Stroke. Protective Effects of Acetazolamide and Hyperbaric Oxygenation on Experimentally Induced Syncope. A Journal of Cerebral Circulation

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1 Stroke A Journal of Cerebral Circulation MARCH-APRIL VOL. I 1970 NO. Protective Effects of Acetazolamide and Hyperbaric Oxygenation on Experimentally Induced Syncope BY YIHONG KONG, M.D., STEVEN LUNZER, M.D.. ALBERT HEYMAN, M.D., AND HERBERT A. SALTZMAN, M.D. Abstract: Protective Effects of Acetazolamide and Hyperbaric Oxygenation on Experimentally Induced Syncope The protective effects of acetazolamide and hyperbaric oxygenation on experimentally induced syncope were evaluated in seven healthy male subjects. Syncope was induced by vigorous hyperventilation and Valsalva maneuver. Each subject performed these procedures three times in each of the following conditions: (1) breathing room air at normal atmospheric pressure, () breathing 100% oxygen at.6 atmospheric pressure, () breathing 9% oxygen at.6 atmospheres and (4) after intravenous injection of 500 mg of acetazolamide while breathing 100% oxygen at.6 atmospheres. With comparable changes of arterial pco and blood pressure during the hyperventilation-valsalva maneuver, syncope occurred in 19 of 1 (91%) hyperventilation-valsalva maneuvers performed at ambient environment, in 18 of 1 (86%) when subject was breathing 9% oxygen at.6 atmospheres, in 14 of 1 (67%) when.6 atmospheres of 100% oxygen was used, and in only 7 of 1 (%) when acetazolamide was used in conjunction with hyperbaric oxygen. Syncope was completely prevented by hyperbaric oxygenation in one subject and by the combination of acetazolamide and hyperbaric oxygen in four subjects. These studies demonstrate that cerebral vasodilation induced by acetazolamide combined with increased oxygen delivery to the brain resulting from hyperbaric oxygenation may preserve cerebral function during the period of hypotension and hypocapnia produced by hyperventilation and Valsalva maneuver. ADDITIONAL KEY WORDS hyperventilation hypocapnia cerebral blood flow systemic arterial hypotension cerebral ischemia Introduction Recent studies have shown that acetazolamide is a potent cerebral vasodilator in both From the Cardiovascular Laboratory and the Center for Cerebrovascular Research, Department of Medicine, Duke University Medical Center, Durham, North Carolina. This paper was presented at the annual meeting of the Southern Section of the American Federation Stroke, Vol. I, March-April 1970 man and experimental animals. 1 " 6 When administered to dogs in conjunction with hyperbaric oxygenation, acetazolamide not only for Clinical Research, New Orleans, Louisiana, January, This work was supported by research grants from the U. S. Public Health Service (HE-0756, NS- 06) and grant-in-aid from the American Heart Association. 69

KONG, LUNZER, HEYMAN, SALTZMAN counteracted the cerebral vasoconstricting effect of hyperoxia, but also increased markedly the cerebral blood flow and oxygen delivery to the brain.

