- Email: [email protected]
Atropine, norepinephrine, and isoproterenol and the cardiac response to experimental lactic acidosis
Atropine, Isoproterenol
Norepinephrine,
and the Cardiac Response to
Experimental LOUIS L.
SMITH,
Lactic Acidosis*
M.D., MARTIN SILBERSCHMID,M.D., AND DAVID B. HINSHAW, M.D.,
Loma Linda,
California
tized with intravenous sodium pentobarbital; no additional anesthesia was administered after this induction. A small polyethylene catheter was inserted into a forepaw vein for the constant infusion of succinylcholine in a dose of 0.03 mg./kg./min. in order to paralyze respiration. A cuffed endotracheal tube was placed into the trachea and attached to a Harvard@ respirator. Oxygen was introduced into the air intake valve of the respirator at a flow rate of 1.5 L./min. using a small catheter in order to insure adequate oxygenation. The respirator stroke rate and volume were adjusted during an initial one to two hour interval to establish baseline pH and blood gas values within normal limits. A Beckman@ LB-l Medical Gas Analyzer was employed to monitor the expired COZ content and to serve as a guide in adjusting the respiratory rate and volume to maintain a normal blood pCOn. The usual respirator volume was 12 ml./kg. of body weight and the rate was fourteen strokes per minute. -4 small midline incision was made for the ligation of both ureters. Body temperature was measured by a Yellow Springs@ telethermometer probe.which was placed into the peritoneal cavity through the aforementioned incision. All animals received 1 mg./kg. of body weight of heparin for anticoagulation. Hemodynamic Observations. The right femoral artery was cannulated with a polyethylene catheter and attached to a high pressure Sanborn@ transducer for monitoring the arterial pressure. The superior vena cava was likewise cannulated via the external jugular vein for the measurement of central venous pressure using a Sanborn low pressure transducer. A polyethylene catheter was placed into the right femoral vein for the subsequent infusion of lactic acid, and the left femoral vessels were cannulated for the measurement of cardiac output by the indi-
From the Department of Surgery, Loma Linda Unioersity, Loma Linda, California 92354. This study was supported by U.S.P.H.S. GraEnt No. HE 04639 (National Heart Institute) and Grant AM 06020 (National Institute of Arthritis and Metabolic Diseases).
E
and
XPERIMENTAL and clinical observations in-
dicate an adverse effect of metabolic acidosis on myocardial function [l-3]. We observed in a previous study that acute addition lactic acidosis causes marked cardiac slowing, sinus arrhythmia, sinus pauses, and occasional sinus arrest in dogs [3]. In addition there was a slight decrease in arterial pressure, a marked reduction in cardiac output, and a progressive rise in the central venous pressure and peripheral resistance. The decrease in cardiac rate and cardiac arrhythmia after acidosis suggested increased vagal activity. The studies reported herein were designed to clarify the role of vagal innervation on the circulatory response to lactic acidosis. Furthermore, the hemodynamic effects of the beta adrenergic agent, isoproterenol, were observed and compared to those resulting from the infusion of norepinephrine. It was hoped that a more effective treatment program could be devised for the management of circulatory failure associated with acute lactic acidosis. MATERIAL AND
METHODS
Thirty-four adult mongrel dogs were used in this study and all experiments were performed in an air conditioned laboratory with an ambient temperature of 21 to 23”~. All animals were lightly anesthe-
* Presented at the Thirty-Eighth Annual Meeting of the Pacific Coast Surgical Association, Monterey, California, February 19-22, 1967. Vol. 114, August
1967
267
Smith, Silberschmid, and Hinshaw
268
TABLE EXPERIMENTAL
Bilateral
Cervical
Base Line
Arterial pressure (mm. Hg) Cardiac output (ml.) Peripheral resistance (units) Central venous pressure (mm. Hg) Cardiac rate (beats/min.)
143 2438 3.7 0.9 181
Atropine
Arterial pressure (mm. Hg) Cardiac output (ml.) Peripheral resistance (units) Central venous pressure (mm. Hg) Heart rate (beats/min.)
Vagotomy-Mean
145 2172 4.7 0.0 176
183 1453 7.6 6.7 103
Post Acidosis
158 1639 6.8 1.4 107
cator dilution principle as previously described by Smith, Foster, and Muller [4] using 1131 Hippuran as the indicator tag. Total peripheral resistance (TPR) was calculated as resistance units from cardiac output (CO) and the blood pressure (BP) using the formula: TPR
=
ACIDOSIS Values
BP in mm. Hg X 60 CO in ml. per minute
Electrocardiograms were taken from the standard limb lead II. These tracings and the pressure measurements were recorded visually on a Sanborn 150 recorder. Hematocrit determinations were made in duplicate using an International@ microcentrifuge. Blood Gas and Biochemical Observations. The pH, pCOz, and pOz were measured by appropriate electrodes and corrected to the temperature of the animal as previously described by Veragut and Smith [S]. Base-line observations Experimental Protocol. were obtained after which acute lactic acidosis was induced by the infusion of 1 molar lactic acid in saline solution. This solution was administered with a Model TM 202 Sigmamotor@ constant infusion pump at the rate of 4 ml./kg./hr. for a total of four hours. PH and blood gas analyses were obtained at hourly intervals to monitor the response to the lactic acid infusion. The rate of infusion was slowed if the pH fell below 7.10 and the infusion rate was adjusted thereafter to maintain a stable pH at as near 7.00 as possible. Experimental observations were made in duplicate after the induction of acidosis. There were four experimental groups: those with bilateral cervical vagotomy (Group I) ; atropine administration (Group II) ; norepinephrine infusion (Group III) ; and isoproterenol infusion (Group IV). All animals were made acidotic as described previously.
