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Influence of THAM on survival in metabolic acidosis due to hypoperfusion
I n f l u e n c e of T H A M o n Survival in Metabolic Acidosis d u e to H y p o p e r f u s i o n By M, N. SRouji, G. A. TRUSLERAND W. ZINGG H E PURPOSE O F this study is to evaluate the efficacy of T H A M (trishydroxymethyl-aminomethane) in improving survival by counteracting metabolic acidosis during an experimentally controlled period of reduced tissue perfusion. Many experimental and clinical studies have demonstrated the efficacy of T H A M in correcting acidosis by virtue of its property as an extra- and intracellular hydrogen ion acceptor. 1 In clinical practice the variations in nature and severity of disease and concomitant therapy preclude a well controlled evaluation of the effect of T H A M on survival. Therefore, certain preparations and methods in experimental animals must be utilized. An experimental model to test the effect of THAM on survival entails a method wherein: 1. Metabolic acidosis is the result of a controlled simulated clinical condition with minimum variations beyond those of the response of the individual experimental animal. 2. T h e degree of metabolic acidosis is the most significant factor leading to death. 3. A quantitative estimation of the true severity of acidosis can be made. 4. T H A M can be administered quantitatively to counteract the acidosis. "The azygos flow principle" has been previously used in studies of hypoperfusion. 2-s Its technical simplicity and ease of control made it suitable for this investigation.
T
MATERIALS AND METHODS
In 25 mongrel dogs with an average weight of 16 Kg. metabolic acidosis was induced by maintaining them on "azygos flow" for a period of 40 minutes. All were given tetracycline orally (500 reg./day) for 3 to 5 days prior to operation and aqueous penicillin (500,000 units) intravenously 10 to 15 minutes before onset of azygos flow. The dogs were anesthetized with 15 mg./Kg, each of Nembutal and Pentothal, an endotracheal tube inserted and connected to a constant volume respirator (Air Shields Inc.). Electrocardiogram Ieads were connected and lead II monitored. Both femoral areas and From the Department of Surgery and the Research Institute of the Hospital for Sick Children, Toronto, and University of Toronto, Ontario, Canada. This study was supported by Public Health Research Grant No. 605-7-250 of the National Health Program, and by the Ontario Heart Foundation. M. N. SRoujI, M.D.: Associate in Surgical Research, University of Pennsylvania, School of Medicine; Assistant Surgeon, Department of Surgery, Children's Hospital of Philadelphia, Philadelphia, Pa. G. A. TRUSLE~,M.D., M.S., F.A.C.S., F.R.C.S.(C): Assistant Surgeon, Hospital for Sick Children; Clinical Teacher, University of Toronto. W. ZINGG, M.D., M.Sc., F.A.C.S., F.R.C.S.(C): Assistant Professor of Surgery, University of Toronto; Associate Scientist, Research Institute. 44 JOURNAL OF PEDIATRIC SURGERY, VOL. 2, No. 1 (FEBRUARY), 1967
I N F L U E N C E OF THAIv[ ON SUBVIVAL IN M E T A B O L I C ACIDOSIS
45
chest were prepared surgically and femoral vessels exposed bilaterally and eannulated. One side was used to monitor pressures continuously in the descending aorta and inferior vena cava (I.V.C.) and the other to collect arterial and venous samples. After a right thoracotomy through the fourth intercostal space, tourniquets were passed around the I.V.C. and around the superior vena cava (S.V.C.) eephalad to the azygos vein. The lungs were then inflated to avoid ateleetasis and arteriovenous shunting. Control blood samples were taken for pH, pCO 2, pO a and hemoglobin and hematocrit. In the control period the respirator rate and volume were adjusted to obtain an arterial pH and pCO e as close to normal as possible and a high PaO z (150-'250 mm. Hg). The pH and blood gases were determined using the pH and Blood Gas Analyzing System, Model 113 of Instrumentation Laboratory Inc. Base deficit was determined from Sigaard-Anderson alignment nomogram. Controlled respiration with oxygen and supplemental nitrous oxide was maintained during and for 2 hours after the period of azygos flow. Statham transducer Model No. P23Db was used to monitor the arterial pressure and Model No. P23BB to monitor the venous pressure. Tracings of arterial and venous pressure, ECG (lead II), and respiration rate were obtained on a multichannel "Brush" recorder. Azygos flow was indueed by tightening the eaval tourniquets thus obstructing both eavae and limiting cardiac inflow to that of the azygos vein and coronary sinus. Blood samples were taken at 5, 10, and 40 minutes during azygos flow and 5, 15, 30, 45, 60, 90, and 120 minutes after resumption of caval flow, In an initial control group of 5 dogs (group I), where no intravenous solutions were given, the maximum arterial base deficit was observed in the 5 minute sample after resumption of caval flow, with a range of 20 to 27 mEq./L. (Table 2). In group II, consisting of 10 dogs, THAM * in 10 per cent glucose in water (1 Molar Sol.) was given, in an amount of 6 ee/Kg. B.W. calculated2~ to counteract the minimum base deficit of 20 mEq./L, observed in group I. In group III, also consisting of 10 dogs, an equal amount of 10 per cent glucose in water was given in relation to body weight. In groups II and III solutions were infused into the I.V.C. during the period between 10 and 35 minutes of azygos flow. Chest closure was started 15 minutes after the azygos flow period, with chest drainage connected to a 3 bottle suction system. All dogs were given antibiotics for 5 days postoperatively. RESULTS I n t h e c o n t r o l g r o u p s ( I a n d I I I ) 11 of t h e 15 d o g s died. I n g r o u p I I ( T H A M i n f u s i o n ) s u r v i v a l r a t e w a s s i g n i f i c a n t l y b e t t e r ( P < 0.01): E i g h t of t h e 10 d o g s in t h e g r o u p s h o w e d c o m p l e t e r e c o v e r y a n d w e r e w e l l m o r e t h a n 3 w e e k s p o s t o p e r a t i v e l y . T h e i n c i d e n c e of r e c o v e r y of vital functions, v e n t r i e u l a r fibrillation, a n d t e m p o r a r y a n d c o m p l e t e s u r v i v a l in e a c h of t h e 3 g r o u p s is s h o w n in T a b l e 1.
