M. TANAKA, T. NISHIKAWA AND T. MIZUTANI

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1 British Journal of Anaesthesia 1996;77: Normovolaemic haemodilution attenuates cardiac depression induced by sodium bicarbonate in canine metabolic acidosis M. TANAKA, T. NISHIKAWA AND T. MIZUTANI Summary This study was designed to determine if coexisting metabolic acidosis or normovolaemic haemodilution, or both, modifies the acute cardiodepressant effect of i.v. sodium bicarbonate. Thirty-one mongrel dogs were anaesthetized with halothane, and the lungs ventilated mechanically; dogs were allocated randomly to one of four groups: control group (pha 7.39 (SD 0.03), base excess 1.0 (1.6) mmol litre 1, haemoglobin 13.9 (.5) g dl 1 (n 8)), metabolic acidosis group (pha 7.1 (0.05), base excess 11. (.1) mmol litre 1, haemoglobin 13.4 (.6) g dl 1 (n 8)), anaemia group (pha 7.40 (0.04), base excess 0.1 (.0) mmol litre 1, haemoglobin 7. (1.1) g dl 1 (n 8)) or anaemia acidosis group (pha 7. (0.04), base excess 11.0 (.) mmol litre 1, haemoglobin 7.4 (0.3) g dl 1 (n 7)). Metabolic acidosis was induced by continuous i.v. infusion of hydrochloric acid mol litre 1. Normovolaemic haemodilution was undertaken by phlebotomy and simultaneous exchange with lactated Ringer s solution at 37 C. Mean arterial pressure (MAP), pulmonary artery pressure, right atrial pressure (RAP), maximum rate of change of pressure in the right ventricle (RV dp/dtmax) and pulmonary blood flow (PBF) were measured at 30 s, 1 and 3 min after administration of 7% sodium bicarbonate solution 1 mmol kg 1 given into the right atrium over 5 s. Sodium bicarbonate produced significant decreases in MAP and RV dp/dtmax at 30 s in all groups except for the anaemia acidosis group (P 0.05). There was a significant decrease in right ventricular stroke volume in the metabolic acidosis group from baseline values (P 0.05), and compared with the three other groups (P 0.05). These results indicate that the cardiodepressant effect of sodium bicarbonate 1 mmol kg 1 i.v. during metabolic acidosis was more pronounced than without acidosis, but was attenuated in the presence of normovolaemic haemodilution. (Br. J. Anaesth. 1996;77:408 41) Key words Acid base equilibrium, metabolic acidosis. Acid-base equilibrium, respiratory acidosis. Complications, hypercapnia. Pharmacology, sodium bicarbonate. Dog. Massive haemorrhage and systemic hypotension treated by replacement with crystalloid solution are frequently accompanied by metabolic acidosis and haemodilution. Although administration of sodium bicarbonate may be considered in these situations, it may reduce peripheral oxygen availability by increaseing extracellular ph 1 and produce paradoxical intracellular acidosis by free diffusion of carbon dioxide liberated from bicarbonate 3. Depression of cardiac performance and peripheral vascular dilatation as a result of paradoxical intracellular acidosis have been implicated in circulatory alterations after bicarbonate administration 4. A combination of these effects has detrimental consequences both metabolically and haemodynamically 5 6. A recent study has demonstrated that maximum depression of cardiac performance by bicarbonate is more pronounced during metabolic acidosis than without acidosis in in vivo canine preparations 7. When normovolaemia is maintained, progressive anaemia causes a modest increase in cardiac output with little change in arterial pressure and heart rate (HR) in both humans 8 9 and animals Systemic vascular resistance is decreased because of peripheral vascular dilatation secondary to anaemia. The pharmacologically depressed myocardium has diminished ability to increase cardiac output in response to haemodilution 10. How augmentation of cardiac output in response to haemodilution is modified by the presence of metabolic acidosis is unknown. In addition, the effects of coexisting metabolic acidosis and normovolaemic haemodilution on myocardial depression produced by sodium bicarbonate have not been examined. This study was designed in an in vivo canine preparation to assess the effects of normovolaemic haemodilution on the acute cardiovascular effects of sodium bicarbonate at physiological arterial ph (pha) and with metabolic acidosis at a pha value of approximately 7.. Materials and methods The study was approved by our institutional Animal Care Committee. We studied 3 adult mongrel dogs of both sexes, weighing kg. All dogs were M. TANAKA, MD, Department of Anaesthesia/Critical Care Medicine, Tsuchiura Kyodo General Hospital, Tsuchiura, Ibaraki and Department of Anaesthesiology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan. T. NISHIKAWA, MD, T. MIZUTANI, MD, Department of Anaesthesia, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan. Accepted for publication: April 5, Correspondence to M.T. Presented in part at the annual meeting of the American Society of Anesthesiologists, San Francisco, CA, October 1994.