in Three
Dogs Minutes
Post Acidosis
Administration-Mean
Base Line
I
LACTIC
30
60
90
120
202 1336 9.4 5.5 138
201 1439 8.8 4.9 143
197 1198 9.9 2.9 142
190 1112 IO.6 2.5 137
Values
in Eight
Dogs
Minutes 30
60
152 1577 6.8 1.5 130
145 1560 7.2 1.5 128
90
144 1526 7.3 1.4 123
120
149 1527 7.2 1.6 125
Bilateral cervical vagotomy (group I, 3 dogs) : After the induction of lactic acidosis and the obtaining of experimental observations, the main vagal nerve trunks were sectioned through a small incision at the base of the neck. Thereafter, hemodynamic blood gas and pH measurements were made at thirty, sixty, ninety, and 120 minute intervals. Final observations were obtained at the completion of the experiment. Atropine administration (group II, 8 dogs): After induction of lactic acidosis and the obtaining of experimental observations, atropine sulfate 1 mg./ 17.5 kg. of body weight was administered intravenously in a single dose. Hemodynamic, pH, and blood gas measurements were made thirty, sixty, ninety, and 120 minutes after atropine administration. Final biochemical observations were made at the completion of the experiment. Norepinephrine infusion (group III, 7 dogs) : These animals received a control infusion of norepinephrine after base-line observations were obtained. A constant infusion of norepinephrine in a 5 per cent solution of dextrose in water was administered by a Harvard infusion pump over a thirty minute period of time. Two dosages were employed, 2.5 gamma/ kg./min. in three animals, and 5 gamma/kg./min. in an additional four dogs. Hemodynamic, pH, and blood gas observations were made at ten and thirty minutes. Acidosis was induced and maintained as outlined previously, after which duplicate observations were made. Thereafter the infusion of norepinephrine was repeated with sampling at ten, thirty, ninety, and 120 minutes. Final biochemical observations were made at the completion of the experiment. Isoproterenol infusion (group xv, 16 dogs): The experimental protocol for this group was identical to that described for group III, except that isoproAmerican
Journal of Surgery
Experimental Lactic Acidosis
269
TABLEII EXPERIMENTAL
Norepinephrine
Base Line
Arterial pressure (mm. Hg) Cardiac output (ml.) Peripheral resistance (units) Central wnous pressure (mm. Cardiac rate (beats/min.) PH pCOt (mm. Hg) ~0% (mm. Hg)
(5y/kg./min.)-Mean
Control 10 Min.
Infusion 30 Min.
150 1810 5.3 1.1 166 7.42 39.5 129
205 2692 4.4 3.1 169 7.35 43 130
176 2518 4.1 2.6 164 7.34 40 122
Isoproterenol
Infusion
(lO~/kg./hr.)-Mean
Hg)
Base Line
Arterial pressure (mm. Hg) cardiac output (ml.) Peripheral resistance (units) Central venous pressure (mm. Cardiac rate (beats/ruin.) PH pCOz (mm. Hg) poz (mm. Hg)
Infusion
Hg)
158 2019 5.5 1.2 167 7.40 39 126
Control 10 Min.
156 2871 3.3 2.5 178 7.36 38 137
in Four Dogs
Post Acidosis
10 Min.
Post Acidosis Infusion 30 Min. 60 Min.
90 Min.
157 1407 7.7 2.5 121 7.07 43 132
195 1476 77.6 2.6 111 7.06 46 134
182 1333 8.3 2.4 115 7.06 44.5 128
158 867 10.4 2.2 117 7.01 43 135
Values
in Nine
10 Min.
154 2940 3.3 4.1 169 7.37 37 114
169 1329 7.6 2.0 107 7.06 42 116
158 2251 4.5 0.8 133 7.05 43 113
Bilateral Cervical Vagotomy (Group I). The mean values for the systemic hemodynamics in this group are shown in Table I. It will be noted that one hour after vagotomy the arterial pressure had increased by 17 per cent and the rate had risen 40 per cent. The latter change was statistically significant (p
Value
Post Acidosis
RESULTS
August
ACIDOSIS
Infusion 30 Min.
terenol in a dose of 2 gamma/kg./hr. in normal saline solution was infused into seven dogs. This dose was increased to 10 gamma/kg./hr. in an additional nine animals.
Vol. 114,
LACTIC
167 1017 11.7 2.0 125 7.00 49.5 125
Dogs
Post Acidosis Infusion 30 Min. 60 Min.
152 2573 3.7 0.8 141 7.03 44 115
157 2424 4.1 1.1 146 7.03 43 122
90 Min.
153 1979 4.9 0.7 142 7.03 43 120
the period of the acidosis and blood gas values were within normal limits throughout the experiment. Norepinephrine Infusion (Group III). This drug was infused into three acidotic dogs in a dose of 2.5 gamma/kg./min. The effect on blood pressure, cardiac output, and cardiac rate was minimal when the infusion was made during acidosis. Therefore, the dose of norepinephrine was increased to 5 gamma/kg./min. with the following findings. Infusion of this larger dose during the control period prior to acidosis caused a 17 per cent increase in the arterial pressure by thirty minutes. This change was not significant (p
270
Smith, Silberschmid,
values for the systemic hemodynamics in this group. The pH ranged between 7.00 and 7.06 during the period of noradrenaline infusion. The pCOz showed minimal elevation and the pOz was within normal limits. In two dogs bigeminy developed during the control infusion and in one animal a second degree A-V block developed when noradrenaline was infused after acidosis. Isoproterenol Infusion (Group IV). This drug was initially infused in a dose of 2 gamma/ kg./hr. to a group of seven dogs prior to and after the induction of acidosis. It was observed that isoproterenol increased cardiac output in both the normal and acidotic environment without increasing arterial or central venous pressures. Peripheral resistance was decreased. It was believed that a larger dose might effect hemodynamic changes which would be more significant. Therefore, isoproterenol was infused in a dose of 10 gamma/kg./hr. to an additional nine animals prior to and after the induction of acidosis. The changes observed in the systemic hemodynamics are shown in Table II. It will be noted that the response observed during the control period was similar to that observed after acidosis. Isoproterenol infusion after acidosis caused a 10 per cent fall in the arterial pressure. This change was not significant (p
This experimental study indicates that the cardiac slowing and arrhythmia observed after the induction of experimental lactic acidosis is due in part to increased vagal activity since both vagotomy and atropine in large dosages increase cardiac rate and restore normal cardiac rhythm.
