmidt, 1953;Jacobson, Harper and McDowell, 19,63) andmore recently Jacdbson and Lawson (1963)§howed that cerelbral infarcts created in dogsby ligation of the middle cerebral artery wereof greater size if the animal was given oxygenat two atmospheres pressure to breathe insteadof air. Nevertheless, Smith, Lawson, Renfrew,Ledingham and 'Sharp (1961), demonstratedthat the hypoxic brain of the dog could be pro-tected if the animal was given oxygen at twiceatmospheric pressure to breathe instead of air.This was done by observing that following liga-tion of the carotid and vertebral arteries whilethe animal breathed oxygen at 2 atmospherespressure the EEG activity continued unaltered,whereas if air was breathed fthe EEG activityceased within 'A minute. The reconciliationof these apparently conflieting results wassupplied 'by Harper. Ledingham and McDowall(1965) who showed tha-t cerebral vasoconstric-tion does not occur when oxygen at twiceatmospheric pressure is breathed provided thebrain has been first rendered hypoxic by re-ducing 'the arterial blood pressure to 50 mm.Hg. by haemorthage.Blood flow through the brain thus appears

to be regulated to meet the requirements of thebrain for oxygen although it has been suggestedthat reduction in cerebral blood flow in responseto a high inspired oxygen tension is a physiolo-gical mechanism designed to protect the brainfrom the damaging effects of hyperbaric oxygen.The site of action of oxygen in the control ofcerebral blood flow is not clear, however, sincevasoconstriction does not occur in the hypoxicbrain despite a high arterial Po.Cowley, Attar, Blair, Esmond, Ollodart and

Flamshimoto (1965) have clearly shown thathyperbaric oxygen has an ameliorating effect onhaemorrh'agic and endotoxic shock and sincethe prdtective effect of hyperbaric oxygen on the

hypoxic brain had already been demonstratedby us, it seemed desirable to determine theeffect of hyperbaric oxygen on the normal andhypoxic kidney. Renal blood flow was measureddirectly by collecting the left renal venouseffluent into a measuring cylinder and thenreturning it to the circulation of the dog bymeans of a sigmamoter pump (Norman, Irvin,Skene and Smith, 1966). It was found that therenal blood flow fell linearly as an inverse func-tion of the inspired Po2 and that the magnitudeof the fall was of the same order as that notedby Jacobson and others (1963) for cerebralblood flow under similar conditions of inspiredPo2. Measurements of renal venous Po2 showedthat when 1 atmosphere of oxygen was breathedthe renal venous effluent was supersaturatedwith oxygen. When these measurements wererepeated at an arterial blood pressure of 60 mm.Hg., however, it was found that when oxygenat atmospheric pressure was breathed, the renalvenous effluenit was no longer supersaturatedwith oxygen and the renal blood flow was notaltered from the value obtained when air wasbreathed. When oxygen at 2 atmospheres pres-sure was breathed, at this level of arterial pres-sure, the renal venous blood was once againsupersaturated with oxygen and the renal bloodflow fell by some 28% of the value obtainedwhen air or oxygen at atmospheric pressurewas breathed.These findings suggest that both the hypoxic

brain and the hypoxic kidney can be protectedby hypetbaric oxygen but they may be damagedby supplying oxygen grossly in excess of theirrequirements. It could be concluded that thesetissues function best within a relatively narrowrange of Po2 in much the same way as theyfunetion best within a relatively narrow rangeof Oni.Our investigations into the effects of various

oxygen tensions on tissue metabolism has led toa reappraisal of the observation of Ivanov (1959)that high oxygen pressures prdtect mice fromthe lethal effects of cyanide. 150 mice weredivided into three groups and each group wasgiven 0.85 mg./Kg. potassium cyanide by intra-peritoneal injection. The 'first group was givenair 'to breathe, 'the second group oxygen atatmospheric pressure, and the third group oxy-gen at 2 atmospheres pressure. The results areshown in Taible 3, where it can be seen that thenercenitage survival increases markedly as theinspired oxygen pressure increases. Althoughcyanide poisoning is becoming increasinglycommon in industry, our interest in these find-ings was mainly in the mechanism which had