Acid-Base and Blood Gas Changes I n all a n i m a l s a n initial rise in p H a n d d e c r e a s e in p C O 2 w a s o b s e r v e d in t h e a r t e r i a l s a m p l e t a k e n a f t e r 5 a n d 10 m i n u t e s of a z y g o s flow ( T a b l e 2), in c o n t r a s t to t h e v e n o u s s a m p l e w h i c h s h o w e d a g r a d u a l d e c r e a s e in p H a n d i n c r e a s e i n pCO2. A b a s e deficit e v i d e n t in b o t h a r t e r i a l a n d v e n o u s s a m p l e s r e v e a l e d t h e e a r l y o n s e t of m e t a b o l i c acidosis. A f t e r t h e first 10 m i n u t e s of a z y g o s flow all t h e a n i m a l s in t h e c o n t r o l g r o u p ( I a n d I I I ) s h o w e d a p r o g r e s s i v e fall in a r t e r i a l a n d v e n o u s p H w i t h an i n c r e a s e in p C O 2 a n d b a s e deficit ( F i g . 1). T h e PaO2 r e m a i n e d h i g h w i t h a ~Talatrol, supplied by Abbott Laboratories Ltd., Montreal, P. Q.
46
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mean of 180 ram. Hg (range: 130-220 mm. Itg). The venous oxygen tension was diminished in all 3 groups with a mean of 12 mm. Hg at 40 minutes of azygos flow (range: 5-23 ram. Hg). In group II, THAM started after 10 minutes of azygos flow prevented a drop in p H in arterial samples of circulating blood during the remaining 30 minutes of azygos flow and produced a decrease in venous pCO2 and in arterial and venous base deficit (Table 2 and Fig. 1). The lowest arterial pH, the maximum pCO2 and base defcit in all 3 groups were observed in samples taken 5 minutes after resumption of caval flow. The magnitude of base defter as well as the degree of its increase over that at the end of 40 minutes of azygos flow appeared to correlate with the survival rate (Fig. 1). Blood Pressure
The depth of arterial hypotension during the first 10 minutes of azygos flow, was eomparable in the 3 groups. In the control groups a further drop in both
INFLUENCE
OF THAM
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Group I
SURVIVAL IN METABOLIC
Group II
Group III
49
ACIDOSIS
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Fig. 2.--Maximum base deficit and maximum blood pressure recorded during the first 10 minutes after azygos flow. The figures represent the mean for each group (group I--control, group II--THAM infusion, group III--glucose infusion). *Two other dogs developed Ventricular fibrillation immediately after caval release. systolic and diastolic blood pressure occurred during the remaining 30 minutes of azygos flow except in the 4 surviving dogs in group III (glucose infusion), In group II, during the infusion of THAM, a tendency for gradual elevation in blood pressure was noted in most of the dogs. Of particular interest was the recovery of blood pressure after caval flow was resumed. In the THAM-treated group, maximum pressures were obtained within the first 10 minutes after resumption of caval flow. A rebound elevation over control level was observed at this time in both systolic and diastolic pressures in all survivors (Fig. 2). In the control groups, and in the 2 dogs that failed to survive despite THAM, maximum pressures during the first 10 minutes after restoration of caval flow were lower than control levels. In all dogs the venous pressure rose immediately after caval occlusion. In survivors of the THAM group the venous pressure at the end of the 40 minutes of azygos flow was higher than that recorded at 10 minutes of such diminished flow. The rise was less in survivors of group III (glucose infusion). In contrast, all other animals showed a gradual fall in venous pressure associated with the increase in metabolic acidosis during azygos flow. The 4 survivors in group III (glucose infusion) exhibited a higher average arterial pressure during, and at the end of azygos flow than that recorded in the rest of the animals in this study, including those surviving with THAM. This was associated with a base deficit after caval release greater than that seen in survivors in the THAM group, but less than the deficit in dogs that died in all 3 groups. Two of the 10 dogs in the THAM group (group II) failed to survive
50
SROUJI, TRUSLEn AND ZINGG
although arterial pressure and spontaneous respiration recovered following resumption of caval flow. Both received the standard dose of THAM in relation to body weight. At the end of 40 minutes of azygos flow these 2 dogs had a very high arteriovenous difference in pH and pCO2, and a large base deficit exceeded only by that observed in the dogs that developed ventricular fibrillation immediately after caval release. After resumption of caval flow, the maximum base deficit, found in these 2 dogs, was greater than that in the survivors in group II (THAM infusion) and group III (glucose infusion). DISCUSSION The azygos flow principle has been used in a number of studies to investigate the effect of hypoperfusion on survival, and influence of resulting metabolic acidosis on cardiovascular function. Survival has varied in the different reports but no long-term survival is reported with azygos flow beyond 35 minutes. Andreason and Watson 2 demonstrated survival with 35 minutes of azygos flow but had no satisfactory survivors with longer periods despite hyperventilation with oxygen. Owens et ald using a similar technic, reported no survivors with azygos flow of more than 35 minutes under normothermie or hypothermic conditions. Cohen and Lillihei 4 limited the duration of azygos flow to 30 minutes in their study of 20 dogs and reported 17 survivors with no pathology when sacrificed 4 to 29 days after the experiment. In this study azygos flow was maintained for 40 minutes. In contrast to the compensatory hyperventilation used in the previous studies, ventilation in the present study was adjusted to obtain an arterial pH and pCO2 in the normal range, in an attempt to standardize the control state of the animals. Hyperventilation is known to result in depression of plasma bicarbonate level with an increase in renal excretion of bicarbonate and potassium leading to loss of buffer base. s,9 Respiratory alkalosis is also associated with accumulation of lactic acid and partial utilization of cellular buffers, l~ McKenzie et al. 11 attributed reduction in whole blood buffer base in hyperventilated dogs to the development of metabolic acidosis secondary to respiratory alkalosis. In experimental studies, animals breathing room air during hemorrhagic shock tend to have a low arterial oxygen saturation22 Gerst et al) 3 showed that decrease in pulmonary blood flow results in a significant increase in the alveolar dead space. Hypoxemia appears to have influenced results of studies 12,14 relating survival to treatment of acidosis in hemorrhagic shock, and has led to discrediting THAM and the importance of correction of acidosis in reducing or eliminating the incidence of irreversibility. 14 Manger et al) 2 using THAM and sodium bicarbonate in hemorrhagic shock showed that survival rate is improved only when both pH control and increased arterial oxygen content are achieved. These authors pointed out that treatment of acidosis with adequate oxygenation will improve oxygen utilization and delay onset of irreversible phase in shock. The significance of the endotoxic factor in relation to survival in experimental hypotension in dogs is difficult to evaluate and control. In this study, an attempt was made to exclude this factor by giving antibiotics orally preoperatively as well as intravenously prior to onset of azygos flow.