and Hinshaw The failure of vagotomy and atropine to increase cardiac output is perplexing in view of the experimental effects of vagal stimulation on cardiac function. Sarnoff and associates [6] observed that vagal nerve stimulation exerts a profound depressant effect on the strength of the atria1 contraction and thereby can influence ventricular filling and ventricular stroke work. The administration of atropine blocked the effect of vagal stimulation on the atrium. DeGeest et al. [7] have presented experimental evidence indicating that efferent vagal stimulation exerts a potent, negative inotropit influence upon the ventricular myocardium. Apparently other autonomic or humeral mediators depressed myocardial function and prevented an increase in cardiac output after vagotomy or atropine administration. In an effort to improve cardiac output, and to increase the cardiac rate during acidosis, we employed the potent beta adrenergic agent, isoproterenol. It was thought that the chronatropic and positive inotropic effect of this drug might prove to be beneficial in improving circulation after the induction of lactic acidosis. A modest effect on cardiac rate and output was observed with small doses of isoproterenol, although when the dose was increased, there was an excellent response to its use after the induction of acidosis. By contrast, norepinephrine did not improve either cardiac rate or cardiac output when infused during acidosis. The failure of norepinephrine to effect an increase in blood pressure, cardiac output, and cardiac rate in the acidotic animal was not unexpected. Darby et al. [S] infused lactic acid into dogs and observed a diminution in response as measured by arterial pressure and ventricular contractile force as the acidosis became more severe. At pH values below 7.0, both epinephrine and norepinephrine usually failed to produce a response. These authors observed that shortly after the period of complete refractoriness was reached, cardiovascular collapse and death occurred, Campbell and associates [9] have also reported a depressed response to intravenous sympathomimetic agents in man during acidosis. Isoproterenol has several actions which make it a desirable agent to employ in low perfusion states associated with cardiac failure. It has a mild peripheral vasodilating effect, thus tending to decrease peripheral resistance. It supports venous return to the heart by its venoconstrictAmerican
Journal
of Suwery
Experimental ing effect. Cardiac output is increased due to its positive inotropic effect on the myocardium. The tendency for this drug to increase cardiac rate is desirable in those patients having cardiac slowing as a result of increased vagal activity. The beneficial effects of isoproterenol were present when this agent was infused, even during severe acidosis. It caused a slight fall in arterial pressure, a marked increase in cardiac output, a fall in peripheral resistance and central venous pressure, as well as an increase in heart rate. Furthermore, this response could be maintained for a prolonged period of time despite the presence of a blood pH below 7.06. The acidosis employed in this study resulted from the addition of hydrogen ions into the extracellular fluid. Therefore, it is reasonable to assume that the intracellular acidosis was not as severe. Furthermore, at no time was the animal’s cell mass subjected to a period of hypoxia such as would occur during a low perfusion state. It is interesting to speculate whether or not a metabolic acidosis produced as a result of cellular hypoxia might have been associated with a greater impairment of myocardial function, and therefore a diminished response to the drugs employed in these experiments. The role of increased vagal activity in the production of cardiac rhythm disorders and cardiac arrest during acidosis has been reported by several authors [1U-121. The importance of vagal imbalance during acidosis thus assumes additional clinical importance. Recently, Gerst, Fleming, and Malm [13] have observed increased susceptibility to ventricular fibrillation during metabolic acidosis as indicated by a decrease in the ventricular fibrillation threshold value. The changes in cardiac rhythmicity and function which occur in an acid environment lend importance to the prompt recognition and treatment of this metabolic disorder in the patient with a low perfusion syndrome whether due to temporary cardiac failure or refractory shock. Treatment should first be directed toward correcting the cause for the low perfusion state; thereafter, attention should be focused on the diagnosis and vigorous treatment of metabolic acidosis should this be present, by the administration of appropriate alkalinizing solutions. The myocardium will thereby by placed in a more favorable setting for function and the threat of arrhythmia diminished. Vol. 114,
Aumst
I967
Lactic
Acidosis
271 SUMMARY
Acute addition lactic acidosis causes marked cardiac slowing, decreased cardiac output, and a progressive rise in the central venous pressure in the dog, suggesting increased vagal activity as well as decreased myocardial function. Bilateral cervical vagotomy and atropine in large dosages were employed to evaluate the role of vagal innervation in producing bradycardia and rhythm changes during acute lactic acidosis. These experimental procedures increased cardiac rate but did not improve cardiac output after the induction of lactic acidosis. Isoproterenol was compared with norepinephrine as a therapeutic agent to improve myocardial function during acidosis. Norepinephrine administration increased arterial pressure by 16 per cent, but did not improve cardiac output or cardiac rate when infused during acidosis. By contrast, isoproterenol caused a 10 per cent fall in arterial pressure, a 93.5 per cent increase in the cardiac output, and a 32 per cent increase in cardiac rate. These experimental findings suggest that increased vagal activity is a cause for the bradycardia and rhythm changes observed during acute lactic acidosis. Isoproterenol was an effective therapeutic agent to improve cardiac output, decrease peripheral resistance, and increase cardiac rate during severe acidosis. The application of these findings to the management of low perfusion states has been discussed. REFERENCES 1. CLOWES, G. H. A., JR., SABGA, G. A., KONITAXIS, A., TOMIN, R., HUGHES, M., and SIMEONE, F. A. Effects of acidosis on cardiovascular function in surgical patients. Ann. Surg., 154: 524, 1961. 2. THROWER, W. B., DARBY, T. D., and ALDINCER, E. E. Acidbase derangements and myocardial contractility. Arch. Surg., 82: 56, 1961. 3. SILBERSCHMID, M., SAITO, S., and SMITH, L. L. Circulatory effects of acute lactic acidosis in dogs prior to and after hemorrhage. Am. J. .Surg., 112: 175, 1966. 4. SMITH, L. L., FOSTER, R. L., and MULLER, W. Intrinsic cardiac output variability in the anesthetized normal and splenectomized dog. Am. J. Physiol., 202: 1155, 1962. 5. VERAGUT, U. P. and SMITH, L. L. Circulatory changes during prolonged respiratory acidosis in normal and hemorrhaged dogs. Surg. Gynec. b Obst., 119: 513, 1964. 6. SARNOPF, S. J., BROCKMAN,S. K., GILMORE, J. P., LINDEN, R. J., and MITCHELL, J. H. Regulation of ventricular contraction: influence of cardiac
272
7.
8.
9.
10.
11.
12.
13.