2 KONG, LUNZER, HEYMAN, SALTZMAN counteracted the cerebral vasoconstricting effect of hyperoxia, but also increased markedly the cerebral blood flow and oxygen delivery to the brain. 6 These experimental findings suggest that the combination of hyperbaric oxygenation and acetazolamide may be of therapeutic value in patients with cerebral ischemic disorders. This study was designed to test this possibility. Transient cerebral ischemia was induced in normal young subjects by brief periods of hypocapnia and hypotension produced by vigorous hyperventilation and Valsalva maneuver. The effects of acetazolamide and hyperbaric oxygenation as well as their combination were studied in these subjects to determine whether these measures could preserve cerebral function under such adverse conditions. Methods Seven healthy male volunteer subjects between the ages of 18 and years were studied in fasting state. The study was carried out on a tilt table in the hyperbaric chamber. Inspiratory gas consisting of room air, 9% or 100% oxygen was administered via a special plastic head tent placed over the subject's head and shoulders. This plastic head tent permitted the subject's face to be observed throughout the study and the gas mixtures to be easily changed. Twelve electroencephalographic electrodes were attached to the scalp of each subject in a bilateral anteroposterior configuration and the electroencephalogram recorded on an eight-channel Grass unit. An indwelling Teflon needle was placed in the left brachial artery and arterial blood pressures were measured with a Statham strain gauge and recorded on a Gilson polygraphic recorder. With the subject in a 40 head-up tilt position, syncope was induced by hyperventilation for one minute followed by a 10-second vigorous Valsalva maneuver. Baseline observations were made of the electroencephalogram, electrocardiogram and arterial blood pressure, all of which were continuously recorded during the hyperventilation and Valsalva maneuver and during the immediate postsyncopal period. Arterial blood samples were obtained at the end of each hyperventilation period and just before the Valsalva maneuver. Arterial ph, po and pco were determined immediately with an IL Instrument in the hyperbaric chamber. In order to detect and record the changes in consciousness, a series of random numbers were read to the subject who was instructed to respond to the even numbers by pressing an electrical marker. Signals from this marker were continuously recorded 70 along with the other physiological measurements during the Valsalva maneuver. The development of syncope was determined by the subject's inability to respond to the auditory stimuli, the appearance of characteristic high-voltage slow wave activity in the electroencephalograms, and the subject's lack of recall for the events associated with the end of the Valsalva maneuver. After practicing the procedures for several times before the study, each subject was instructed to perform three hyperventilation-valsalva maneuvers during each of the following four experimental conditions: (1) 15 minutes after intravenous administration of 10 ml of saline solution (used as a placebo) while breathing room air at normal atmospheric pressure; () 15 minutes after intravenous injection of saline solution while breathing 100% oxygen at.6 atmospheres absolute (.6 ATA or 0 PSIG); () 15 minutes after intravenous injection of saline while breathing 9% oxygen and 91% nitrogen at.6 atmospheres. (This gas mixture at this atmospheric pressure gives an alveolar po value similar to those obtained while breathing room air at normal atmospheric pressures.); and (4) 15 minutes after intravenous administration of 500 mg of acetazolamide while breathing 100% oxygen at.6 atmospheres. Results An example of the physiological recordings during a typical syncopal reaction induced by hyperventilation-valsalva maneuver at ambient environment is shown in figure 1. Starting from the top, there are records of electroencephalogram, two-second time signals, arterial blood pressure, signals indicating the subject's finger movements in response to the verbal cues, electrocardiogram, and the duration of the Valsalva maneuver. After one minute of hyperventilation, Subject A. B. had an arterial po of 1 mm Hg, and a reduction of arterial pco to mm Hg. When the mean arterial blood pressure fell to the level of 6 mm Hg, the subject fainted and failed to respond to verbal cues. At the same time, high-amplitude slow waves appeared diffusely in the electroencephalogram confirming the occurrence of syncope. The effects of acetazolamide and hyperbaric oxygenation in preventing syncope induced by the hyperventilation-valsalva maneuver are illustrated in figure. The same physiological parameters were recorded during a hyperventilation-valsalva maneuver by the Strok; Vol. I, March-April 1970

3 EFFECTS OF ACETAZOLAMIDE AND HYPERBARIC OXYGENATION ON SYNCOPE HYPERVENTILATION AND VALSALVA MANEUVER 1 ATA - AIR AAO<J FIGURE 1 y4«example of the physiological recordings during a typical syncopal reaction to the hyperventilation-valsalva maneuver performed at ambient environment. See text for details. EEG mmhg RaOi'15 HYPERVENTILATION AND VALSA1VA MANEUVER ATA -100% 0, ACETAZOLAMIDE AAO<5 Mater- (TsS FIGURE A record of hyperventilation-valsalva maneuver performed at atmospheres of 100% oxygen after receiving acetazolamide by the same subject as shown in figure 1. See text for details. same subject (A.B.) 15 minutes after receiving 500 mg of acetazolamide intravenously while breathing 100% oxygen at.6 atmospheres. The arterial pco after hyperventilation ( mm Hg) was comparable to that at the ambient environment, but the Stroke, Vol. I, March-April 1970 arterial po had risen to 1,5 mm Hg. Even though the mean blood pressure fell again to 6 mm Hg at the end of the Valsalva maneuver, the subject did not lose consciousness and continued to respond with finger movements. Significant electroencephalograph- 71

4 KONG, LUNZER, HEYMAN, SALTZMAN TABLE 1 Changes Observed During Hypervenfilation-Valsalva Sublet Condition* ph (1) B.A. () K.S. () S.M. (4) V.P Arterial blood poi (mm Hg) ,488 1, 1, ,57 1,561 1, ,50 1,50 1, ,5 1,58 1, , 1,515 1, ,6 1,615 1, ,4 1,490 1, Maneuvers pco, (mm Hg) Low* it MBPf (mm Hg) Syncope Stroke, Vol. I, March-April,970