INFLUENCE
OF THAM
O N SURVIVAL I N M E T A B O L I C
ACIDOSIS
51
The early onset of metabolic acidosis with low tissue perfusion has been demonstrated in numerous reports comparing flow rates in eardiopulmonary bypass. Similar metabolic studies have shown the early onset of metabolic acidosis with 10 minutes of azygos flow?, 5,~,15 In the study of Cohen and Lillihei 4 the azygos flow was estimated to be 8-14 ee./Kg./minute, which is less than 10 per cent of the generally accepted basal cardiac output for anesthetized dogs. Progressive increase in acidosis with longer periods of azygos flow appears to be a very important factor in survival and one of the limiting factors in the previously reported studies. In this investigation an estimate of the naagnitude of tissue acidosis resulting from 40 minutes of azygos flow was obtained from the sampled circulating mixed arterial blood 5 minutes after resumption of caval flow in control group I. In the THAM-treated dogs, the total dose was infused between 10 to 35 minutes of azygos flow to allow satisfactory distribution and equilibration with accessible tissues before the blood sample at the termination of azygos flow was collected (Fig, 1). Schwartz et al. 1~ studying the distribution of administered hydrogen ion with continuous versus intermittent infusion demonstrated the importance of obtaining a representative blood sample by allowing time for attaining equilibrium with the tissues. Of interest in the present study is the correlation of mortality rate with the severity of base deficit observed 5 minutes after resumption of normal flow, as well as the increase of that value over the base deficit obtained at the end of 40 minutes of azygos flow (Fig. 1). The increase of the base deficit after eaval release reflected the degree of tissue hypoxia and anaerobic metabolism during the period of azygos flow. This also indicates the inability of blood samples obtained during a state of tissue hypoperfusion to reflect the degree of tissue acidosis. Crowell et al. have shown the relationship of tissue acidity 17 and intravascular coagulation is to irreversibility of shock. This led to the use of vasodilators in shock, 19,2~ and their influence on occurrence of disseminated intravaseular coagulation. 2t Two dogs in the THAM-treated group failed to survive, though at 40 minutes of azygos flow the arterial blood was only slightly acidotic. However, the precipitous fall in arterial pH and marked increase in base deficit soon after the return of normal tissue perfusion and blood mixing indicate the severity of the tissue acidosis during the period of hypotension (Fig. 1). Arteriolar vasoconstriction and stagnation in the capillary vascular beds masked the degree of acidosis at the cellular level. The clinical implications of these findings are evident. Reassessment of the base deficit after successful resuscitation of circulatory failure is mandatory to prevent the deleterious effects of acidosis and recurrence of hypotension. Sudden release of acid metabolites from previously poorly perfused tissues may flood the coronary circulation causing an immediate deterioration of myocardial contractility 5,1~ and lowering the threshold for ventricular fibrillation32 Survival in 4 dogs of the control group given glucose (group III) may have been related to the higher arterial pressure than that recorded in the rest of the animals during the period of azygos flow. It is postulated that the higher
59~
SROUJI, TRUSLEI:~ AND Z1NGG
arterial pressure reflected better tissue perfusion, which is supported by the smaller increase in base deficit observed in these dogs following caval release (Fig. 1). A rebound increase in blood pressure after 10 minutes of azygos flow or low tissue perfusion with cardiopulmonary bypass has been related to marked increase in circulating eatecholamines. 3,~'G'15 However, when the period of low tissue perfusion was increased to 15-30 minutes no rebound elevation in blood pressure was observed, and the blood pressure frequently failed to return to normal control levelsY ,1~ In the present study, all untreated dogs failed to show a rebound elevation in blood pressure in contrast to survivors in the THAMtreated group where the rebound phenomenon was observed even after 40 minutes of azygos flow, particularly in those showing the least base deficit after eaval release (Fig. 2). Several authors 5,15,e:~2~ have demonstrated decreased myocardial contractility, cardiac output, and blood pressure in the acidotic state with decreased response to exogenous sympathomimetic drugs, and marked improvement in response after correction of the acidosis. Endogenous cateeholamines are markedly increased in response to hypotension and hypoxia. 3,6,12 Acidosis per se is also considered a potent factor in increasing endogenous cathecholamine production22,z7,28 Thus, the controversial need for exogenous sympathomimetic amines may be reduced or totally obviated by early correction of the acidosis thus activating the normal response to abundantly available endogenous catecholamines. It was further shown by Nahas et al. 27 that an increase in oxygen uptake due to elevated levels of cateeholamines occurs in presence of normal or alkaline pH but not in acidosis. Susceptibility to ventricular fibrillation has been shown by Gerst et al. "-'-~to be directly related to excess of fixed acids, while a base excess has a protective action. Restoring pH alone to normal by hyperventilation does not reduce the risk of ventrieular fibrillation in presence of a base deficit. Clinically, the dosage, concentration, and rate of administration depend on severity and urgency of the condition under treatment, the need for restriction of I.V. fluids as well as the concurrent presence of mechanical ventilation or its ready availability2 Due to its hypoglycemie action in large doses THAM is usually dissolved in 5-10 per cent glucose in water. Under the experimental conditions of this study no untoward effects were observed with one Molar solution of THAM in 10 per cent glucose in water with controlled ventilation. SUMMARY AND CONCLUSIONS
Metabolic acidosis associated with hypoperfusion was induced by subjecting 25 dogs to azygos flow for 40 minutes. In the control groups, 11 of the 15 dogs subsequently died. In contrast, 8 of the 10 dogs given THAM survived. Two deaths in the THAM group were related to severe uncorrected base deficit, indicating insufficient THAM treatment. The data lead to the following conclusions: 1. Survival appears to be inversely related to severity of metabolic acidosis as well as to the increase of base deficit after resumption of normal flow.
