The Changes in Cerebral Vascular Resistance of Man in Experimental Alkalosis and Acidosis

THE CHANGES IN CEREBRAL VASCULAR RESISTANCE OF MAN IN EXPERIMENTAL ALKALOSIS AND ACIDOSIS

James F. Schieve, William P. Wilson

J Clin Invest. 1953;32(1):33-38. https://doi.org/10.1172/JCI102707.

Research Article

Find the latest version: https://jci.me/102707/pdf THE CHANGES IN CEREBRAL VASCULAR RESISTANCE OF MAN IN EXPERIMENTAL ALKALOSIS AND ACIDOSIS' By JAMES F. SCHIEVE 2 AND WILLIAM P. WILSON (From the Departments of Medicine and Psychiatry, Duke University School of Medicine, Durham, N. C.) (Submitted for publication July 3, 1952; accepted October 8, 1952) Available evidence suggests that cerebral vascu- spectively, were produced in man. The changes lar resistance in man is primarily under chemi- which occurred in CBF and cerebral vascular re- cal control. Past studies indicate that neurogenic sistance were noted and compared to the changes stimuli, hormonal influences and most drugs have previously reported after respiratory acidosis and little ability to dilate cerebral vessels significantly. alkalosis. The potent chemical regulators which dilate cere- METHOD bral vessels have been shown to be: 1) anoxia and The subjects studied were patients on the Medical Serv- 2) either CO2 retention or decrease in the pH of ice of Duke Hospital. They were convalescing from a arterial blood (1, 2). Using the nitrous oxide variety of illnesses and cannot be considered as a group of normal people. Six subj ects were patients at Butner technique, Kety found increased cerebral blood State Hospital. These patients were ill with schizo- flow (CBF) in subjects breathing 10 per cent 02. phrenia and presented no physical illnesses. Metabolic He also showed that the increased CBF of respira- alkalosis was produced by intravenous infusion of 1000 tory acidosis produced by breathing 5 per cent or ml. of 3 per cent NaHCO8 or 1000 ml. of 1.2 per cent 7 per cent CO2 was associated with increased CO2 NaHCOs over a period of sixty minutes. Metabolic acidosis was established by slower infusion of approxi- content and a lowered pH of arterial blood and mately 350 cc. of 0.8 per cent NHCl intravenously over decreased CBF of respiratory alkalosis following a period of 60 to 90 minutes. NH4Cl caused slight hy- hyperventilation with a lowered CO2 content and perpnea, and nausea occurred if the speed of the infusion elevated pH. was increased. Changes in pulse rate and blood pres- Because of a tendency to an increase in CBF sure did not occur if the drip rate was kept below the nausea threshold. in late stages of diabetic acidosis, it was suggested The effect of changes in blood volume was determined originally by Kety, Polis, Nadler, and Schmidt by administering 1000 ml. of 0.85 per cent NaCl solution (3) that the pH level might be more important intravenously over a period of one hour. The effects of than the CO2 content in regulation of cerebral both volume change and hypertonicity on the cerebral cir- vascular tone. This viewpoint has been stated culation were observed after the intravenous administra- by others (4, Some doubt this tion of 1000 ml. of 2 per cent NaCl solution over a period 5). about inter- of one hour. pretation is suggested by earlier findings of Bronk Cerebral blood flow (CBF) was measured, using the and Gesell (6). In 1927, they found that intra- nitrous oxide technique described by Kety and Schmidt venous injection of sodium carbonate and sodium (7) and modified by Scheinberg and Stead (8). Oxygen bicarbonate increased blood flow in the femoral differences in volume per cent (A-VO,) were determined and the carotid arteries of dogs under anesthesia. by the method of Hickam and Frayser (9) on the inte- grated arterial and cerebral venous blood specimens, re- The present study attempts to separate the ef- spectively, or on the arterial and venous blood samples fect on cerebral vessels of changes in pH and CO2 obtained immediately before and after the patient breathed content. By infusing NaHCO8 and NH4Cl in- NO. Cerebral metabolic rate of oxygen consumption travenously, metabolic alkalosis and acidosis, re- (CMRO,) in cubic centimeters of oxygen used per minute, per 100-grams of brain, was calculated by multiply- 1 This investigation was supported by the Life In- ing the rate of CBF in cc./min./100 gms. of brain by the surance Medical Research Fund (in part), by Air Force A-VO, differences in volumes per cent. Arterial blood Contract 33 (038)-27878 (in part), and by a research pH changes were determined anaerobically by a glass grant from the National Heart Institute, of the National electrode, using a Beckman pH meter, and the readings Institutes of Health, Public Health Service (in part). were corrected to 370 C. Arterial blood hemoglobin levels 2American Heart Association Research Fellow. Pres- were measured, using spectrophotometric methods. Blood ent adress: Department of Medicine, Ohio State Uni- pressure readings were made by the auscultatory method, versity, Columbus, Ohio. using a sphygmomanometer with the arm held at heart 33 34 JAMES F. SCHIEVE AND WILLIAM P. WILSON