Smith, Silberschmid, and Hinshaw
sympathetic and vagal nerve stimulation on atria1 and ventricular dynamics. Circulation Res., 8: 1108, 1960. DEGEEST, H., LEVY, M. N., ZIESKE, H. and LIPMAN, R. I. Depression of ventricular contractility by stimulation of the vagus nerves. Circulation lies., 17 : 222, 1965. DARBY, T. D., ALDINGER, E. E., GADSDEN, R. H., and THROWER, W. B. Effects of metabolic acidosis on ventricular isometric systolic tension and the response to epinephrine and levarterenol. Circulation lies., 8: 1242, 1960. CAMPBELL, G. S., HOULE, D. B., CRISP, N. W., WEIL, M. H., and BROWN, E. G. Depressed response to intravenous sympathomimetic agents in humans during acidosis. Dis. Chest, 33: 18, 1958. CAMPBELL, G. S. Cardiac arrest: further studies on the effect of pH changes on vagal inhibition of the heart. Surgery, 38: 615, 1955. SLOAN, H. E. The vagus nerve in cardiac arrest: the effect of hypercapnia, hypoxia and asphyxia on reflex inhibition of the heart. Surg. Gynec. 6r Obst., 91: 257, 1950. YOUNG, W. G., JR., SEALY, W. C., HARRIS, J., and BOTWIN, A. The effects of hypercapnia and hypoxia on the response of the heart to vagal stimulation. Surg. Gynec. b Obst., 93: 51, 1951. GERST, P. H., FLEMING, W. H., and MALM, J. R. Increased susceptibility of the heart to ventricular fibrillation during metabolic acidosis. Circulation, 19: 63, 1966. DISCUSSION
JOHN E. CONNOLLY (Los Angeles, Calif.): I am in agreement with the findings and conclusions of these authors’ careful laboratory studies which emphasize the advantages of isoproterenol and the disadvantages in certain instances of norepinephrine. Isoproterenol not only acts directly on the heart, but it also causes peripheral vasodilatation, which diminishes the resistance to cardiac work. Dr. Stemmer, working in our laboratory, has measured the carotid and femoral blood flows with flowmeters, along with cardiac output and blood pressures. Ephedrine caused a prolonged elevation of the blood pressure and an initial elevation of carotid blood flow, followed by a sustained depression in carotid flow. Levophed@ produced a momentary ride in the femoral and carotid flows, followed by a sustained depression, while the peripheral pressure gradually returned to base line. Isoproterenol produced an initial slight depression of carotid flow, followed by a rise of the blood pressure. The conclusions, from both the studies of Dr. Smith and Dr. Stemmer and their associates, are that there are hazards clinically in the use of ephedrine, Levophed and Neo-Synephrine@, if adequate peripheral and carotid blood flows are to be main-
tained. A small dose of one of these agents may be given initially to a patient in shock until the blood pressure is raised, at which time isoproterenol therapy should be instituted. The build up of CO2 improves carotid arterial flow and adequate cerebral perfusion. Isoproterenol is useful in virtually all types of cardiac disease except in some instances of stenotic coronary artery disease. Low cardiac output after surgical procedures will result in acidosis. In trying to treat the acidosis we are not getting at the basic problem; this is where isoproterenol may be very effective in reversing the situation, along with the bicarbonate or THAM. In the absence of a normal circulating blood volume, isoproterenol can depress the blood pressure to very hazardous levels; consequently, the circulating blood volume must be restored before the drug is used. ALFRED GOLDMAN (Beverly Hills, Calif.): We have been interested in circulatory assist for shock. There might well be a place for small doses of norepinephrine, as Dr. Connolly just suggested, and from some of our data this use of norepinephrine shows marked increases not only in pressure but also in flow parameters. We measured flow with electromagnetic pulsatile flowmeters around carotid, coronary, pulmonary, mesenteric, and renal arteries and then used circulatory assist in the form of venoarterial phased pulsatile partial bypass (VAPPPB) after producing ventricular fibrillation by ligation of the circumflex coronary artery. The effect of a small dose of norepinephrine in a continuous drip on these regional flows, together with circulatory assist pumping is shown during ventricular fibrillation. Here a rise from 8.3 cc. to 19 cc. per minute in the left anterior descending coronary artery, more than 100 per cent in the coronary flow, occurred with the institution of the instillation of norepinephrine. At times we have seen a marked increase in mesenteric, renal, and carotid flows when we add norepinephrine. After defibrillation such regional flows are maintained. The pressure parameters are increased very markedly with only the pumping and restoration of the sinus rhythm; in one instance the systolic pressure was 44 mid-diastolically, but was increased to 80 with the instillation of norepinephrine. Consequently, we cannot say altogether that norepinephrine is a totally bad drug to use in such catastrophic states, since it increased vital regional flows with VAPPPB. Ross ROBERTSON (Vancouver, B. C.): Dr. Smith and his co-workers are to be congratulated on the clearest and most concise presentation of experimental data that I have ever heard. I am most interested in his results, because for some years we have been using Isuprel@ clinically, and have found that it is the only effective drug for the treatment of American
Jorwnal
of Swgery
Experimental Lactic Acidosis acute myocardial failure. Isuprel must be given with great caution in a concentration of 1 in 200,000 with a minidrip. The minidrip may be flowing at from six to thirty drops per minute. It must be regulated with great care for otherwise there is a very rapid increase in cardiac rate. We have found Isuprel to be of great benefit. It increases the urinary as well as the cardiac output. The venous pressure must be watched carefully for with the dilatation of the peripheral vessels a rapid increase in blood volume may be required. BENSON B. ROE (San Francisco, Calif.) : Two very important clinical inferences can be drawn from this excellent experimental study. First, we may infer that blood pressure should be eliminated as an index of adequate perfusion. We have seen patients whose blood pressures were nearly at normal levels a few minutes before they died as a result of inadequate perfusion; this paper demonstrates very well that flow is not related to pressure. Secondly, acidosis, although somewhat depressing to cardiac output, is not as devastating as has been inferred by many. The hazard of overtreatment is significant. Blood gas studies on patients given sodium bicarbonate after cardiac arrest or depression have revealed the presence of severe alkalosis. Consequent hypokalemia can produce ventricular fibrillation. WILEY F. BARKER (Los Angeles, Calif.) : There is one other point implied, which should be stressed, concerning the variability of effect depending upon the dose. I first learned in a nonclinical situation many years ago that growth hormones in plants would either stimulate or repress the development of roots in Concord grape cuttings, depending on a change of concentration from one to one hundred parts per million. Several years ago we were studying animals subjected to standard amounts of bleeding in which renal blood flow fell acutely. If one were to use
Vol. 114, Auzust 1967
273
norepinephrine, Neo-Synephrine, or Aramine@’ to restore blood pressure to the expected normal level for that animal, one could completely stop all renal blood flow (as measured by a flowmeter). If, however, one carefully titrated the dose of vasopressor, one could achieve a very modest increase in peripheral arterial pressure and at the same time achieve a modest increase in renal blood flow. I believe that there is in the several organs a differential sensitivity to many of these vasoactive agents, and that we must be aware of this and not be misled by response to one given dosage. LOUIS L. SMITH (closing): In answer to Dr. Goldman, we agree that there is a difference in the experimental model used in this study and the clinical setting observed in shock in that there was no cellular hypoxia. In our studies on animals we observed the specific hemodynamic effects of a fixed acid load on the cardiovascular response prior to and after certain treatments. We agree also that arterial pressure is an inadequate gauge of low perfusion syndrome and myocardial function. The dosage of isoproterenol is important and in our studies it was large. No adverse effect with this agent was seen whereas larger dose of norepinephrine occasionally resulted in bigeminy and second degree heart block. Blood volume must be adequately replaced. Again we rely on the measurement of vital signs, including central venous pressure, serial hematocrits, and urine output as a gauge of blood volume replacement, rather than relying on a single measured blood volume value. Low perfusion states and/or refractory shock are very complex clinical problems and one must treat the specific causes for this condition. This study shows that metabolic acidosis is another defect which can be treated and which will improve the cardiovascular function in these patients.