INFLUENCE OF THA3/I ON SUllVIVAL IN I~r
ACIDOSIS
53
2. Given i n a d e q u a t e dosage, T H A M improves survival u n d e r conditions of n o n h e m o r r h a g i c low tissue perfusion in presence of elevated arterial oxygen tension. 3. T h e s p e e d of r e c o v e r y of b l o o d pressure following caval release was related to acid base status. A r e b o u n d increase over control levels o b s e r v e d in survivors in the T H A M - t r e a t e d g r o u p was absent in b o t h control groups. 4. T h e d a t a p r e s e n t e d indicate t h a t p H determinations alone are i n a d e q u a t e in assessing the acid-base status, a n d can be misleading in p l a n n i n g optimal treatment. Base excess is a m o r e relevant guide for evaluation a n d t h e r a p y for states associated w i t h h y p o p e r f u s i o n . 5. Prior to restoration of a d e q u a t e tissue perfusion, arterial acid-base values do n o t reflect the m a g n i t u d e of tissue m e t a b o l i c acidosis. W h e n n o r m a l perfusion returns, the acid metabolites released from the tissues m a y p r o d u c e deleterious circulatory effects. SUMMARIO IN I N T E R L I N G U A Sub conditiones de respiration controlate, permittente un alte tension arterial de oxygeno, le principio del "fluxo de azygos" esseva usate in inducer hypoperfusion e acidosis metabolic. Le severitate del acidosis tissu]ar non esseva satisfactorimente manffeste in specimens de sanguine obtenite durante le hypoperfusion, pro que deficits maximal de base arterial occurreva tosto post le re-initiation de un adequate perfusion tissular. Dece-un de 15 canes de controlo moriva, durante que 8 de 10 canes tractate con un predeterminate dose de solution de THAM superviveva. Le superviventia pare esser relationate con le severitate del acidosis metabolic. ACKNOWLEDGMENTS We wish to thank Dr. L. Te for his assistance with anesthetic administration and control of ventilation, and Mrs. M. Scott, Miss S. Spicer and Mr. M. Behamdouni for their technical help. REFERENCES
1. Nahas, G. G.: The clinical pharmacology of THAM tris (hydroxymethyl) aminomethane. Clin. Pharmac. Therap. 4:783, 1963. 2. Andreason, A. T., and Watson, F.: Experimental cardiovascular surgery, "the azygos factor." Brit. J. Surg. 39: 548, 1952. 3. Belisle, C. A., Woods, E. F., Nunn, D. B., Parkes, E. F., Lee, W. H., Jr., and Richradson, J. H.: The role of epinephrine and norepinephrine in rebound cardiovascular phenomena in azygos flow studies of cardiopulmonary bypass in dogs. J. Thoracic & Cardiovas. Surg. 39:815, 1960. 4. Cohen, M., and Lillihei, C. W.: A quantitative study of the "azygos factor" during vena caval occlusion in the dog. Surg. Gynec. Obst. 98:225, 1954.
5. Darby, T. D., Aldinger, E. E., Gadsden~ t/. H., and Thrower, W. B.: Effects of metabolic acidosis on ventricular isometric systolic tension and the response to epinephrine and levarterenol. Circ. Res. 8:1242, 1960. 6. Lee, W. H., Jr., Darby, T. D., Ashmore, J. D., and Parker, E. F.: Myocardial contractile force as a measure of cardiac function during cardiopulmonary bypass procedures. Surg. Forum 8: 398, 1958. 7. Owens, J. C., Liddle, E. B., Tune, L., and Zeavin, I.: Studies on occlusion of the inferior vena cava above and below the hepatic vein in normothermic and hypothermic dogs. Surg. Forum 4:63, 1953. 8. Barker, E. S., Singer, R. B., Elkinton, J. R., and Clark, J. K.: The renal response in man to acute experimental
54 respiratory alkalosis and acidosis. J. Clin. Invest. 36:515, 1957. 9. Eickenholtz, A., Mulhausen, R. Q., Anderson, W. E., and MacDonald, F. M.: Primary hypocapnia: a cause of metabolic acidosis. J. Appl. Physiol. 17:283, 1962. 10. Nims, L. F., Gibbs, E. L., and Lennox, W. G.: Arterial and cerebral venous blood changes produced by altering arterial CO 0. J. Biol. Chem. 145:189, 1942. 11. MacKenzie, G. J., Davis, S, H., Mason, A. H. B., and Wade, J. D.: Causes of metabolic acidosis in extracorporeal circulation at normothermia. Thorax 18:215, 1963. 12. Manger, W, M., Nahas, G. G., Hassam, D., Habif, D. V., and Papper, E. M.: Effect of pH control and increased 02 delivery on the course of hemorrhagic shock. Ann. Surg. 156:503, 1962. 13. Gerst, P. H., Rattenberg, C., and Holaday, D. A.: The effects of hemorrhage on pulmonary circulation and respiratory gas exchange. J. Clin. Invest. 38: 524, 1959. 14. Selmonosky, C. A., Goetz, R. H., and State, D.: The role of acidosis in the irreversibility of experimental hemorrhagic shock. J.S.R. 3:491, 1963. 15. Thrower, E. B., Darby, T. D., and Aldinger, E. E.: Acid-base derangements and myocardial contractility. Arch. Surg. 82:56, 1961. 16. Schwartz, W. T., Orning, K. J., and Porter, R.: The internal distribution of hydrogen ions with varying degrees of metabolic acidosis. J. Clin. Invest. 36: 373, 1957. 17. Crowell, J. W., Bounds, S. H., and Johnson, W. W.: Effects of varying the hematocrit ratio on the susceptibility to hemorrhagic shock. Amer. J. Physiol. 192:171, 1958. 1 8 . - - , Sharpe, G. P., Lambright, R. L., and Read, W. L.: The mechanism of death after resuscitation following acute circulatory failure. Surgery 38: 696, 1955. 19. Nickerson, M.: Drug therapy of shock. In K. D. Bock (Ed.) Shock, Patho-
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genesis and Therapy. Berlin-Gottingen, Heidelberg, Springer-Verlag. 1962, p. 356. Remington, J. W., Hemilton, W. J., Boyd, G. H., Hamilton, W. F., Jr., and Caddell, H. M.: Role of vasoconstriction in the response,of the dog to hemorrhage. Amer. J. Physiol. 161: 116, 1950. Hardaway, R. N., Elovitz, M. J., Brewster, W. R., Jr., Houchin, D. N., Renzi, N. L., and Jackson, D. R.: Influence of vasoconstrictors and vasodilators on disseminated intravascular coagulation in irreversible hemorrhagic shock. Surg. Gynee. Obst. 119: 1053, 1964. Gerst, P. H., Fleming, W. H., and Maim, J. R.: Relationship between acidosis and ventrieular fibrillation. Surg. Forum 15:242, 1964. Campbell, G. S., Houle, D. B., Crisp, N. W., Jr., Weil, M. H., and Brown, E. B.: Depressed response to I.V. sympathicomimetie agents in humans during acidosis. Dis. Chest 33: I8, 1958. Clowes, G. H. A., Jr., Sabgha, 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. Kirtle, C. F., Aoki, H., and Brown, E. B., Jr.: The role of pH and CO 2 in the distribution of blood flow. Surgery 57:139, 1965. Well, M. H., Houle, D. B., Brown, E. B., Jr., and Campbell, G. S.: Influence of acidosis on the effectiveness of the vasopressor agents. Circulation 16:949, 1957. Nahas, G. G., Ligou, J. G., and Mehlman, B.: Effects of pH changes on 0 2 uptake and plasma catecholamine levels in the dog. Amer. J. Physiol. I98:60, 1960. Woods, E. F., and Richardson, J. A.: Survey of agents producing cardiovascular manifestations of epinephrine discharge. J. Pharmacol. Exper. Therap. 114:445, 1955.