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Air1 Atmos48/50

TABLE 3

MORTALITY

02I Atmos28/50

02

2 Atmos10/50

Mortality of mice given a standard dose of potas-siumr cyanide and itreated with air or oxygen at one ortwo atmospheres pressure for two hours.

allowed oxygen to by-pass an apparentlyblocked metabolic pathway. Il't is possible thatoxygen exeets its therapeu'tic effect by increas-ing the rate of detoxification of cyanide to a

non-toxic thiocyanate or 'that it is due to adistutbance of the equilibrium ibetween cyto-chrome oxidase + CN and cytochrome oxidasecyanide, driviing the reaction to the left and free-ing increased amounts of cytochrome oxidasefor 'the con'tinuance of cellular respiration. Athird possilble mechanism is that sufficient cellu-lar respiration continues by some cyanide-insen-sitive (pathway to enable continuance of life untilthe cyanide has 'been detoxified. This problemhas not yet 'been 'finally elucidated but it hasbeen shown that there is an increase in theoxygen consum'ption of tissues poisoned bycyanide and studied in a Warlburg apparatus ifthe gas 'phase is changed from air to oxygen atatmospheric pressure '(Skene, Norman andSmith, 1965, 1966).Andther recent dbservation made in this

department of the metajbolic activity of highoxygen pressures is the depressant action whichit has on the secretion of acid and ,pepsin by therat stomach *(Caridis, Normanand Smith, 1966).The Shay pylorus liga'tion technique has beenused and it has been shown that progressiveincrease in the oxygen tension breathed resultsin a reduction of acid and 'pepsin secretion untilthe former is nearly abolished when the rat hasbreathed oxygen lat 2 atmospheres pressures for9 hours. This is not part of a general depressionin gastro-intestinal secretion since the other frac-tions of the ga9tric secretion are unaffected asare the secretions of the liver, pancreas an'dsmall bowel. The altered gastric secretion is notdue to 'the physical effects of compression nor isit affected iby histamine. 'it appears to be due toa direct action on the parietal cell of the gastricmucosa, 'prdbably in the nature of an enzymicinactivation. The precise nature of this action isstill under investigation.Whether these observations on gas'tric secre-

tion have any bearing on the treatment of pepticulcer is open to doubt since the effect is transientand is gone within 48 hours of exposure to oxy-gen. In addition, the duration of treatmentrequired to produce a marked effect is ratherclose to that needed to cause dangerous side-actions.

Although a gradual appreciation of the natureof oxygen poisoning is being acquired there hasbeen no suggestion, as yet, as to how the suscep-tible tissues may be protected during hyperbaricoxygen therapy. It seemed reasonable, 'therefore,to discover whether oxygen toxicity could beused to clinical advantage, such as in the des-truction of aerdbic, pathogenic micro-organisms.McAllister, Stark, 'Norman and Rose (1963)re-opened 'this field by demonstrating that oxy-gen at 2 atmospheres pressure had a bacterio-static effect on a variety of pathogenic, aerobicmicro-organisms such as Ps. pyocyanea, Staph.aureus, E. coli and Aspergillus fumigatus.Further work in this department has suggested,however, that it is unlikely to be possible to usehyperbaric oxygen effectively in the treatmentof generalised infedtions since it would not bepossilble to raise the tissue Po, to sufficienit levelsfor sufficiently long to cause bacteriostasis with-out producing oxygen poisoning in the patient.The more likely application of 'these in vitroobservations appears to ibe in the treatment ofsurface infections such as occur in burns andsuperficial wounds. In such cases it is possibleto expose the infected surface to hyperbaricoxygen by means of a ipolythene bag, while thenatient breathes air in a pressure chamber.Under these conditions treatment can be con-tinued for as long as necessary. Experimentshave 'been carried out in guinea-pigs to test thishypothesis (Irvin, Norman, Suwanagul andSmith, 1966). Capsules wi'th gas inlet and remov-able tops were sutured over two wounds, one oneach flank of the guinea pig. In one group ofexperiments the wounds were infected with Ps.pyocyanea, while in another group they wereinfected with Staph. aureus. The animals wereplaced in a pressure chamJber breathing air at2 atmospheres pressure and air was passedover one wound whiile oxygen was passed overthe other. This treatment was continued for 72hours and swabs were taken at 18 hour intervals,which showed a marked bacteriostatic effect onthe wounds treated with oxygen, compared toair controls. This effect 'persisted for the dura-tion of the *treatment and indicates the need forfurther evaluation of this 'technique as a formof therapy for widespread surface infection,

