THE EFFECT OF PROLONGED HYPEROXIA ON THE CARDIOVASCULAR SYSTEM OF ANAESTHETIZED DOGS

Brit. J. Anaesth. (1972), 44, 469

THE EFFECT OF PROLONGED HYPEROXIA ON THE CARDIOVASCULAR SYSTEM OF ANAESTHETIZED DOGS G. SMITH AND I. McA. LEDINGHAM SUMMARY

High inspired oxygen concentrations are known to produce peripheral vasoconstriction and a fall in heart rate and cardiac output. In general mean arterial blood pressure remains unchanged (Whalen et al., 1964; McGuinness and McCrae, 1965; Whitehorn, Edelmann and Hitchcock, 1946). Oxygen at normal atmospheric pressure reduces myocardial contractility within minutes (Daniell and Bagwell, 1968) and oxygen at twice atmospheric pressure (2 ATA) has a rapid depressant effect on left ventricular function (Kioschos et al., 1969). A progressive fall in cardiac output has been reported in anaesthetized, ventilated dogs exposed to oxygen at 2 ATA for 3-4 hours (McBride, 1969) and recently myocardial failure has been advanced as one of the factors contributing to acute pulmonary oxygen toxicity (Clarke, Sandison and Ledingham, 1969). Wood, using rats exposed to oxygen at 3 ATA, noted persistent hypertension and considered that left ventricular failure might be a feature of oxygen toxicity (Wood, Seager and Perkins, 1967). The present study was designed to examine in more detail the haemodynamic effects of prolonged hyperoxia and, in particular, to observe the degree of reversibility of any cardiac changes after discontinuation of the oxygen administration. METHODS

Six mongrel dogs of weight range 15-20 kg were anaesthetized with thiopentone (dose range 350-420 mg), intubated and ventilated with 0.4% trichloroethylene vaporized in oxygen or oxygen/nitrogen

mixture. Controlled ventilation was obtained with a Starling pump, the tidal volume of which was adjusted to maintain a constant end-tidal Pco2 in the range 34-45 mm Hg. Reflex movements were controlled by the intermittent intramuscular administration of suxamethonium chloride. Portex plastic cannulae were inserted into the right atrium and aorta via the femoral vessels. A Sones No. 7 catheter was inserted via the common carotid artery into the left ventricle and another via the external jugular vein into the pulmonary artery. The intracardiac catheters were positioned under direct fluoroscopic vision. Arterial and ventricular pressures were measured using Elema-Schonander EMT35 pressure transducers (range 0-300 mm Hg) and right atrial and pulmonary artery pressures were monitored using EMT33 pressure transducers (range 0-30 mm Hg). All pressures and lead II of the electrocardiograph were recorded on the ink-jet recorder (Mingograf 81). Cardiac output was measured using the dye-dilution technique (indocyanine green) with a Waters densitometer (XP-302). Left ventricular dp/dt was obtained as the tangent to the upsweep of the ventricular wave form recorded at the speed of 250 mm/sec. The mean of four such tangents was calculated for each set of readings. Arterial and mixed venous blood was analysed for Poo, Pco, and pH using the Radiometer equipG.

SMITH, B.SC., F.F.A.R.C.S.; I. McA.

LEDINGHAM, M.B.,

CH.B.; University Departments of Anaesthesia and Surgery, Western Infirmary, Glasgow, Scotland.

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Six dogs have been anaesthetized with trichloroethylene and ventilated with 100% oxygen at 2 atmospheres absolute for 8 hours followed by a 2-hour period of ventilation with 15% oxygen/85% nitrogen. A fall in cardiac output of approximately 30% occurred within 4 hours of commencing 100% oxygen ventilation, accompanied by a fall in left ventricular dp/dt(max), a 70% increase in systemic vascular resistance and a rise in left ventricular end-diastolic pressure. On resumption of oxygen/nitrogen at the end of 8 hours, there was a rapid restoration of all parameters towards the initial values. It would appear that the changes in cardiac output and vascular resistance with oxygen are not progressive within an 8-hour period and that myocardial oxygen toxicity is reversible in this time.