TABLE I Effect of a 60-minute intravenous infusion of 1000 ml. of isotonic NaCZ (0.9%) in six subjects

Control *S.D. tS.E. Experiment S.D. S.E. p Value CBF 60 ±17 ±7 60 414 46 n.s. ml./min./100-grams brain A-V02 Difference 6.5 ±i1.3 ±.5 6.2 4.9±.4 n.s. vols. % CMRO2 3.7 ±.5 ±4.2 3.7 i.6 ±.2 n.s. ml. 02 used/min./100-grams brain CVR 1.7 ± 1 ±.6 1.6 4.8 4.5 n.s. (mean arterial BP/CBF) Arterial pH 7.36 ±.01 ±.005 7.35 ±.01 ±.005 n.s. units Arterial Hemoglobin 14.0 ±1.1 4.5 12.7 ±1 ±.5 .05 grams %

* Standard Deviation = S = N2_ (Zx)' t Standard Error = S N-i level. The mean arterial blood pressure was calculated this effect. Hemodilution of approximately the by adding one-third of the pulse pressure to the diastolic same magnitude occurred with both isotonic and blood pressure. In each study, the CBF was measured by the N20 tech- hypertonic saline, and neither changed pH sig- nique, both before and during infusions of NaHCO&, NaCl, nificantly. and NH4C1. In five instances after infusion of NaHCOa, and in one instance after infusion of NH4C1, the patient Metabolic alkalosis breathed 5 per cent CO, for four minutes. In these six instances, the changing A-VO, difference before and during Tables III and IV show the effect of intra- CO2 inhalation was measured. From the change in venous infusions of approximately 1000 ml. of A-VO2 difference, a third cerebral blood flow was esti- isotonic (1.2 per cent) and hypertonic (3 per cent mated utilizing the fact that during 5 per cent CO2 inhala- NaHCO8), respectively. Similar results occur in tion, CMRO, remains constant (2). both instances, but the changes are greater after RESULTS 3 per cent NaHCO3, suggesting a quantitative action of the bicarbonate ion. The increase in Control studies wsth saline blood flow with hypertonic NaHCO8 solution is The results recorded in Table I show that in- greater than that produced by hypertonic NaCl travenous infusion of 1000 ml. of isotonic (0.9 per solution. The sharp increase in CBF after 3 per cent) saline over sixty minutes has no effect on cent NaHCO3 is comparable to that found after CBF, or CMRO2, A-VO3 difference, or pH of inhalation of 5 per cent CO2. The increased CBF arterial blood. Significant decreases in hemo- after bicarbonate infusion is associated with an in- globin values occur, indicating a measurable decreased pH of arterial blood. The increased CBF gree of hemodilution. Table II shows the results after CO2 inhalation is associated with decreased in six patients after infusion of 1000 ml. of 2 per pH of arterial blood. cent NaCl. This is approximately isotonic with a Although CO2 tensions were not measured 3 per cent solution of NaHCO,. There is a 10 in the NaHCO3 infusion experiments reported per cent, but statistically insignificant, increase in here, other studies (10-12) suggest that after CBF. A significant narrowing in A-V02 differ- NaHCO3 infusion, the CO2 tension changes are ence does occur. This, combined with the direc- minimal, while changes in the bicarbonate ion tional change in cerebral blood flow, suggests that content are great. The absence of visible changes hypertonic saline solution does increase cerebral in respiratory rate and depth after NaHCO8 in- blood flow. We have no ready explanation for fusion also suggests little change in CO2 tension. CEREBRAL VASCULAR RESISTANCE IN ALKALOSIS AND ACIDOSIS 35