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July, 1966 NORMAN and SMITH: Hyperbaric Oxygen 455

which may be difficult to control with antilbi-otics. Considerable work is also being done onthe mode of action of high oxygen pressures onbacteria and the indications are that it may bedue to a mutation rather than an enzymicinactivation.

REFERENCES

ASTRUP, P. (1964): An Abnormality in the Oxygen-dissociation Curve of Blood from Patients withBuerger's Disease and Patients with Non-specificMyocarditis. Lancet, ii, 1152.

BERNHARD, W. F., TANK, E. S. (1963): Effect of Oxy-gen Inhalation at 3.0 to 3.6 Atmospheres Absoluteupon Infants with Cyanotic Congenital HeartDisease. Surgery. 54, 203.

BERNHARD, W. F. (1966): IProceedings of 3rd Internat.Conf. on Hyperbaric Oxygenation. (In Press).

CARIDIS, D. T., NORMAN, J. N., and SMITH, G. (1966):The Effect of Hyperbaric Oxygen on Gastric AcidSecretion. Proc. 3rd Intern. Conf. on HyperbaricOxygenation. (In the Press).

CHARDACK, W. M., GAGE, A. A., FEDERICO, A. J.,CUSICK, J. K., MATSUMOTO, P. J. H., and LANPHIER,E. H. (1964): Reduction by Hyperbaric Oxygena-tion of the Mortality from Ventricular Fibrillationfollowing Coronary Artery Ligation. Circulat. Res.15, 497.

CHURCHILL-DAVIDSON, .I., SANGER, C., and THOMLIN-SON, R. H. (1955): High Pressure Oxygen andRadiotherapy. Lancet, i, 1091.

COWLEY, R. A., ATTAR, S., 'BLAIR, E., ESMOND, W. G.,OLLODART, R., and HASHIMOTO, S. (1'965): Hyper-baric Oxygenation in Hypoxic Shock States. InHyperbaric Oxygenation. p.333. Ed. Ledingham, I.McA. Edinburgh and London: E. & S. Livingstone.

DONALD, I. A., and TANKEL, H. I. 1(1962): TraumaticIschaemia. Postgrad. med. J. 38, 695.

DOUGLAS, T. A., LAWSON, D. D., LEDINGHAM, I. MlcA.,NORMAN, J. N., SHARP, G. R. and SMITH, G. (1962):Carbon Monoxide Poisoning. Lancet, i, 68.- (1964): Carbon Monoxide Poisoning, In ClinicalApplication of Hyperbaric Oxygen. Ed. Boerema,I., p.161. Amsterdam: Elsevier.

HARPER, A. M., LEDINGHAM, I.McA., and MCDOWALL,D. CG. (1965): The Influence of Hyperbaric Oxygenon the Blood Flow and Oxygen Uptake of theCerebral Cortex in Hypovalaemic Shock. In Hyper-baric Oxygen. p. 342, Ed. Ledingham, I. McA.,Edinburgh and London: E. & S. Livingstone.

IRVIN, T. T., NORMAN, J. N., SUWANAGUL, A., SMITH,G. (1966): Hyperbaric Oxygen in the Treatmentof Infections by Aerobic Micro-organisms, Lancet,i, 392.

IVANOV. K. P. (1959): Effect of Increased OxygenPressure on Animals Poisoned by PotassiumCyanide, Farmakol. Toksikol, 22, 468.

JACOBSON, I., HARPER, A. M., MCDOWALL, D. G.,(1963): The Effects of Oxygen under Pressure onCerebral Blood Flow and Cerebral Venous OxygenTension, Lancet, ii, 549.

JACOBSON, I., LAWSON, D. D. (1963): The Effect ofHyperbaric Oxygen on Experimental Cerebral In-farction in the Dog with Preliminary Correlations ofCerebral Blood flow at 2 Atmospheres of Oxygen,J. Neurosurg., 20, 849.