Norepinephrine,
and the Cardiac Response to
Experimental LOUIS L.
SMITH,
Lactic Acidosis*
M.D., MARTIN SILBERSCHMID,M.D., AND DAVID B. HINSHAW, M.D.,
Loma Linda,
California
tized with intravenous sodium pentobarbital; no additional anesthesia was administered after this induction. A small polyethylene catheter was inserted into a forepaw vein for the constant infusion of succinylcholine in a dose of 0.03 mg./kg./min. in order to paralyze respiration. A cuffed endotracheal tube was placed into the trachea and attached to a Harvard@ respirator. Oxygen was introduced into the air intake valve of the respirator at a flow rate of 1.5 L./min. using a small catheter in order to insure adequate oxygenation. The respirator stroke rate and volume were adjusted during an initial one to two hour interval to establish baseline pH and blood gas values within normal limits. A Beckman@ LB-l Medical Gas Analyzer was employed to monitor the expired COZ content and to serve as a guide in adjusting the respiratory rate and volume to maintain a normal blood pCOn. The usual respirator volume was 12 ml./kg. of body weight and the rate was fourteen strokes per minute. -4 small midline incision was made for the ligation of both ureters. Body temperature was measured by a Yellow Springs@ telethermometer probe.which was placed into the peritoneal cavity through the aforementioned incision. All animals received 1 mg./kg. of body weight of heparin for anticoagulation. Hemodynamic Observations. The right femoral artery was cannulated with a polyethylene catheter and attached to a high pressure Sanborn@ transducer for monitoring the arterial pressure. The superior vena cava was likewise cannulated via the external jugular vein for the measurement of central venous pressure using a Sanborn low pressure transducer. A polyethylene catheter was placed into the right femoral vein for the subsequent infusion of lactic acid, and the left femoral vessels were cannulated for the measurement of cardiac output by the indi-
From the Department of Surgery, Loma Linda Unioersity, Loma Linda, California 92354. This study was supported by U.S.P.H.S. GraEnt No. HE 04639 (National Heart Institute) and Grant AM 06020 (National Institute of Arthritis and Metabolic Diseases).
E
and
XPERIMENTAL and clinical observations in-
dicate an adverse effect of metabolic acidosis on myocardial function [l-3]. We observed in a previous study that acute addition lactic acidosis causes marked cardiac slowing, sinus arrhythmia, sinus pauses, and occasional sinus arrest in dogs [3]. In addition there was a slight decrease in arterial pressure, a marked reduction in cardiac output, and a progressive rise in the central venous pressure and peripheral resistance. The decrease in cardiac rate and cardiac arrhythmia after acidosis suggested increased vagal activity. The studies reported herein were designed to clarify the role of vagal innervation on the circulatory response to lactic acidosis. Furthermore, the hemodynamic effects of the beta adrenergic agent, isoproterenol, were observed and compared to those resulting from the infusion of norepinephrine. It was hoped that a more effective treatment program could be devised for the management of circulatory failure associated with acute lactic acidosis. MATERIAL AND
METHODS
Thirty-four adult mongrel dogs were used in this study and all experiments were performed in an air conditioned laboratory with an ambient temperature of 21 to 23”~. All animals were lightly anesthe-
* Presented at the Thirty-Eighth Annual Meeting of the Pacific Coast Surgical Association, Monterey, California, February 19-22, 1967. Vol. 114, August
1967
267
Smith, Silberschmid, and Hinshaw
268
TABLE EXPERIMENTAL
Bilateral
Cervical
Base Line
Arterial pressure (mm. Hg) Cardiac output (ml.) Peripheral resistance (units) Central venous pressure (mm. Hg) Cardiac rate (beats/min.)
143 2438 3.7 0.9 181
Atropine
Arterial pressure (mm. Hg) Cardiac output (ml.) Peripheral resistance (units) Central venous pressure (mm. Hg) Heart rate (beats/min.)
Vagotomy-Mean
145 2172 4.7 0.0 176
183 1453 7.6 6.7 103
Post Acidosis
158 1639 6.8 1.4 107
cator dilution principle as previously described by Smith, Foster, and Muller [4] using 1131 Hippuran as the indicator tag. Total peripheral resistance (TPR) was calculated as resistance units from cardiac output (CO) and the blood pressure (BP) using the formula: TPR
=
ACIDOSIS Values
BP in mm. Hg X 60 CO in ml. per minute
Electrocardiograms were taken from the standard limb lead II. These tracings and the pressure measurements were recorded visually on a Sanborn 150 recorder. Hematocrit determinations were made in duplicate using an International@ microcentrifuge. Blood Gas and Biochemical Observations. The pH, pCOz, and pOz were measured by appropriate electrodes and corrected to the temperature of the animal as previously described by Veragut and Smith [S]. Base-line observations Experimental Protocol. were obtained after which acute lactic acidosis was induced by the infusion of 1 molar lactic acid in saline solution. This solution was administered with a Model TM 202 Sigmamotor@ constant infusion pump at the rate of 4 ml./kg./hr. for a total of four hours. PH and blood gas analyses were obtained at hourly intervals to monitor the response to the lactic acid infusion. The rate of infusion was slowed if the pH fell below 7.10 and the infusion rate was adjusted thereafter to maintain a stable pH at as near 7.00 as possible. Experimental observations were made in duplicate after the induction of acidosis. There were four experimental groups: those with bilateral cervical vagotomy (Group I) ; atropine administration (Group II) ; norepinephrine infusion (Group III) ; and isoproterenol infusion (Group IV). All animals were made acidotic as described previously.