TABLE II Effect of a 60-minute intravenous infusion of 1000 ml. of hypertonic NaCi (2.0%) in seven subjects

Control S.D. S.E. Experiment S.b. S.E. D Value CBF 59 412 ±5 66 416 46 n.s. ml./min./100-grams brain A-V02 Difference 6.2 4.95 4.4 5.0 4.5 ±.2 .01 vols. % CMRO2 3.6 -.5 .2 3.3 +.8 4.3 n.s. ml. 02 used/min./100-grams brain CVR 1.5 ±.4 A.l 1.4 ±.A ±.2 n.s. (mean arterial BP/CBF) Arterial pH 7.35 ±.01 ±.007 7.33 ±.02 ±.01 n.s. units Arterial Hemoglobin 13.0 ±1.4 ±.6 11.5 41 J.4 .05 grams %

TABLE III Effects of a 60-minute intravenous infusion of 1000 ml. of isotonic NaHCOs (1.2%) in six subjects

Control S.D. S.E. Experiment S.D. S.E. p Value CBF 60 ±12 :15 78 :1:18 ±7 . to.05 ml./min./100-grams brain A-VO2 Difference 6.1 ±.8 ±.3 5.1 ±.7 i.3 .02 vols. % CMRO2 3.6 ±.6 ±.2 3.9 ±.5 ±.2 n.s. ml. 02 used/min./100-grams brain CVR 1.6 4.3 ±.05 1.2 ±.2 4.04 .05 (mean arterial BP/CBF) Arterial pH 7.39 ±:.01 ±.004 7.48 4.01 4±.005 .01 units Arterial Hemoglobin 12.3 ±.8 +.3 11.3 ±1.7 4.7 n.s. grams %

TABLE IV Effect of a 60-minute intravenous infusion of 1000 mn. of hypertonic NaHCO, (3%) in ten subjects

Control S.D. S.E. Experiment S.D. S.E. p Value CBF 52 ±11 ±3 88 ±15 ±5 .01 ml./min./100-grams brain A-VO2 Difference 6.9 41.4 ±.4 4.2 ±.7 ±.2 .01 vols. % CMRO2 3.6 41.1 ±.3 3.4 ±.8 4.3 n.s. ml. 02 used/min./100-grams brain CVR 1.8 ±.4 ±.1 1.1 ±.3 ±.1 .01 (mean arterial BP/CBF) Arterial pH 7.34 4.03 ±.01 7.52 ±.02 ±.006 .01 units Arterial Hemoglobin 13.6 ±1.3 ±.4 12.2 ±1.4 +.4 .02 grams % 36 JAMES F. SCHIEVE AND WILLIAM P. WILSON

TABLE V Efect of a 60 to 90-minute intravenous infusion of 350 cc. of NH4CI (0.8%) in sevn subjects