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ment. All values were corrected for the temperature fall in cardiac output during hyperoxia was mirrored difference between the electrodes and mid-oesopha- by a significant rise in (A-V)O2 content difference geal temperature (monitored continuously with an Ellab thermocouple) using the dog cursor on the The values for left ventricular dp/dt(max) revealed Radiometer blood gas calculator (984-300) (Severing- an apparent fall by about 27% within 4 hours haus, 1966). Oxygen contents were calculated accord- although this did not reach the level of significance. ing to the formula: Blood oxygen content (ml/100 Left ventricular end-diastolic pressure rose sigml)=Hb(g) (measured by the cyanmet-haemoglobin nificantly from 0.4 + 0.24 mm Hg initially to 6.66 + method) x 1.34 x % saturation/100+Po 2 (mm Hg) x 2.5 mm Hg (0.025>P>0.01). 0.0031. (Bunsen coefficient.) DISCUSSION After induction of anaesthesia, some 1-2 hours were allowed to elapse for a steady state to obtain. Alveolar oedema has been consistently reported as a A full set of measurements were then made with the finding in acute oxygen toxicity (Binger, Faulkner animals being ventilated with 15% oxygen/85% and Moore, 1927; Kistler, Caldwell and Weibel, nitrogen at 2 ATA (referred to hereafter as air 1967). Many factors have been implicated to explain equivalent). these changes, including the direct toxic effect of The inspired gas was then changed to 100% oxygen on capillary endothelium (Bean, 1945) and oxygen at 2 ATA for a period of 8 hours after which profound sympatho-adrenal stimulation (Bean, 1956). each dog was ventilated with the original gas mixture Undoubtedly, there are many factors influencing of 15% oxygen/85% nitrogen at 2 ATA for a final these changes (Bean, 1965) but so far, the contribu2 hours. A set of measurements consisted of arterial tion played by myocardial oxygen toxicity has not and mixed venous blood gases, heart rate, systemic been clearly defined. arterial pressure, right atrial and pulmonary artery In the isolated heart, high-pressure oxygen causes pressures, left ventricular pressure (including the a reduction in contractility (Rumberger, Retzlaff and end-diastolic pressure) and dp/dt(max). During the Bleichert, 1970) and a toxic action of oxygen has period of hyperoxia, measurements were made at been demonstrated in at least some of the normal approximately 2-hourly intervals. Results have been cardiac metabolic pathways (Haugaard, Hess and evaluated statistically using the paired Student <-test. Itskevitz, 1957). In the intact animal breathing oxygen at 3.6 ATA for brief periods, a fall in contractility RESULTS has been reported in association with a fall in cardiac The haemodynamic and blood gas data obtained output and stroke volume (Kioschos et al., 1969). The before, during and after the period of hyperoxia are effect of prolonged hyperoxia has so far not been established but it seemed possible that a progressive indicated in tables I and II. Heart rate and mean pressure showed only minor decline in contractility could give rise to changes of fluctuations on exposure to hyperoxia, and on pulmonary congestion and oedema similar to those subsequent exposure to air equivalent heart rate seen in left ventricular failure. This problem is difremained unaltered; mean arterial pressure was ficult to investigate in the intact animal as pulmonary slightly reduced (P<0.05). Cardiac output showed a changes start to occur after 12 hours or so in dogs fall by 43% (0.01>P>0.005) within 4 hours of ventilated with 100% oxygen at 2 ATA, possibly hyperoxia and there was no significant change for due to the direct toxic effect of oxygen. For this the subsequent 4 hours. On returning to air equiva- reason, an arbitrary time of exposure to hyperoxia lent, a dramatic rise in cardiac output occurred and of 8 hours was selected in the present study. values not significantly different from initial values The results indicate that a gradual decline in were obtained within \ hour (0.35>P>0.3). The cardiac output occurred over 4 hours with little subbulk of the change in cardiac output was accounted sequent change thereafter. The gradual nature of for by a reduction in stroke volume (0.05>P>0.025). these changes supports the view that this effect is Both systemic vascular resistance and pulmonary operating through a disturbance of the function of vascular resistance rose significantly in the later various enzyme systems since direct vascular effects stages of hyperoxia (P<0.01 in both). would be more rapid. The vascular changes observed The rise in oxygen consumption on first exposure must therefore be regarded as secondary to alterations to oxygen was not significant (0.10>P>0.05) and it in cardiac output. Swift recovery occurred on returnremained unchanged thereafter. For this reason, the ing to air equivalent, establishing not only that the

EFFECT OF PROLONGED HYPEROXIA ON CARDIOVASCULAR SYSTEM

47J

TABLE I. Blood gas and haemodynamic data obtained before, during and after exposure of anaesthetized dogs to 100% oxygen at 2 ATA for 8 hours. Results are expressed as the means + standard error of the mean.