5 EFFECTS OF ACETAZOLAMIDE AND HYPERBARIC OXYGENATION ON SYNCOPE , , ,5 84 (5) J.M (6) S.L. (7) F.S ,479 1,50 1, ,487 1,511 1, ,415 1,8 1, ,457 1,444 1,476 no ,4 1,414 1, ,4 1,486 1, Conditions: 1 = room air at normal atmospheric pressure; = 100% oxygen at.6 atmospheres; = 9% oxygen at.6 atmospheres; 4 = acetazolamide plus 100% oxygen at.6 atmospheres. tlowest mean blood pressure during Valsalva maneuver. () = syncope occurred; ( ) syncope did not occur ic abnormalities did not appear except for the Table 1 summarizes the findings in all artifacts produced by muscle contraction and seven subjects. For each individual subject, head movements. Normal alpha rhythms can hyperventuation-valsarva maneuver produced be seen in the third electroencephalographic a comparable degree of hypocapnia and tracing (P4-O) of this figure. hypotension in all four experimental condi- Stroke, Vol. I, March-April

$' " ' \ in inmis i n n FIGURE I - I ATA - Ail H-. ATA-100%0 m. ATA 9 % 0 H-.$

6 KONG, LUNZER, HEYMAN, SALTZMAN A.B. RESPONSE Of INDIVIDUAL SUBJECT MBP. PoCOj AND THEIR RELATIONSHIP TO DEVELOPMENT OF SYNCOPE 40 - I.I ATA-AIR D. ATA-100* 0 0 o 0 '' -&*"* :?' " ' \ in inmis i n n FIGURE I - I ATA - Ail H-. ATA-100%0 m. ATA 9 % 0 H-.ATA- IOO%O Acetozolomide The responses of each individual subject to the hyperventilation-valsalva maneuvers performed in different experimental conditions. Each subject performed three hyperventilation-valsalva maneuvers in each of the four conditions as listed at the right lower corner. The bar graphs show the number of these maneuvers which resulted in syncope. Note that syncope was completely prevented by hyperbaric oxygenation in one subject and by the combination of acetazolamide and hyperbaric oxygenation in four of the seven subjects. tions. As shown in figure, when the subjects were breathing room air at ambient pressure or 9% oxygen at.6 atmospheres ("air equivalent"), hyperventilation-valsalva maneuver almost always produced syncope in every subject. The combination of hyperbaric oxygenation and acetazolamide prevented the INCIDENCE OF HYPERVENTILATION-VALSALVA MANEUVER I ATA-Air RESULTING IN SYNCOPE ).ATA-9%0.ATA-IOO%O Acetozo!omide i n m H PERIOD FIGURE 4 The over-all incidence of syncope which resulted from the hyperventilation-valsalva maneuvers performed in different experimental conditions in all seven subjects m. ATA-9X ' '. '? ', IS.. ATA-100% Oj AcetazolamWe 0 //! i_ "0" <^ M.BR (mmhg) FIGURE 5 The levels of mean blood pressure and arterial carbon dioxide tension induced by hyperventilation-valsalva maneuvers and their relationship to the development of syncope. In each panel the arterial pco is indicated on the ordinate and the lowest mean arterial blood pressure during Valsalva maneuver on the abscissa. The solid dots represent Valsalva maneuvers which resulted in syncope, and the open circles those without syncope. The shaded rectangle represents the area included by the critical levels of arterial pco s and mean arterial blood pressure below which all syncopal reactions developed. Note that the critical level of mean arterial blood pressure was lower when the subjects were given hyperbaric oxygenation and acetazolamide. syncope in four of seven subjects and reduced the frequency of syncope in another subject (S. M.). In one of the subjects (V. P.) syncopal episodes were also completely prevented by hyperbaric oxygenation alone. In the remaining two of the seven subjects neither the hyperbaric oxygenation nor its combination with acetazolamide provided a protective effect. The over-all incidence of syncope resulting from the hyperventilation-valsalva maneuvers is shown in figure 4. In each experimental condition, a total of 1 hyperventilation- Valsalva maneuvers were performed by seven subjects. In ambient environment, 19 of 1 (91%) hyperventilation-valsalva maneuvers produced loss of consciousness. Similar results were obtained when the subjects were breathing 9% oxygen at.6 atmospheric pressure during which 18 of the 1 (86%) attempts resulted in syncope. Hyperbaric oxygenation alone seemed to have some protective effect; and syncope only occurred in 14 of 1 (67% ) hyperventilation-valsalva maneuvers. The greatest reduction in the incidence of syncope was observed after the subject had re- 74 Stroke, Vol. I, March-April 1970

EFFECTS OF ACETAZOLAMIDE AND HYPERBARIC OXYGENATION ON SYNCOPE ceived intravenously 500 mg of acetazolamide under hyperbaric oxygenation.