KETY, S. S., SCHMIDT, C. F. (1946): Effects of Active

and Passive Hyperventilation on Cerebral BloodFlow, Cerebral Oxygen Consumption, CardiacOutput, and Pressure of Normal Young Man, J.clin. Invest., 25, 107.

LAMBERTSON, C. J., KOUGH, R. H., COOPER, D. Y.,EMMEL, G. L., LOESCHUKE, H. H., SCHMIDT, C. F.(1953): Effects in Man of Oxygen Inhalation at 1and 3.5 Atmospheres upon Blood Gas Transport,Cerebral Circulation and Cerebral Metabolism, J.appl. Physiol., 5, 471.

LEDINGHAM, I. McA., NORMAN, J. N. (1965): Meta-bolic Effects of Combined Hypothermia and Hyper-baric Oxygen in Experimental Total CirculatoryArrest. In, Hyperbaric Oxygenation. Ed. Leding-ham, I. McA., p. 125. Edinburgh and London:E. & S. Livingstone.

MCALISTER, T. A., STARK, J. M., NORMAN, J. N.,Ross, R. M., 1(1963): Inhibitory Effects of Hyper-bar,ic Oxygen on Bacteria and Fungi, Lancet, ii,1040.

MEIJNE, N. G., (1965): Flow Distribution Changesduring Extra-corporeal Circulation at 3 atmospheresAbsolute. In Hyperbaric Oxygenation. Ed. Leding-ham, I. McA., p. 136. Edinburgh and London:E. & S. Livingstone.

NORMAN, J. N., IRVIN, T. T., SKENE, W. G., SMITH,G. (1966): The Renal Response to HyperbaricOxygen. 3rd Intern. Conference on HyperbaricOxygenation. (In the press).

NORMAN, J. N., DOUGLAS, T. A., SMITH, G. (1966):The Effect of Hypothermia and Hyperbaric Oxy-gen on Tissue Metabolism, Surg. Gynec., Obstet.,122, 778.

SKENE, W. G., NORMAN, J. N., SMITH, G. (1966):The Effect of Hyperbaric Oxygen in CyanidePoisoning. Proc. 3rd Intern. Conference on Hyper-baric Oxygen. (In the press).

SKENE, W. G., NORMAN, J. N., SMITH, G. (1965):The Effect of Hyperbaric Oxygen in CyanidePoisoning, Scot. med. J., 10, 87.

SMITH, G. (1962): The Treatment of Carbon Mon-oxide Poisoning with Oxygen at Two AtmospheresAbsolute, Ann. Occup. Hyg.. 5, 259.

SMITH, G., LAWSON, D. D. (1958): ExperimentalCoronary Arterial Occlusion: Effects of theAdministration of Oxygen under Pressure, Scot.med. J., 3, 346.-, (1962): The Protective Effect of Inhalation ofOxygen at Two Atmospheres Absolute Pressure inAcute Coronary Artery Occlusion, Surg. Gynec.Obstet., 114, 320.

SMITH, G., SHARP, G. R. (1960): Treatment of CarbonMonoxide Poisoning with Oxygen Under Pressure,Lancet, ii, 905.

SMITH, G. LAWSON, D. D., RENFREW, S., LEDINGHAM,I. McA., SHARP, G. R. (1961): Preservation ofCerebral Cortical Activity by Breathing Oxygenat Two Atmospheres of Pressure during CerebralIschaemia, Surg. Gynec. Obstet., 113, 13.

SMITH, G., LEDINGHAM, I. McA., NORMAN. J. N.,DOUGLAS, T. A., BATES, E. H., LEE, F. D. (1963):Prolongation of the Time of "Safe" CirculatoryArrest by Preliminary Hyperbaric Oxygenation andBody Cooling, Surg. Gynec. Obstet.. 117, 411.

SMITH, G., LEDINGHAM, I. McA., SHARP, G. R.,NORMAN, J. N., BATES, E. H. (1962): Treatment ofCoal-gas Poisoning with Oxygen at Two Atmos-pheres Pressure, Lancet, i, 816.

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