On 15 %O, at

Measurement Pao2 (mm Hg)

time prior to commencing O2 i hour prior to 100% O, 187 ±30

O. consumption (ml/min) (A-V) O2 content difference (ml/100 ml) Paco2 (mm Hg)

2.7 ±0.9

i hr

2i hr

1283 + 74

1270

97

+ 12

3.8

+ 0.3

88

74

80

+4

+ 10

±0.8 42.1 + 1.4

48.5 + 5.7

240 + 30

8 hr 1257 + 55

±12 5.2

+ 1.6

50.1+7.6 200 ±10

+ 98

38.3

41 ±2.1

4 hr 1275 + 86

Subsequent interval on returning to 15% O, at 2 ATA

51.7

±8.6

5.1

4.6

ihr 144

1 | hr

2 hr

150

175

±15

+ 14

±10

76

92

±5

±10

±22

81 4.3

3.4

3.6

+ 1.4

±0.6

+ 1.5

±0.6

±0.7

41.5 + 2.5 85.0 + 18.0

41.8 + 2.3 76.0 + 17.0

41.2 + 2.1 55.0

38.0 + 1.9 51.0

±2.2

±10.0

±8.0

380+ 8C1 640 + 200 680 + 180

37.7 45.0 + 8.0

480 ±140 420 + 100 400 ±130

TABLE II. Haemodynamic data obtained before during and after exposure of anaesthetized dog:s to 100% oxygen at 2 ATA for 8 hours. The results are expressed as the means + standard error of the mean. On 15% O 2 at time prior to Interval after commencing Subsequent interval after commencing O, 100% O2 iat 2 ATA returning; to air equivalent 2 hr l i hr Measurement \ hr i hr 2i hr 8 hr 4 hr i hr Heart rate (beat/min) Mean arterial pressure (mm Hg) Central venous pressure (mm Hg) Mean pulmonary artery

pressure (mm Hg) Cardiac output (l./min) Stroke volume (ml) dp/dt max

(mm Hg/sec)

Left ventricular end-diastolic pressure (mm Hg)

162 ±69 135 ±9 —2.0 ±1.0 7.0

±1.0 2.86 ±0.39

19.4 +4.6 3706

+551

0.4 + 0.24

159

153

160

134

142

146

+ 17

+ 11

+5

+ 10

+ 10

±9

122

+8

-1.5

+ 0.6 8.2

+ 0.8

2.73 + 0.37 18.5 + 3.5 3613 + 497 0.5

+ 0.24

135

123

122

114

117

+ 11

+ 19

+7 + 0.7 + 0.6 13.3 + 0.8 1.93 + 0.33 15.8 + 1.2 2700 + 245 6.66 + 2.5

+9

+ 12

~~-0.6 + 0.4 ~9.3 + 1.4 "2.07 + 0.31 14.5

+ 3.2

3013 + 291 ~ 0.33 + 0.21

changes were reversible after 8 hours but also that the preparation was very stable. These changes were accompanied by corresponding changes in cardiac contractility. Electronic differentiation of the signal is essential for accurate measurement of dp/dt(max) and the absence of this limits the significance which may be attached to the present results (coefficient of variation of duplicate readings, 12%). Nevertheless, a change of 27% suggests that dp/dt(max) exhibited a downward trend. dp/dt(max) alone, although correlating well with contractility in the isolated heart (Reeves