in Three
Dogs Minutes
Post Acidosis
Administration-Mean
Base Line
I
LACTIC
30
60
90
120
202 1336 9.4 5.5 138
201 1439 8.8 4.9 143
197 1198 9.9 2.9 142
190 1112 IO.6 2.5 137
Values
in Eight
Dogs
Minutes 30
60
152 1577 6.8 1.5 130
145 1560 7.2 1.5 128
90
144 1526 7.3 1.4 123
120
149 1527 7.2 1.6 125
Bilateral cervical vagotomy (group I, 3 dogs) : After the induction of lactic acidosis and the obtaining of experimental observations, the main vagal nerve trunks were sectioned through a small incision at the base of the neck. Thereafter, hemodynamic blood gas and pH measurements were made at thirty, sixty, ninety, and 120 minute intervals. Final observations were obtained at the completion of the experiment. Atropine administration (group II, 8 dogs): After induction of lactic acidosis and the obtaining of experimental observations, atropine sulfate 1 mg./ 17.5 kg. of body weight was administered intravenously in a single dose. Hemodynamic, pH, and blood gas measurements were made thirty, sixty, ninety, and 120 minutes after atropine administration. Final biochemical observations were made at the completion of the experiment. Norepinephrine infusion (group III, 7 dogs) : These animals received a control infusion of norepinephrine after base-line observations were obtained. A constant infusion of norepinephrine in a 5 per cent solution of dextrose in water was administered by a Harvard infusion pump over a thirty minute period of time. Two dosages were employed, 2.5 gamma/ kg./min. in three animals, and 5 gamma/kg./min. in an additional four dogs. Hemodynamic, pH, and blood gas observations were made at ten and thirty minutes. Acidosis was induced and maintained as outlined previously, after which duplicate observations were made. Thereafter the infusion of norepinephrine was repeated with sampling at ten, thirty, ninety, and 120 minutes. Final biochemical observations were made at the completion of the experiment. Isoproterenol infusion (group xv, 16 dogs): The experimental protocol for this group was identical to that described for group III, except that isoproAmerican
Journal of Surgery
Experimental Lactic Acidosis
269
TABLEII EXPERIMENTAL
Norepinephrine
Base Line
Arterial pressure (mm. Hg) Cardiac output (ml.) Peripheral resistance (units) Central wnous pressure (mm. Cardiac rate (beats/min.) PH pCOt (mm. Hg) ~0% (mm. Hg)
(5y/kg./min.)-Mean
Control 10 Min.
Infusion 30 Min.
150 1810 5.3 1.1 166 7.42 39.5 129
205 2692 4.4 3.1 169 7.35 43 130
176 2518 4.1 2.6 164 7.34 40 122
Isoproterenol
Infusion
(lO~/kg./hr.)-Mean
Hg)
Base Line
Arterial pressure (mm. Hg) cardiac output (ml.) Peripheral resistance (units) Central venous pressure (mm. Cardiac rate (beats/ruin.) PH pCOz (mm. Hg) poz (mm. Hg)
Infusion
Hg)
158 2019 5.5 1.2 167 7.40 39 126
Control 10 Min.
156 2871 3.3 2.5 178 7.36 38 137
in Four Dogs
Post Acidosis
10 Min.
Post Acidosis Infusion 30 Min. 60 Min.
90 Min.
157 1407 7.7 2.5 121 7.07 43 132
195 1476 77.6 2.6 111 7.06 46 134
182 1333 8.3 2.4 115 7.06 44.5 128
158 867 10.4 2.2 117 7.01 43 135
Values
in Nine
10 Min.
154 2940 3.3 4.1 169 7.37 37 114
169 1329 7.6 2.0 107 7.06 42 116
158 2251 4.5 0.8 133 7.05 43 113
Bilateral Cervical Vagotomy (Group I). The mean values for the systemic hemodynamics in this group are shown in Table I. It will be noted that one hour after vagotomy the arterial pressure had increased by 17 per cent and the rate had risen 40 per cent. The latter change was statistically significant (p
Value
Post Acidosis
RESULTS
August
ACIDOSIS
Infusion 30 Min.
terenol in a dose of 2 gamma/kg./hr. in normal saline solution was infused into seven dogs. This dose was increased to 10 gamma/kg./hr. in an additional nine animals.
Vol. 114,
LACTIC
167 1017 11.7 2.0 125 7.00 49.5 125
Dogs
Post Acidosis Infusion 30 Min. 60 Min.
152 2573 3.7 0.8 141 7.03 44 115
157 2424 4.1 1.1 146 7.03 43 122
90 Min.
153 1979 4.9 0.7 142 7.03 43 120
the period of the acidosis and blood gas values were within normal limits throughout the experiment. Norepinephrine Infusion (Group III). This drug was infused into three acidotic dogs in a dose of 2.5 gamma/kg./min. The effect on blood pressure, cardiac output, and cardiac rate was minimal when the infusion was made during acidosis. Therefore, the dose of norepinephrine was increased to 5 gamma/kg./min. with the following findings. Infusion of this larger dose during the control period prior to acidosis caused a 17 per cent increase in the arterial pressure by thirty minutes. This change was not significant (p
270
Smith, Silberschmid,
values for the systemic hemodynamics in this group. The pH ranged between 7.00 and 7.06 during the period of noradrenaline infusion. The pCOz showed minimal elevation and the pOz was within normal limits. In two dogs bigeminy developed during the control infusion and in one animal a second degree A-V block developed when noradrenaline was infused after acidosis. Isoproterenol Infusion (Group IV). This drug was initially infused in a dose of 2 gamma/ kg./hr. to a group of seven dogs prior to and after the induction of acidosis. It was observed that isoproterenol increased cardiac output in both the normal and acidotic environment without increasing arterial or central venous pressures. Peripheral resistance was decreased. It was believed that a larger dose might effect hemodynamic changes which would be more significant. Therefore, isoproterenol was infused in a dose of 10 gamma/kg./hr. to an additional nine animals prior to and after the induction of acidosis. The changes observed in the systemic hemodynamics are shown in Table II. It will be noted that the response observed during the control period was similar to that observed after acidosis. Isoproterenol infusion after acidosis caused a 10 per cent fall in the arterial pressure. This change was not significant (p
This experimental study indicates that the cardiac slowing and arrhythmia observed after the induction of experimental lactic acidosis is due in part to increased vagal activity since both vagotomy and atropine in large dosages increase cardiac rate and restore normal cardiac rhythm.