T
MATERIALS AND METHODS
In 25 mongrel dogs with an average weight of 16 Kg. metabolic acidosis was induced by maintaining them on "azygos flow" for a period of 40 minutes. All were given tetracycline orally (500 reg./day) for 3 to 5 days prior to operation and aqueous penicillin (500,000 units) intravenously 10 to 15 minutes before onset of azygos flow. The dogs were anesthetized with 15 mg./Kg, each of Nembutal and Pentothal, an endotracheal tube inserted and connected to a constant volume respirator (Air Shields Inc.). Electrocardiogram Ieads were connected and lead II monitored. Both femoral areas and From the Department of Surgery and the Research Institute of the Hospital for Sick Children, Toronto, and University of Toronto, Ontario, Canada. This study was supported by Public Health Research Grant No. 605-7-250 of the National Health Program, and by the Ontario Heart Foundation. M. N. SRoujI, M.D.: Associate in Surgical Research, University of Pennsylvania, School of Medicine; Assistant Surgeon, Department of Surgery, Children's Hospital of Philadelphia, Philadelphia, Pa. G. A. TRUSLE~,M.D., M.S., F.A.C.S., F.R.C.S.(C): Assistant Surgeon, Hospital for Sick Children; Clinical Teacher, University of Toronto. W. ZINGG, M.D., M.Sc., F.A.C.S., F.R.C.S.(C): Assistant Professor of Surgery, University of Toronto; Associate Scientist, Research Institute. 44 JOURNAL OF PEDIATRIC SURGERY, VOL. 2, No. 1 (FEBRUARY), 1967
I N F L U E N C E OF THAIv[ ON SUBVIVAL IN M E T A B O L I C ACIDOSIS
45
chest were prepared surgically and femoral vessels exposed bilaterally and eannulated. One side was used to monitor pressures continuously in the descending aorta and inferior vena cava (I.V.C.) and the other to collect arterial and venous samples. After a right thoracotomy through the fourth intercostal space, tourniquets were passed around the I.V.C. and around the superior vena cava (S.V.C.) eephalad to the azygos vein. The lungs were then inflated to avoid ateleetasis and arteriovenous shunting. Control blood samples were taken for pH, pCO 2, pO a and hemoglobin and hematocrit. In the control period the respirator rate and volume were adjusted to obtain an arterial pH and pCO e as close to normal as possible and a high PaO z (150-'250 mm. Hg). The pH and blood gases were determined using the pH and Blood Gas Analyzing System, Model 113 of Instrumentation Laboratory Inc. Base deficit was determined from Sigaard-Anderson alignment nomogram. Controlled respiration with oxygen and supplemental nitrous oxide was maintained during and for 2 hours after the period of azygos flow. Statham transducer Model No. P23Db was used to monitor the arterial pressure and Model No. P23BB to monitor the venous pressure. Tracings of arterial and venous pressure, ECG (lead II), and respiration rate were obtained on a multichannel "Brush" recorder. Azygos flow was indueed by tightening the eaval tourniquets thus obstructing both eavae and limiting cardiac inflow to that of the azygos vein and coronary sinus. Blood samples were taken at 5, 10, and 40 minutes during azygos flow and 5, 15, 30, 45, 60, 90, and 120 minutes after resumption of caval flow, In an initial control group of 5 dogs (group I), where no intravenous solutions were given, the maximum arterial base deficit was observed in the 5 minute sample after resumption of caval flow, with a range of 20 to 27 mEq./L. (Table 2). In group II, consisting of 10 dogs, THAM * in 10 per cent glucose in water (1 Molar Sol.) was given, in an amount of 6 ee/Kg. B.W. calculated2~ to counteract the minimum base deficit of 20 mEq./L, observed in group I. In group III, also consisting of 10 dogs, an equal amount of 10 per cent glucose in water was given in relation to body weight. In groups II and III solutions were infused into the I.V.C. during the period between 10 and 35 minutes of azygos flow. Chest closure was started 15 minutes after the azygos flow period, with chest drainage connected to a 3 bottle suction system. All dogs were given antibiotics for 5 days postoperatively. RESULTS I n t h e c o n t r o l g r o u p s ( I a n d I I I ) 11 of t h e 15 d o g s died. I n g r o u p I I ( T H A M i n f u s i o n ) s u r v i v a l r a t e w a s s i g n i f i c a n t l y b e t t e r ( P < 0.01): E i g h t of t h e 10 d o g s in t h e g r o u p s h o w e d c o m p l e t e r e c o v e r y a n d w e r e w e l l m o r e t h a n 3 w e e k s p o s t o p e r a t i v e l y . T h e i n c i d e n c e of r e c o v e r y of vital functions, v e n t r i e u l a r fibrillation, a n d t e m p o r a r y a n d c o m p l e t e s u r v i v a l in e a c h of t h e 3 g r o u p s is s h o w n in T a b l e 1.
Acid-Base and Blood Gas Changes I n all a n i m a l s a n initial rise in p H a n d d e c r e a s e in p C O 2 w a s o b s e r v e d in t h e a r t e r i a l s a m p l e t a k e n a f t e r 5 a n d 10 m i n u t e s of a z y g o s flow ( T a b l e 2), in c o n t r a s t to t h e v e n o u s s a m p l e w h i c h s h o w e d a g r a d u a l d e c r e a s e in p H a n d i n c r e a s e i n pCO2. A b a s e deficit e v i d e n t in b o t h a r t e r i a l a n d v e n o u s s a m p l e s r e v e a l e d t h e e a r l y o n s e t of m e t a b o l i c acidosis. A f t e r t h e first 10 m i n u t e s of a z y g o s flow all t h e a n i m a l s in t h e c o n t r o l g r o u p ( I a n d I I I ) s h o w e d a p r o g r e s s i v e fall in a r t e r i a l a n d v e n o u s p H w i t h an i n c r e a s e in p C O 2 a n d b a s e deficit ( F i g . 1). T h e PaO2 r e m a i n e d h i g h w i t h a ~Talatrol, supplied by Abbott Laboratories Ltd., Montreal, P. Q.