-0.5 + 0.6 11.0

+ 1.3

1.64 + 0.29 10.4

+ 2.1

2682 + 387

3.5

+ 1.45

-0.8 + 0.5 11.8

+ 1.7

2.37 + 0.41 17.9 + 4.3 3341 + 503 2.16 + 0.94

159

±2

114

±6

±0.7

11.5

-0.8 + 0.7 12.0

+ 0.8

±1.6

-0.7

2.60 + 0.44 19.1

+ 5.4

3708 + 595

2.60 ±0.37 19.7 + 3.3 3905 + 649

1.0

0.5

+ 0.36

±0.34

and Hefner, 1962) is a complex function in the intact organism and other parameters require definition before a fall in contractility can be assumed. In this study, the decline in dp/dt(max) was accompanied by a rise in preload (LVED pressure) and an unchanged afterload (mean aortic pressure) with no significant change in heart rate. This fits the criteria of Wallace and his associates (1963) for defining a fall in myocardial contractility. This work is consistent with the hypothesis that there is a decline in myocardial contractility on exposure to oxygen at 2 ATA but that reversal can

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Systemic vascular resistance (dyne sec cm- 5 ) Pulmonary vascular resistance (dyne sec cm- 5 )

65 ±12

Interval after commencing 100% (0 2 at 2 ATA

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BRITISH JOURNAL OF ANAESTHESIA

occur up to 8 hours in the dog. There is also support for the concept that myocardial failure may be involved in the process of acute oxygen toxicity and may be responsible for some of the alveolar oedema seen in the classical Lorrain Smith effect (Smith, 1899). ACKNOWLEDGEMENT

The authors are grateful to the Medical Research Council for generous financial support. REFERENCES

(Lond.), 24, 19.

Wallace, A. G., Skinner, N. S. jr., and Mitchell, J. H. (1963). Haemodynamic determinants of the maximal rate of rise of left ventricular pressure. Amer. J. Physiol., 205, 30. Whalen, R. E., Fuson, R., Saltzman, H. A., Steiffel, J. W., and Heyman, A. (1964). Effects of hyperbaric oxygenation on blood gases in animals and man. Clin. Res., 12, 58. Whitehorn. W. V., Edelmann, A., and Hitchcock, F. A. (1946). The cardiovascular responses to the breathing of 100 per cent oxygen at normal barometric pressure. Amer. J. Physiol, 146, 61.

EFFETS D'UNE HYPEROXIE PROLONGEE SUR LE SYSTEME CARDIOVASCULAIRE DE CHIENS ANESTHESIES SOMMAIRE

Six chiens ont ete anesthesies au trichlorethylene et la respiration a ete assuree pendant 8 heures par une ventilation de 100 p.cent d'oxygene a deux atmospheres absolues puis pendant une periode de deux heures par un melange de 15 p.cent d'O2 et de 85 p.cent de N2. Une chute du debit cardiaque de l'ordre de 30 p.cent environ est survenue pendant les quatre heures consecutives au debut de la ventilation par Poxygene pur et s'est accompagnee d'une chute du rapport dp/dt (max) au niveau du ventricule gauche, d'une augmentation de 70 p.cent de la resistance peripherique et d'une ascension de la pression telesystolique au niveau du ventricule gauche. Lors de la reprise du melange O 2 /N 2 au bout des huit premieres heures, on a note un retour rapide de tous les parametres a leurs valeurs de depart. II semblerait que les modifications intervenues dans le debit cardiaque et la resistance vasculaire peripherique, sous oxygene, ne presentent pas un caractere progressif pendant une periode de huit heures et que la toxicite de l'oxygene vis-a-vis du myocarde soit reversible a ce moment.