and Hinshaw The failure of vagotomy and atropine to increase cardiac output is perplexing in view of the experimental effects of vagal stimulation on cardiac function. Sarnoff and associates [6] observed that vagal nerve stimulation exerts a profound depressant effect on the strength of the atria1 contraction and thereby can influence ventricular filling and ventricular stroke work. The administration of atropine blocked the effect of vagal stimulation on the atrium. DeGeest et al. [7] have presented experimental evidence indicating that efferent vagal stimulation exerts a potent, negative inotropit influence upon the ventricular myocardium. Apparently other autonomic or humeral mediators depressed myocardial function and prevented an increase in cardiac output after vagotomy or atropine administration. In an effort to improve cardiac output, and to increase the cardiac rate during acidosis, we employed the potent beta adrenergic agent, isoproterenol. It was thought that the chronatropic and positive inotropic effect of this drug might prove to be beneficial in improving circulation after the induction of lactic acidosis. A modest effect on cardiac rate and output was observed with small doses of isoproterenol, although when the dose was increased, there was an excellent response to its use after the induction of acidosis. By contrast, norepinephrine did not improve either cardiac rate or cardiac output when infused during acidosis. The failure of norepinephrine to effect an increase in blood pressure, cardiac output, and cardiac rate in the acidotic animal was not unexpected. Darby et al. [S] infused lactic acid into dogs and observed a diminution in response as measured by arterial pressure and ventricular contractile force as the acidosis became more severe. At pH values below 7.0, both epinephrine and norepinephrine usually failed to produce a response. These authors observed that shortly after the period of complete refractoriness was reached, cardiovascular collapse and death occurred, Campbell and associates [9] have also reported a depressed response to intravenous sympathomimetic agents in man during acidosis. Isoproterenol has several actions which make it a desirable agent to employ in low perfusion states associated with cardiac failure. It has a mild peripheral vasodilating effect, thus tending to decrease peripheral resistance. It supports venous return to the heart by its venoconstrictAmerican
Journal
of Suwery
Experimental ing effect. Cardiac output is increased due to its positive inotropic effect on the myocardium. The tendency for this drug to increase cardiac rate is desirable in those patients having cardiac slowing as a result of increased vagal activity. The beneficial effects of isoproterenol were present when this agent was infused, even during severe acidosis. It caused a slight fall in arterial pressure, a marked increase in cardiac output, a fall in peripheral resistance and central venous pressure, as well as an increase in heart rate. Furthermore, this response could be maintained for a prolonged period of time despite the presence of a blood pH below 7.06. The acidosis employed in this study resulted from the addition of hydrogen ions into the extracellular fluid. Therefore, it is reasonable to assume that the intracellular acidosis was not as severe. Furthermore, at no time was the animal’s cell mass subjected to a period of hypoxia such as would occur during a low perfusion state. It is interesting to speculate whether or not a metabolic acidosis produced as a result of cellular hypoxia might have been associated with a greater impairment of myocardial function, and therefore a diminished response to the drugs employed in these experiments. The role of increased vagal activity in the production of cardiac rhythm disorders and cardiac arrest during acidosis has been reported by several authors [1U-121. The importance of vagal imbalance during acidosis thus assumes additional clinical importance. Recently, Gerst, Fleming, and Malm [13] have observed increased susceptibility to ventricular fibrillation during metabolic acidosis as indicated by a decrease in the ventricular fibrillation threshold value. The changes in cardiac rhythmicity and function which occur in an acid environment lend importance to the prompt recognition and treatment of this metabolic disorder in the patient with a low perfusion syndrome whether due to temporary cardiac failure or refractory shock. Treatment should first be directed toward correcting the cause for the low perfusion state; thereafter, attention should be focused on the diagnosis and vigorous treatment of metabolic acidosis should this be present, by the administration of appropriate alkalinizing solutions. The myocardium will thereby by placed in a more favorable setting for function and the threat of arrhythmia diminished. Vol. 114,
Aumst
I967
Lactic
Acidosis
271 SUMMARY
Acute addition lactic acidosis causes marked cardiac slowing, decreased cardiac output, and a progressive rise in the central venous pressure in the dog, suggesting increased vagal activity as well as decreased myocardial function. Bilateral cervical vagotomy and atropine in large dosages were employed to evaluate the role of vagal innervation in producing bradycardia and rhythm changes during acute lactic acidosis. These experimental procedures increased cardiac rate but did not improve cardiac output after the induction of lactic acidosis. Isoproterenol was compared with norepinephrine as a therapeutic agent to improve myocardial function during acidosis. Norepinephrine administration increased arterial pressure by 16 per cent, but did not improve cardiac output or cardiac rate when infused during acidosis. By contrast, isoproterenol caused a 10 per cent fall in arterial pressure, a 93.5 per cent increase in the cardiac output, and a 32 per cent increase in cardiac rate. These experimental findings suggest that increased vagal activity is a cause for the bradycardia and rhythm changes observed during acute lactic acidosis. Isoproterenol was an effective therapeutic agent to improve cardiac output, decrease peripheral resistance, and increase cardiac rate during severe acidosis. The application of these findings to the management of low perfusion states has been discussed. REFERENCES 1. CLOWES, G. H. A., JR., SABGA, G. A., KONITAXIS, A., TOMIN, R., HUGHES, M., and SIMEONE, F. A. Effects of acidosis on cardiovascular function in surgical patients. Ann. Surg., 154: 524, 1961. 2. THROWER, W. B., DARBY, T. D., and ALDINCER, E. E. Acidbase derangements and myocardial contractility. Arch. Surg., 82: 56, 1961. 3. SILBERSCHMID, M., SAITO, S., and SMITH, L. L. Circulatory effects of acute lactic acidosis in dogs prior to and after hemorrhage. Am. J. .Surg., 112: 175, 1966. 4. SMITH, L. L., FOSTER, R. L., and MULLER, W. Intrinsic cardiac output variability in the anesthetized normal and splenectomized dog. Am. J. Physiol., 202: 1155, 1962. 5. VERAGUT, U. P. and SMITH, L. L. Circulatory changes during prolonged respiratory acidosis in normal and hemorrhaged dogs. Surg. Gynec. b Obst., 119: 513, 1964. 6. SARNOPF, S. J., BROCKMAN,S. K., GILMORE, J. P., LINDEN, R. J., and MITCHELL, J. H. Regulation of ventricular contraction: influence of cardiac
272
7.
8.
9.
10.
11.
12.
13.