46
SROUJI, TRUSLER AND ZINGG
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SROUJI, TRUSLElq AND ZINGG
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Group II (Tham infusion)
o survivors 9 died Group Ill Icontrol glucose infusion,) a survivors 9 died
Fig. 1.--Arterial base deficit (mean • minutes after azygos flow.
standard error) before, during, and 5
mean of 180 ram. Hg (range: 130-220 mm. Itg). The venous oxygen tension was diminished in all 3 groups with a mean of 12 mm. Hg at 40 minutes of azygos flow (range: 5-23 ram. Hg). In group II, THAM started after 10 minutes of azygos flow prevented a drop in p H in arterial samples of circulating blood during the remaining 30 minutes of azygos flow and produced a decrease in venous pCO2 and in arterial and venous base deficit (Table 2 and Fig. 1). The lowest arterial pH, the maximum pCO2 and base defcit in all 3 groups were observed in samples taken 5 minutes after resumption of caval flow. The magnitude of base defter as well as the degree of its increase over that at the end of 40 minutes of azygos flow appeared to correlate with the survival rate (Fig. 1). Blood Pressure
The depth of arterial hypotension during the first 10 minutes of azygos flow, was eomparable in the 3 groups. In the control groups a further drop in both
INFLUENCE
OF THAM
ON
Group I
SURVIVAL IN METABOLIC
Group II
Group III
49
ACIDOSIS
Group II 8 Dogs
Group I 0
Group III 4 Dogs
10
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30 120 Z
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Fig. 2.--Maximum base deficit and maximum blood pressure recorded during the first 10 minutes after azygos flow. The figures represent the mean for each group (group I--control, group II--THAM infusion, group III--glucose infusion). *Two other dogs developed Ventricular fibrillation immediately after caval release. systolic and diastolic blood pressure occurred during the remaining 30 minutes of azygos flow except in the 4 surviving dogs in group III (glucose infusion), In group II, during the infusion of THAM, a tendency for gradual elevation in blood pressure was noted in most of the dogs. Of particular interest was the recovery of blood pressure after caval flow was resumed. In the THAM-treated group, maximum pressures were obtained within the first 10 minutes after resumption of caval flow. A rebound elevation over control level was observed at this time in both systolic and diastolic pressures in all survivors (Fig. 2). In the control groups, and in the 2 dogs that failed to survive despite THAM, maximum pressures during the first 10 minutes after restoration of caval flow were lower than control levels. In all dogs the venous pressure rose immediately after caval occlusion. In survivors of the THAM group the venous pressure at the end of the 40 minutes of azygos flow was higher than that recorded at 10 minutes of such diminished flow. The rise was less in survivors of group III (glucose infusion). In contrast, all other animals showed a gradual fall in venous pressure associated with the increase in metabolic acidosis during azygos flow. The 4 survivors in group III (glucose infusion) exhibited a higher average arterial pressure during, and at the end of azygos flow than that recorded in the rest of the animals in this study, including those surviving with THAM. This was associated with a base deficit after caval release greater than that seen in survivors in the THAM group, but less than the deficit in dogs that died in all 3 groups. Two of the 10 dogs in the THAM group (group II) failed to survive
50
SROUJI, TRUSLEn AND ZINGG
although arterial pressure and spontaneous respiration recovered following resumption of caval flow. Both received the standard dose of THAM in relation to body weight. At the end of 40 minutes of azygos flow these 2 dogs had a very high arteriovenous difference in pH and pCO2, and a large base deficit exceeded only by that observed in the dogs that developed ventricular fibrillation immediately after caval release. After resumption of caval flow, the maximum base deficit, found in these 2 dogs, was greater than that in the survivors in group II (THAM infusion) and group III (glucose infusion). DISCUSSION The azygos flow principle has been used in a number of studies to investigate the effect of hypoperfusion on survival, and influence of resulting metabolic acidosis on cardiovascular function. Survival has varied in the different reports but no long-term survival is reported with azygos flow beyond 35 minutes. Andreason and Watson 2 demonstrated survival with 35 minutes of azygos flow but had no satisfactory survivors with longer periods despite hyperventilation with oxygen. Owens et ald using a similar technic, reported no survivors with azygos flow of more than 35 minutes under normothermie or hypothermic conditions. Cohen and Lillihei 4 limited the duration of azygos flow to 30 minutes in their study of 20 dogs and reported 17 survivors with no pathology when sacrificed 4 to 29 days after the experiment. In this study azygos flow was maintained for 40 minutes. In contrast to the compensatory hyperventilation used in the previous studies, ventilation in the present study was adjusted to obtain an arterial pH and pCO2 in the normal range, in an attempt to standardize the control state of the animals. Hyperventilation is known to result in depression of plasma bicarbonate level with an increase in renal excretion of bicarbonate and potassium leading to loss of buffer base. s,9 Respiratory alkalosis is also associated with accumulation of lactic acid and partial utilization of cellular buffers, l~ McKenzie et al. 11 attributed reduction in whole blood buffer base in hyperventilated dogs to the development of metabolic acidosis secondary to respiratory alkalosis. In experimental studies, animals breathing room air during hemorrhagic shock tend to have a low arterial oxygen saturation22 Gerst et al) 3 showed that decrease in pulmonary blood flow results in a significant increase in the alveolar dead space. Hypoxemia appears to have influenced results of studies 12,14 relating survival to treatment of acidosis in hemorrhagic shock, and has led to discrediting THAM and the importance of correction of acidosis in reducing or eliminating the incidence of irreversibility. 14 Manger et al) 2 using THAM and sodium bicarbonate in hemorrhagic shock showed that survival rate is improved only when both pH control and increased arterial oxygen content are achieved. These authors pointed out that treatment of acidosis with adequate oxygenation will improve oxygen utilization and delay onset of irreversible phase in shock. The significance of the endotoxic factor in relation to survival in experimental hypotension in dogs is difficult to evaluate and control. In this study, an attempt was made to exclude this factor by giving antibiotics orally preoperatively as well as intravenously prior to onset of azygos flow.