Control S.D. S.E. Experiment S.D. S.E. p Value CBF 66 ±12 45 52 4:8 43 .05 to .02 ml./min./100-grams brain A -V02 Difference 6.3 ±.5 4.2 8.6 ±.8 ±.3 .01 vols. % CMRO2 4.2 4.7 +.3 4.4 ±.5 ±.2 n.s. ml. 02 used/min./100-grams brain CVR 1.3 4.3 ±.1 1.6 4.5 4±.1 .01 (mean arterial BP/CBF) Arterial pH units 7.36 ±.014 ±.005 7.32 ±.016 ±.006 .05 C02content 50 ±3 ±1 46 1 .1 to.0 VOlS. % =3 Hemoglobin 13.0 42 ±.7 12.4 ±2 ±.6 n.s. grams %

p C02i548 -47 3 47 42 n.s. mm. Hg

Metabolic acidosis sis produced in some other fashion than by HN4C1 should be It In Table V are recorded the effects of the slow studied. is possible that we are really measuring, in part, the effects of NH4 ion infusion of 0.8 per cent NH4C1 on the cerebral rather than the uncomplicated effects of acidosis. circulation. There is a reduction in blood flow, the A-V02 difference widens greatly, and no Carbon dioxide inhalation in metabolic alkalosis change in CMRO2 occurs. There is a consistent and acidosis drop in arterial pH and serum CO2 content and very little change in CO2 tension. Thus, metabolic In Figures 1 and 2 are schematically drawn the acidosis, as produced by NH4C1 is accompanied by effect of CO2 when breathed by alkalotic and a reduction of CBF, in contrast to respiratory aci- acidotic subjects, respectively. When the sub- dosis in which CBF is increased. Metabolic acido- ject who is alkalotic from NaHCO5 breathes CO2, a sharp further increase in CBF occurs while pH Pa Ca2 Content returns toward, but does not quite reach, pre- CARTEIALOuODARTERIA L BLOOD bicarbonate levels. Similarly demonstrated, but ACIDOSIS in a reverse fashion, are the results in RESPIRATORY(ihalati°o CO2) 4t t (Figure 2) a metabolic acidotic subject who breathes CO2. Here, CBF increases above pre-ammonium chlo- RESPIRATORY ALKAILOSIS m 4' (blowing off CO) * ride levels while pH becomes even lower.