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Bean, J. W. (1945). Effects of oxygen at increased pressure. Physiol. Rev., 25, 1. (1956). Reserpine, chlorpromazine and the hypothalamus in reactions to oxygen at high pressure. Amer. J. Physiol, 187, 389. (1965). Factors influencing clinical oxygen toxicity. Ann. N.Y. Acad. Set., 117, 745. Binger, C. A. L., Faulkner, J. M., and Moore, R. L. (1927). Oxygen poisoning in mammals. J. exp. Med., 45, 849. Clarke, G. M., Sandison, A. T., and Ledingham, I. McA. (1969). Acute pulmonary oxygen toxicity: a pathophysiological study in spontaneously breathing anaesthetised dogs. Proceedings of the 4th International Congress on Hyperbaric Medicine (eds. Wada, J., and Awa, T.), p. 1. Tokyo: Igaku Shoin. Daniell, H. B., and Bagwell, E. E. (1968). Effects of high oxygen on coronary flow and heart force. Amer. J. Physiol, 214, 1454. Haugaard, N., Hess, M. E., and Itskevitz, H. (1957). The toxic action of oxygen on glucose and pyruvate oxidation in heart homogenates. J. biol. Chem., 227, 605. Kioschos, J. M., Behar, V. S., Saltzman, H. A., Thompson, H. K., Myers, N. E., Smith, W. W., and Mclntosh, H. D. (1969). Effect of hyperbaric oxygenation on left ventricular function. Amer. J. Physiol, 216, 161. Kistler, G. S., Caldwell, P. R. B., and Weibel, E. R. (1967). Development of fine structural damage to alveolar and capillary lining cells in oxygen poisoned rat lungs. J. Cell Biol, 33, 605. McBride, T. I. (1969). Experimental studies on myocardial blood flow and metabolism with special reference to hyperbaric oxygen. M.D. Thesis, University of Glasgow. McGuinness, J. B., and McCrae, M. (1965); in Hyperbaric Oxygenation, (ed. I. McA. Ledingham), p. 118. Edinburgh : Livingstone. Reeves, T. J., and Hefner, L. L. (1962). Isometric contraction and contractility in the intact mammalian ventricle. Amer. Heart J., 64, 525. Rumberger, E., Retzlaff, E., and Bleichert, A. (1970). Der einfluss noher sauerstoffdrucke auf die kontraktilitat des herzmuskels des Warmbluters (meerschweinchen). Pflugers Arch. ges. Physiol, 315, 125. Severinghaus, J. W. (1966). Blood gas calculator. J. appl. Physiol, 21, 1108. Smith, J. Lorrain (1899). The pathological effects due to increase of oxygen tension in the air breathed. J. Physiol.

Wood, C. D., Seager, L. D., and Perkins, G. (1967). Blood pressure changes and pulmonary oedema in the rat associated with hyperbaric oxygen. Aerospace Med., 38, 479.

DIE AUSWIRKUNGEN EINER VERLANGERTEN HYPEROXIDOSE AUF DAS KARDIOVASKULARE SYSTEM BEI ANAESTHESIERTEN HUNDEN ZUSAMMENFASSUNG

6 Hunde warden mit Trichlorathylen anaesthesiert und mit 100% Sauerstoff bei 2 Atmospharen absolutem Druck 8 Stunden lang beatmet, danach 2 Stunden lang mit 15% Sauerstoff/85% Stickstoff. Der Herz-Auswurf fiel urn ungefahr 30% innerhalb von 4 Stunden nach Beginn der 100% Sauerstoff-Beatmung, ausserdem fiel die linksventrikulare dp/dt (max) ab, und der Gefasswiderstand stieg um 70% an, sowie der Druck des linken Ventrikels und der diastolische Druck. Bei Wiederaufnahme der Sauerstoff-Stickstoff Beatmung nach 8 Stunden gingen alle Werte schnell wieder auf die Anfangswert zuriick. So scheint es, dass die Veranderungen des Herzschlagyolumens und des Gefasswiderstandes unter Sauerstoff nicht fortschreitend sind innerhalb einer 8-Stunden-Periode und dass die toxische Schadigung des Myocards durch Sauerstoff in dieser Zeit reversibel ist. EL EFECTO DE HIPOXIA PROLONGADA SOBRE EL SISTEMA CARDIOVASCULAR DE PERROS ANESTESIADOS RESUMEN

Seis perros han sido anestesiados con tricloroetileno y ventilados con oxigeno al 100 por ciento a dos atmdsferas absolutas durante 8 horas seguidas por un periodo de 3 horas de ventilation con O, al 15 por ciento/N2 al 85 por ciento. Hubo un descenso en el gasto cardiaco de aproximadamente el 30 por ciento dentro de 4 horas despues de comenzar la ventilation con oxigeno al 100 por ciento, acompanado por una reduction en la dp/dt (max) ventricular izquierda, con incremento del 70 por ciento en la resistencia vascular general y una elevation en la presi6n diastolica final ventricular izquierda. Al recomenzar con O 2 /N 2 despues de ocho horas hubo rapida restauracion de todos los parametxos hacia los valores iniciales. Parece ser que los cambios en el gastro cardiaco y resistencia vascular con oxigeno no son progresivos dentro de un periodo de 8 horas y que la toxicidad miocardica del oxigeno es reversible durante este tiempo.