INFLUENCE
OF THAM
O N SURVIVAL I N M E T A B O L I C
ACIDOSIS
51
The early onset of metabolic acidosis with low tissue perfusion has been demonstrated in numerous reports comparing flow rates in eardiopulmonary bypass. Similar metabolic studies have shown the early onset of metabolic acidosis with 10 minutes of azygos flow?, 5,~,15 In the study of Cohen and Lillihei 4 the azygos flow was estimated to be 8-14 ee./Kg./minute, which is less than 10 per cent of the generally accepted basal cardiac output for anesthetized dogs. Progressive increase in acidosis with longer periods of azygos flow appears to be a very important factor in survival and one of the limiting factors in the previously reported studies. In this investigation an estimate of the naagnitude of tissue acidosis resulting from 40 minutes of azygos flow was obtained from the sampled circulating mixed arterial blood 5 minutes after resumption of caval flow in control group I. In the THAM-treated dogs, the total dose was infused between 10 to 35 minutes of azygos flow to allow satisfactory distribution and equilibration with accessible tissues before the blood sample at the termination of azygos flow was collected (Fig, 1). Schwartz et al. 1~ studying the distribution of administered hydrogen ion with continuous versus intermittent infusion demonstrated the importance of obtaining a representative blood sample by allowing time for attaining equilibrium with the tissues. Of interest in the present study is the correlation of mortality rate with the severity of base deficit observed 5 minutes after resumption of normal flow, as well as the increase of that value over the base deficit obtained at the end of 40 minutes of azygos flow (Fig. 1). The increase of the base deficit after eaval release reflected the degree of tissue hypoxia and anaerobic metabolism during the period of azygos flow. This also indicates the inability of blood samples obtained during a state of tissue hypoperfusion to reflect the degree of tissue acidosis. Crowell et al. have shown the relationship of tissue acidity 17 and intravascular coagulation is to irreversibility of shock. This led to the use of vasodilators in shock, 19,2~ and their influence on occurrence of disseminated intravaseular coagulation. 2t Two dogs in the THAM-treated group failed to survive, though at 40 minutes of azygos flow the arterial blood was only slightly acidotic. However, the precipitous fall in arterial pH and marked increase in base deficit soon after the return of normal tissue perfusion and blood mixing indicate the severity of the tissue acidosis during the period of hypotension (Fig. 1). Arteriolar vasoconstriction and stagnation in the capillary vascular beds masked the degree of acidosis at the cellular level. The clinical implications of these findings are evident. Reassessment of the base deficit after successful resuscitation of circulatory failure is mandatory to prevent the deleterious effects of acidosis and recurrence of hypotension. Sudden release of acid metabolites from previously poorly perfused tissues may flood the coronary circulation causing an immediate deterioration of myocardial contractility 5,1~ and lowering the threshold for ventricular fibrillation32 Survival in 4 dogs of the control group given glucose (group III) may have been related to the higher arterial pressure than that recorded in the rest of the animals during the period of azygos flow. It is postulated that the higher
59~
SROUJI, TRUSLEI:~ AND Z1NGG
arterial pressure reflected better tissue perfusion, which is supported by the smaller increase in base deficit observed in these dogs following caval release (Fig. 1). A rebound increase in blood pressure after 10 minutes of azygos flow or low tissue perfusion with cardiopulmonary bypass has been related to marked increase in circulating eatecholamines. 3,~'G'15 However, when the period of low tissue perfusion was increased to 15-30 minutes no rebound elevation in blood pressure was observed, and the blood pressure frequently failed to return to normal control levelsY ,1~ In the present study, all untreated dogs failed to show a rebound elevation in blood pressure in contrast to survivors in the THAMtreated group where the rebound phenomenon was observed even after 40 minutes of azygos flow, particularly in those showing the least base deficit after eaval release (Fig. 2). Several authors 5,15,e:~2~ have demonstrated decreased myocardial contractility, cardiac output, and blood pressure in the acidotic state with decreased response to exogenous sympathomimetic drugs, and marked improvement in response after correction of the acidosis. Endogenous cateeholamines are markedly increased in response to hypotension and hypoxia. 3,6,12 Acidosis per se is also considered a potent factor in increasing endogenous cathecholamine production22,z7,28 Thus, the controversial need for exogenous sympathomimetic amines may be reduced or totally obviated by early correction of the acidosis thus activating the normal response to abundantly available endogenous catecholamines. It was further shown by Nahas et al. 27 that an increase in oxygen uptake due to elevated levels of cateeholamines occurs in presence of normal or alkaline pH but not in acidosis. Susceptibility to ventricular fibrillation has been shown by Gerst et al. "-'-~to be directly related to excess of fixed acids, while a base excess has a protective action. Restoring pH alone to normal by hyperventilation does not reduce the risk of ventrieular fibrillation in presence of a base deficit. Clinically, the dosage, concentration, and rate of administration depend on severity and urgency of the condition under treatment, the need for restriction of I.V. fluids as well as the concurrent presence of mechanical ventilation or its ready availability2 Due to its hypoglycemie action in large doses THAM is usually dissolved in 5-10 per cent glucose in water. Under the experimental conditions of this study no untoward effects were observed with one Molar solution of THAM in 10 per cent glucose in water with controlled ventilation. SUMMARY AND CONCLUSIONS
Metabolic acidosis associated with hypoperfusion was induced by subjecting 25 dogs to azygos flow for 40 minutes. In the control groups, 11 of the 15 dogs subsequently died. In contrast, 8 of the 10 dogs given THAM survived. Two deaths in the THAM group were related to severe uncorrected base deficit, indicating insufficient THAM treatment. The data lead to the following conclusions: 1. Survival appears to be inversely related to severity of metabolic acidosis as well as to the increase of base deficit after resumption of normal flow.