Smith, Silberschmid, and Hinshaw
sympathetic and vagal nerve stimulation on atria1 and ventricular dynamics. Circulation Res., 8: 1108, 1960. DEGEEST, H., LEVY, M. N., ZIESKE, H. and LIPMAN, R. I. Depression of ventricular contractility by stimulation of the vagus nerves. Circulation lies., 17 : 222, 1965. DARBY, T. D., ALDINGER, E. E., GADSDEN, R. H., and THROWER, W. B. Effects of metabolic acidosis on ventricular isometric systolic tension and the response to epinephrine and levarterenol. Circulation lies., 8: 1242, 1960. CAMPBELL, G. S., HOULE, D. B., CRISP, N. W., WEIL, M. H., and BROWN, E. G. Depressed response to intravenous sympathomimetic agents in humans during acidosis. Dis. Chest, 33: 18, 1958. CAMPBELL, G. S. Cardiac arrest: further studies on the effect of pH changes on vagal inhibition of the heart. Surgery, 38: 615, 1955. SLOAN, H. E. The vagus nerve in cardiac arrest: the effect of hypercapnia, hypoxia and asphyxia on reflex inhibition of the heart. Surg. Gynec. 6r Obst., 91: 257, 1950. YOUNG, W. G., JR., SEALY, W. C., HARRIS, J., and BOTWIN, A. The effects of hypercapnia and hypoxia on the response of the heart to vagal stimulation. Surg. Gynec. b Obst., 93: 51, 1951. GERST, P. H., FLEMING, W. H., and MALM, J. R. Increased susceptibility of the heart to ventricular fibrillation during metabolic acidosis. Circulation, 19: 63, 1966. DISCUSSION
JOHN E. CONNOLLY (Los Angeles, Calif.): I am in agreement with the findings and conclusions of these authors’ careful laboratory studies which emphasize the advantages of isoproterenol and the disadvantages in certain instances of norepinephrine. Isoproterenol not only acts directly on the heart, but it also causes peripheral vasodilatation, which diminishes the resistance to cardiac work. Dr. Stemmer, working in our laboratory, has measured the carotid and femoral blood flows with flowmeters, along with cardiac output and blood pressures. Ephedrine caused a prolonged elevation of the blood pressure and an initial elevation of carotid blood flow, followed by a sustained depression in carotid flow. Levophed@ produced a momentary ride in the femoral and carotid flows, followed by a sustained depression, while the peripheral pressure gradually returned to base line. Isoproterenol produced an initial slight depression of carotid flow, followed by a rise of the blood pressure. The conclusions, from both the studies of Dr. Smith and Dr. Stemmer and their associates, are that there are hazards clinically in the use of ephedrine, Levophed and Neo-Synephrine@, if adequate peripheral and carotid blood flows are to be main-
tained. A small dose of one of these agents may be given initially to a patient in shock until the blood pressure is raised, at which time isoproterenol therapy should be instituted. The build up of CO2 improves carotid arterial flow and adequate cerebral perfusion. Isoproterenol is useful in virtually all types of cardiac disease except in some instances of stenotic coronary artery disease. Low cardiac output after surgical procedures will result in acidosis. In trying to treat the acidosis we are not getting at the basic problem; this is where isoproterenol may be very effective in reversing the situation, along with the bicarbonate or THAM. In the absence of a normal circulating blood volume, isoproterenol can depress the blood pressure to very hazardous levels; consequently, the circulating blood volume must be restored before the drug is used. ALFRED GOLDMAN (Beverly Hills, Calif.): We have been interested in circulatory assist for shock. There might well be a place for small doses of norepinephrine, as Dr. Connolly just suggested, and from some of our data this use of norepinephrine shows marked increases not only in pressure but also in flow parameters. We measured flow with electromagnetic pulsatile flowmeters around carotid, coronary, pulmonary, mesenteric, and renal arteries and then used circulatory assist in the form of venoarterial phased pulsatile partial bypass (VAPPPB) after producing ventricular fibrillation by ligation of the circumflex coronary artery. The effect of a small dose of norepinephrine in a continuous drip on these regional flows, together with circulatory assist pumping is shown during ventricular fibrillation. Here a rise from 8.3 cc. to 19 cc. per minute in the left anterior descending coronary artery, more than 100 per cent in the coronary flow, occurred with the institution of the instillation of norepinephrine. At times we have seen a marked increase in mesenteric, renal, and carotid flows when we add norepinephrine. After defibrillation such regional flows are maintained. The pressure parameters are increased very markedly with only the pumping and restoration of the sinus rhythm; in one instance the systolic pressure was 44 mid-diastolically, but was increased to 80 with the instillation of norepinephrine. Consequently, we cannot say altogether that norepinephrine is a totally bad drug to use in such catastrophic states, since it increased vital regional flows with VAPPPB. Ross ROBERTSON (Vancouver, B. C.): Dr. Smith and his co-workers are to be congratulated on the clearest and most concise presentation of experimental data that I have ever heard. I am most interested in his results, because for some years we have been using Isuprel@ clinically, and have found that it is the only effective drug for the treatment of American
Jorwnal
of Swgery
Experimental Lactic Acidosis acute myocardial failure. Isuprel must be given with great caution in a concentration of 1 in 200,000 with a minidrip. The minidrip may be flowing at from six to thirty drops per minute. It must be regulated with great care for otherwise there is a very rapid increase in cardiac rate. We have found Isuprel to be of great benefit. It increases the urinary as well as the cardiac output. The venous pressure must be watched carefully for with the dilatation of the peripheral vessels a rapid increase in blood volume may be required. BENSON B. ROE (San Francisco, Calif.) : Two very important clinical inferences can be drawn from this excellent experimental study. First, we may infer that blood pressure should be eliminated as an index of adequate perfusion. We have seen patients whose blood pressures were nearly at normal levels a few minutes before they died as a result of inadequate perfusion; this paper demonstrates very well that flow is not related to pressure. Secondly, acidosis, although somewhat depressing to cardiac output, is not as devastating as has been inferred by many. The hazard of overtreatment is significant. Blood gas studies on patients given sodium bicarbonate after cardiac arrest or depression have revealed the presence of severe alkalosis. Consequent hypokalemia can produce ventricular fibrillation. WILEY F. BARKER (Los Angeles, Calif.) : There is one other point implied, which should be stressed, concerning the variability of effect depending upon the dose. I first learned in a nonclinical situation many years ago that growth hormones in plants would either stimulate or repress the development of roots in Concord grape cuttings, depending on a change of concentration from one to one hundred parts per million. Several years ago we were studying animals subjected to standard amounts of bleeding in which renal blood flow fell acutely. If one were to use
Vol. 114, Auzust 1967
273
norepinephrine, Neo-Synephrine, or Aramine@’ to restore blood pressure to the expected normal level for that animal, one could completely stop all renal blood flow (as measured by a flowmeter). If, however, one carefully titrated the dose of vasopressor, one could achieve a very modest increase in peripheral arterial pressure and at the same time achieve a modest increase in renal blood flow. I believe that there is in the several organs a differential sensitivity to many of these vasoactive agents, and that we must be aware of this and not be misled by response to one given dosage. LOUIS L. SMITH (closing): In answer to Dr. Goldman, we agree that there is a difference in the experimental model used in this study and the clinical setting observed in shock in that there was no cellular hypoxia. In our studies on animals we observed the specific hemodynamic effects of a fixed acid load on the cardiovascular response prior to and after certain treatments. We agree also that arterial pressure is an inadequate gauge of low perfusion syndrome and myocardial function. The dosage of isoproterenol is important and in our studies it was large. No adverse effect with this agent was seen whereas larger dose of norepinephrine occasionally resulted in bigeminy and second degree heart block. Blood volume must be adequately replaced. Again we rely on the measurement of vital signs, including central venous pressure, serial hematocrits, and urine output as a gauge of blood volume replacement, rather than relying on a single measured blood volume value. Low perfusion states and/or refractory shock are very complex clinical problems and one must treat the specific causes for this condition. This study shows that metabolic acidosis is another defect which can be treated and which will improve the cardiovascular function in these patients.