7 EFFECTS OF ACETAZOLAMIDE AND HYPERBARIC OXYGENATION ON SYNCOPE ceived intravenously 500 mg of acetazolamide under hyperbaric oxygenation. At this time only 7 of 1 (%) hyperventilation-valsalva maneuvers resulted in syncope. The critical levels of mean arterial blood pressure and arterial pco below which syncope could be induced are shown in figure 5. In ambient environment, syncope almost always occurred when the arterial pco levels fell below mm Hg and the mean blood pressure below 90 mm Hg. These critical levels were not significantly changed by increased atmospheric pressure or by hyperbaric oxygenation alone. However, with the combination of hyperbaric oxygenation and acetazolamide, syncope did not occur until the mean arterial blood pressure fell below the level of 64 mm Hg and the arterial pco below mm Hg. Discussion Hyperbaric oxygenation produces a very high oxygen tension in the arterial blood and would be expected to increase oxygen delivery to the brain. For this reason, hyperbaric oxygenation has been used in the treatment of patients with cerebral arterial occlusive disease. 8 The vasoconstricting effect of oxygen, however, produces a decrease in cerebral blood flow 7 " 9 and may reduce availability of various substrates to the brain. The possible beneficial effects of hyperbaric oxygen therapy are thus limited. In order to counteract the vasoconstricting effect of hyperoxia, it has been suggested that cerebral vasodilating agents be administered concomitantly with hyperbaric therapy. One such cerebral vasodilator is acetazolamide, an inhibitor of carbonic anhydrase. This agent has been found to increase the total cerebral blood flow in humans with or without cerebrovascular disease by as much as to 110%. 1-1 When administered to experimental animals under hyperbaric oxygenation, acetazolamide not only counteracted the cerebral vasoconstricting effect of oxygen, but also produced a significant increase in both fast and slow components of cerebral blood flow as measured by radioactive xenon techniques. 6 With the concomitant increase in arterial oxygen tension, the calculated oxygen delivery to the brain was also significantly increased. This study evaluates the possible protective effects of acetazolamide and hyperbaric oxygenation on one form of syncope (the socalled "fainting lark") induced by byperventi- Sfroke, Vol. I, March-April 1970 lation and a forceful Valsalva maneuver. The loss of consciousness caused by the "fainting lark" is mainly related to: (1) the reduction of cerebral perfusion caused by a sudden decrease in systemic blood pressure at the end of the Valsalva maneuver 10 and () the cerebral vasoconstriction due to hypocapnia secondary to hyperventilation. 11 A third factor which may contribute to the reduction in cerebral circulation is the secondary elevation in pressure within the cranial cavity which is transmitted via the venous system from the increased intrathoracic and intra-abdominal pressures during the Valsalva maneuver. 1 The combination of all three factors usually produce sufficient reduction in cerebral perfusion to induce loss of consciousness. The findings in this study indicate that the incidence of syncope can be reduced by hyperbaric oxygenation alone or in combination with acetazolamide. It was likewise found that the critical level of the mean arterial blood pressure necessary for inducing loss of consciousness was also decreased by the combination of hyperoxia and acetazolamide. When compared with their responses during the control period, the subjects receiving acetazolamide during hyperbaric oxygenation were able to tolerate more severe degrees of hypotension before losing consciousness. In a previous study, 18 the inhalation of 100% oxygen at ambient atmospheres was found to have no effect in preventing this form of syncope, but instead may have facilitated the development of loss of consciousness in some subjects. Inhalation of 100% oxygen at.6 atmospheres of pressure in the present study seemed to reduce the incidence of syncope as compared to the responses during the control period or during inhalation of the "air equivalent" (i.e., 9% oxygen at.6 atmospheric pressure). It seems likely that hyperbaric oxygenation alone may produce sufficient increase in oxygen delivery to the brain to overcome the ischemia due to vasoconstricting effects of oxygen. The exact mechanism by which acetazolamide increases cerebral blood flow is not entirely clear. The administration of acetazolamide has been found to increase tissue pco in the brain ' ls By inhibiting carbonic anhydrase, acetazolamide apparently delays the conversion of free carbon dioxide into bicarbonate in erythrocytes and impairs the carbon 75

KONG, LUNZER, HEYMAN, SALTZMAN dioxide transport. Carbon dioxide thus accumulates in brain tissue and produces selective cerebral vasodilatation.