INFLUENCE OF THA3/I ON SUllVIVAL IN I~r
ACIDOSIS
53
2. Given i n a d e q u a t e dosage, T H A M improves survival u n d e r conditions of n o n h e m o r r h a g i c low tissue perfusion in presence of elevated arterial oxygen tension. 3. T h e s p e e d of r e c o v e r y of b l o o d pressure following caval release was related to acid base status. A r e b o u n d increase over control levels o b s e r v e d in survivors in the T H A M - t r e a t e d g r o u p was absent in b o t h control groups. 4. T h e d a t a p r e s e n t e d indicate t h a t p H determinations alone are i n a d e q u a t e in assessing the acid-base status, a n d can be misleading in p l a n n i n g optimal treatment. Base excess is a m o r e relevant guide for evaluation a n d t h e r a p y for states associated w i t h h y p o p e r f u s i o n . 5. Prior to restoration of a d e q u a t e tissue perfusion, arterial acid-base values do n o t reflect the m a g n i t u d e of tissue m e t a b o l i c acidosis. W h e n n o r m a l perfusion returns, the acid metabolites released from the tissues m a y p r o d u c e deleterious circulatory effects. SUMMARIO IN I N T E R L I N G U A Sub conditiones de respiration controlate, permittente un alte tension arterial de oxygeno, le principio del "fluxo de azygos" esseva usate in inducer hypoperfusion e acidosis metabolic. Le severitate del acidosis tissu]ar non esseva satisfactorimente manffeste in specimens de sanguine obtenite durante le hypoperfusion, pro que deficits maximal de base arterial occurreva tosto post le re-initiation de un adequate perfusion tissular. Dece-un de 15 canes de controlo moriva, durante que 8 de 10 canes tractate con un predeterminate dose de solution de THAM superviveva. Le superviventia pare esser relationate con le severitate del acidosis metabolic. ACKNOWLEDGMENTS We wish to thank Dr. L. Te for his assistance with anesthetic administration and control of ventilation, and Mrs. M. Scott, Miss S. Spicer and Mr. M. Behamdouni for their technical help. REFERENCES
1. Nahas, G. G.: The clinical pharmacology of THAM tris (hydroxymethyl) aminomethane. Clin. Pharmac. Therap. 4:783, 1963. 2. Andreason, A. T., and Watson, F.: Experimental cardiovascular surgery, "the azygos factor." Brit. J. Surg. 39: 548, 1952. 3. Belisle, C. A., Woods, E. F., Nunn, D. B., Parkes, E. F., Lee, W. H., Jr., and Richradson, J. H.: The role of epinephrine and norepinephrine in rebound cardiovascular phenomena in azygos flow studies of cardiopulmonary bypass in dogs. J. Thoracic & Cardiovas. Surg. 39:815, 1960. 4. Cohen, M., and Lillihei, C. W.: A quantitative study of the "azygos factor" during vena caval occlusion in the dog. Surg. Gynec. Obst. 98:225, 1954.
5. Darby, T. D., Aldinger, E. E., Gadsden~ t/. H., and Thrower, W. B.: Effects of metabolic acidosis on ventricular isometric systolic tension and the response to epinephrine and levarterenol. Circ. Res. 8:1242, 1960. 6. Lee, W. H., Jr., Darby, T. D., Ashmore, J. D., and Parker, E. F.: Myocardial contractile force as a measure of cardiac function during cardiopulmonary bypass procedures. Surg. Forum 8: 398, 1958. 7. Owens, J. C., Liddle, E. B., Tune, L., and Zeavin, I.: Studies on occlusion of the inferior vena cava above and below the hepatic vein in normothermic and hypothermic dogs. Surg. Forum 4:63, 1953. 8. Barker, E. S., Singer, R. B., Elkinton, J. R., and Clark, J. K.: The renal response in man to acute experimental
54 respiratory alkalosis and acidosis. J. Clin. Invest. 36:515, 1957. 9. Eickenholtz, A., Mulhausen, R. Q., Anderson, W. E., and MacDonald, F. M.: Primary hypocapnia: a cause of metabolic acidosis. J. Appl. Physiol. 17:283, 1962. 10. Nims, L. F., Gibbs, E. L., and Lennox, W. G.: Arterial and cerebral venous blood changes produced by altering arterial CO 0. J. Biol. Chem. 145:189, 1942. 11. MacKenzie, G. J., Davis, S, H., Mason, A. H. B., and Wade, J. D.: Causes of metabolic acidosis in extracorporeal circulation at normothermia. Thorax 18:215, 1963. 12. Manger, W, M., Nahas, G. G., Hassam, D., Habif, D. V., and Papper, E. M.: Effect of pH control and increased 02 delivery on the course of hemorrhagic shock. Ann. Surg. 156:503, 1962. 13. Gerst, P. H., Rattenberg, C., and Holaday, D. A.: The effects of hemorrhage on pulmonary circulation and respiratory gas exchange. J. Clin. Invest. 38: 524, 1959. 14. Selmonosky, C. A., Goetz, R. H., and State, D.: The role of acidosis in the irreversibility of experimental hemorrhagic shock. J.S.R. 3:491, 1963. 15. Thrower, E. B., Darby, T. D., and Aldinger, E. E.: Acid-base derangements and myocardial contractility. Arch. Surg. 82:56, 1961. 16. Schwartz, W. T., Orning, K. J., and Porter, R.: The internal distribution of hydrogen ions with varying degrees of metabolic acidosis. J. Clin. Invest. 36: 373, 1957. 17. Crowell, J. W., Bounds, S. H., and Johnson, W. W.: Effects of varying the hematocrit ratio on the susceptibility to hemorrhagic shock. Amer. J. Physiol. 192:171, 1958. 1 8 . - - , Sharpe, G. P., Lambright, R. L., and Read, W. L.: The mechanism of death after resuscitation following acute circulatory failure. Surgery 38: 696, 1955. 19. Nickerson, M.: Drug therapy of shock. In K. D. Bock (Ed.) Shock, Patho-
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genesis and Therapy. Berlin-Gottingen, Heidelberg, Springer-Verlag. 1962, p. 356. Remington, J. W., Hemilton, W. J., Boyd, G. H., Hamilton, W. F., Jr., and Caddell, H. M.: Role of vasoconstriction in the response,of the dog to hemorrhage. Amer. J. Physiol. 161: 116, 1950. Hardaway, R. N., Elovitz, M. J., Brewster, W. R., Jr., Houchin, D. N., Renzi, N. L., and Jackson, D. R.: Influence of vasoconstrictors and vasodilators on disseminated intravascular coagulation in irreversible hemorrhagic shock. Surg. Gynee. Obst. 119: 1053, 1964. Gerst, P. H., Fleming, W. H., and Maim, J. R.: Relationship between acidosis and ventrieular fibrillation. Surg. Forum 15:242, 1964. Campbell, G. S., Houle, D. B., Crisp, N. W., Jr., Weil, M. H., and Brown, E. B.: Depressed response to I.V. sympathicomimetie agents in humans during acidosis. Dis. Chest 33: I8, 1958. Clowes, G. H. A., Jr., Sabgha, 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. Kirtle, C. F., Aoki, H., and Brown, E. B., Jr.: The role of pH and CO 2 in the distribution of blood flow. Surgery 57:139, 1965. Well, M. H., Houle, D. B., Brown, E. B., Jr., and Campbell, G. S.: Influence of acidosis on the effectiveness of the vasopressor agents. Circulation 16:949, 1957. Nahas, G. G., Ligou, J. G., and Mehlman, B.: Effects of pH changes on 0 2 uptake and plasma catecholamine levels in the dog. Amer. J. Physiol. I98:60, 1960. Woods, E. F., and Richardson, J. A.: Survey of agents producing cardiovascular manifestations of epinephrine discharge. J. Pharmacol. Exper. Therap. 114:445, 1955.