METABOLIC ALKALOSIS DISCUSSION (I.v. NAHC03) t Sodium bicarbonate increases cerebral flow by METABOLIC ACIDOSIS cerebral vascular resistance. NH4C1 (i.v. NH4CL) 4- 41 decreasing decreases cerebral blood flow by increasing cere- FIG. 1. THIS CHART SHOWS THE DIRECTIONAL bral vascular resistance. Earlier studies (2) have CHANGES IN CBF ARTERIAL PH AND ARTERIAL CO. shown that increased and decreased amounts of CONTENT AS FOUND BY KETY AND SCHMIDT IN RESPIRA- TORY ACIDOSIS AND ALKALOSIS AND BY THIS STUDY IN carbon dioxide in the arterial blood increase and METABOLIC ALKALOSIS AND ACIDOSIS decrease CBF, respectively. The summary chart CEREBRAL VASCULAR RESISTANCE IN ALKALOSIS AND ACIDOSIS 37 160 cerebral blood flow changes, no correlation exists. However, when one compares the directional changes in total CO2 content of arterial blood with 100 those of CBF, one finds complete correlation. CONCLUSIONS CBF 7.52 1. Metabolic alkalosis, as produced by giving 3 per cent NaHCO3 solution intravenously, increases CBF 65 per cent above resting normal 7.38 values; isotonic bicarbonate solution (1.2 per ______pH, 7.40 cent) causes a 30 per cent increase. 2. The increase in CBF after NaHCO8 is not primarily due to changes in intravascular volume because an equivalent degree of hemodilution NAHCO3 5% C0 2 produced by the infusion of isotonic NaCl solu- FIG. 2. SCHEMATICALLY DRAWN ARE THE CHANGES IN tion does not cause an increase in CBF. CBF AND PH OF ARTERIAL BLOOD BEFORE AND DURING THE 3. Infusion of 2 per cent NaCl solution does ADMINISTRATION OF 1000 ML. OF 3 PER CENT NaHCOs cause a demonstrable increase in CBF. It is not OVER A 60-MINUTE TIME PERIOD of the order of magnitude produced by the infu- At the second arrow, 5 per cent CO, was inhaled and the changes recorded occurred after four minutes. sion of an equally hypertonic solution of NaHCO8. 4. Intravenous infusion of 0.8 per cent NH4C1 (Figure 3) indicates by arrow the directional solution reduced CBF approximately 20 to 25 changes in CBF, pH and CO2 content which oc- per cent. cur in respiratory acidosis and alkalosis as de- 5. These studies, when coupled with previous scribed by Kety, and metabolic alkalosis and aci- studies of Kety, show that-in the absence of dosis as found in this study. When one compares anoxia-cerebral vascular tone is more closely re- the directional changes in arterial blood pH with lated to total CO2 content of arterial blood rather than arterial pH levels. 76 ACKNOWLEDGMENTS CBF 66 The authors are indebted to Dr. James P. Murdock, Superintendent, State Hospital, Butner, North Caro- 52 lina, for his invaluable cooperation. These studies were done with the technical assistance of Miss Melba Holder, Mrs. Mary Robertson and Mrs. Helen Rowe. PH.-7.36 7.32 REFERENCES 1. Kety, S. S., Circulation and metabolism of the human brain in health and disease. Am. J. Med., 7.28 1950, 8, 205. 2. Kety, S. S., and Schmidt, C. F., The effects of altered arterial tensions of carbon dioxide and oxygen on NH4C1 5% GC2 cerebral blood flow and cerebral oxygen consumption of normal young men. J. Clin. Invest., 1948, FIG. 3. SCHEMATICALLY DRAWN ARE THE CHANGES IN 27, 484. CBF AND PH OF ARTERIAL BLOOD BEFORE AND Arm IN- 3. Kety, S. S., Polis, B. D., Nadler, C. S., and Schmidt, TRAVENOUS INFUSION OF 0.8 PER CENT NH4EC OVER A C. F., The blood flow and oxygen consumption of PERIOD OF 60 To 90 MINUTES the human brain in diabetic acidosis and coma. J. At the second arrow 5 per cent CO. was inhaled and the Clin. Invest., 1948, 27, 500. changes recorded occurred after four minutes. 4. Patterson, J. L., Jr., Heyman, A., and Duke, T. W., 38 JAMES F. SCHIEVE AND WILLIAM P. WILSON

Cerebral circulation and metabolism in chronic flow, oxygen utilization, glucose utilization, and pulmonary emphysema. Am. J. Med., 1952, 12, peripheral resistance, with observations of the ef- 382. fect of tilting and anxiety. J. Clin. Invest., 1949, 5. Scheinberg, P., and Jayne, H. W., Factors influencing 28, 1163. cerebral blood flow and metabolism. A review. 9. Hickam, J. B., and Frayser, R., Spectrophotometric Circulation, 1952, 5, 225. determination of blood oxygen. J. Biol. Chem., 6. Bronk, D. W., and Gesell, R., The regulation of res- 1949, 180, 457. piration. X. Effects of carbon dioxide, sodium bi- 10. Davies, H. W., Haldane, J. B. S., and Kennaway, E. carbonate and sodium carbonate on the carotid and L., Experiments on the regulation of the blood's femoral flow of blood. Am. J. Physiol., 1927, 82, alkalinity. J. Physiol., 1920, 54, 32. 170. 11. Hooker, D. R., Wilson, D. W., and Connett, H., The 7. Kety, S. S., and Schmidt, C. F., The determination of perfusion of the mammalian medulla: The effect cerebral blood flow in man by the use of nitrous of carbon dioxide and other substances on the res- oxide in low concentrations. Am. J. Physiol., 1945, piratory and cardio-vascular centers. Am. J. 143, 53. Physiol., 1917, 43, 351. 8. Scheinberg, P., and Stead, E. A., Jr., The cerebral 12. Scott, R. W., The significance of undissociated carbon blood flow in male subjects as measured by the dioxide in respiration. Am. J. Physiol., 1918, nitrous oxide technique. Normal values for blood 47, 43.