8 KONG, LUNZER, HEYMAN, SALTZMAN dioxide transport. Carbon dioxide thus accumulates in brain tissue and produces selective cerebral vasodilatation. There may be several mechanisms by which the combination of hyperbaric oxygenation and acetazolamide prevented loss of consciousness in our subjects: First, the increased carbon dioxide tension in the brain induced by acetazolamide may lower cerebrovascular resistance, thus increasing cerebral blood flow. Secondly, the high tissue pco in the brain resulting from inhibition of carbonic anhydrase may prevent the cerebral vasoconstriction secondary to hyperventilation and hypocapnia. Finally, the combination of high arterial oxygen tension provided by hyperbaric oxygenation and the increase in cerebral perfusion may result in sufficient increase in oxygen delivery to the brain to preserve cerebral function despite the hypocapnia and hypotension produced by the hyperventilation-valsalva maneuver. Although the combination of acetazolamide and hyperbaric oxygenation may be effective in counteracting the transient decrease in cerebral perfusion in normal subjects, their effects on the ischemic brain tissue or in patients with cerebrovascular disorders remain unknown. The potential benefits of using such therapy in patients with acute cerebrovascular insufficiency and during cerebrovascular surgery still remain to be determined. References 1. Posner JB, Plum F: The toxic effects of carbon dioxide and acetazolamide in hepatic encephalopathy. J Clin Invest 9: (Aug) 19. Ehrenrelch DL, Bums RA, Alman RW, and Fazekas JF: Influence of acetazolamide on cerebral blood flow. Arch Neurol 5: -, Gotoh F, Meyer JS, and Tomita M: Carbonic anhydrase inhibition and cerebral venous blood gases and ions in man. Arch Int Med 117: 9-46 (Jan) Cotev S, Lee J, and Severinghaus JW: The effects of acetazolamide on cerebral blood flow and cerebral tissue PO. Anesthesiology : (May-June) Kong Y, Lunzer S, Heyman A, Thompson HK Jr, and Saltzman HA: Effects of acetazolamide on cerebral blood flow of dogs during hyperbaric oxygenation. Amer Heart J 78: -7, Heyman A, Saltzman HA, and Whalen RE: The use of hyperbaric oxygenation in the treatment of cerebral ischemia and infarction. Circulation : Suppl : 0- (May) Kery SS, Schmidt CF: The effects of altered arterial tensions of carbon dioxide and oxygen on cerebral blood flow and cerebral oxygen consumption of normal young man. J Clin Invest : (July) Lambertsen CJ, Kough RH, Cooper DY, Emmel AL, Loeschicke HH, and Schmidt CF: Oxygen toxiciry. Effects in man of oxygen inhalation at 1 and.5 atmospheres upon blood gas transport, cerebral circulation and cerebral metabolism. J Appl Physiol 5: (March) Jacobson I, Harper AM, and McDowell DG: The effects of oxygen at 1 and atmospheres on the blood flow and oxygen uptake of the cerebral cortex. Surg Gyn Obst 119: (Oct) McHenry LC Jr, Fazekas JF, and Sullivan JF: Cerebral hemodynamics of syncope. Amer J Med Sc 1: (Feb) Kety SS, Schmidt CF: The effect of active and passive hyperventilation in cerebral blood flow, cerebral oxygen consumption, cardiac output and blood pressure of normal young man. J Clin Invest : (Jan) Hamilton WF, Woodbury RA, and Harper HT Jr: Arterial, cerebrospinal and venous pressure in man during cough and strain. Amer J Physiol 141:4-50 (Mar) Klein LJ, Saltzman HA, Heyman A, and Sieker HO: Syncope induced by the Valsalva maneuver. A study of the effects of arterial blood gas tension, glucose concentration and blood pressure. Amer J Med 7: -8 (Aug) Meyer JS, Gotoh F, and Tazakl Y: Inhibitory action of carbon dioxide and acetazolamide in seizure activity. Electroenceph Clin Neurophysiol 1: (Aug-Dec) Brzezinski J, Kjallquist A, and Siesjo BK: Mean carbon dioxide tension in the brain after carbonic anhydrase inhibition. J Physiol (London) 188: 1- (Jan) Stroke, Vol. /, March-April 1970

Retinal vascular response to breathing increased carbon dioxide and oxygen concentrations. Regina Frayser and John B. Hickam

Retinal vascular response to breathing increased carbon dioxide and oxygen concentrations Regina Frayser and John B. Hickam The retina has a high rate of oxygen consumption, and the retinal vessels are