2 Haemodilution, acidosis and bicarbonate 409 anaesthetized with thiamylal 15 mg kg 1 and the trachea intubated. The lungs were ventilated mechanically with room air supplemented with oxygen via a cuffed tracheal tube, using a volume-cycled animal ventilator (model R-60, Aika Co., Ltd, Tokyo, Japan). End-tidal halothane concentrations were measured continuously (Capnomac Ultima, Datex, Helsinki, Finland) and maintained at %. Suxamethonium 0 mg was given i.v. at the time of tracheal intubation followed by 10 mg h 1 thereafter to produce neuromuscular block. During all measurements, pulmonary arterial blood temperature was maintained at C. Lactated Ringer s solution was administered at a constant rate of 10 ml kg 1 h 1 during surgical preparation and equilibration period, followed by 5 ml kg 1 h 1 during haemodynamic measurements. An i.v. cannula was inserted into a forelimb vein for administration of lactated Ringer s solution. Lead II of the electrocardiogram (model 36A, NEC San-ei Instruments Co., Ltd, Tokyo, Japan) was monitored continuously using subcutaneous electrodes. HR was measured on a beat-to-beat basis by a cardiotachometer (model 131, NEC San-ei Instruments Co., Ltd, Tokyo, Japan) triggered by lead II of the electrocardiogram. Measurement of arterial pressure and blood sampling for blood-gas analysis and measurement of haemoglobin concentration (88 Blood Gas System, Ciba-Corning, Medfield, MA, USA) were performed via the femoral arterial catheter. A flow-directed, balloon-tipped pulmonary artery catheter (5Fr Thermodilution Catheter, Arrow, Reading, PA, USA) was inserted via the femoral vein to permit continuous monitoring of pulmonary artery pressure. Another catheter was positioned in the right atrium from the contralateral femoral vein for monitoring right atrial pressure (RAP). A 5-French gauge catheter-tipped transducer (model MPC-500, Miller Instruments Inc., Houston, TX, USA) was inserted via the right external jugular vein and positioned in the right ventricle to obtain maximum rate of change of pressure in the right ventricle (RV dp/dtmax) using a differential amplifier (model 133, NEC San-ei Instruments Co., Ltd, Tokyo, Japan). After the pulmonary trunk was dissected free of the surrounding tissue through a left-sided thoracotomy in the fourth intercostal space, an electromagnetic flow probe of appropriate size (model FR 1 16 mm, Nihon-Koden Co., Ltd, Tokyo, Japan) was placed around the pulmonary trunk for continuous measurement of pulmonary blood flow (PBF). The flow probe was calibrated with 0.9% saline solution in vitro before implantation, and PBF was measured continuously with a square-wave electromagnetic blood flowmeter (model MFV-300, NihonKoden Co., Ltd, Tokyo, Japan). All recordings were made on an eight-channel recorder (model Recti-Horiz-8K, NEC San-ei Instruments Co., Ltd, Tokyo, Japan). The dogs were allocated randomly to one of four groups: control (n 8), metabolic acidosis (n 8), anaemia (n 8) or anaemia acidosis (n 8). After a stabilization period of at least h after the surgical procedures, in the control group ( Pa CO kpa and base excess 3 mmol litre 1 ) 7% sodium bicarbonate solution 1 mmol kg 1 (1. ml kg 1 ) was given into the right atrium over 5 s, and haemodynamic variables were recorded continuously for 3 min. Ventilator settings were kept constant during these measurements. Metabolic acidosis of base deficit less than 8 mmol litre 1 was induced and maintained in the metabolic acidosis group by continuous infusion of hydrochloric acid mol litre 1 at an approximate rate of ml h 1, while Pa CO was maintained at kpa. After a stabilization period of at least h, after establishment of the target metabolic acidosis, 7% sodium bicarbonate solution 1 mmol kg 1 (1. ml kg 1 ) was given into the right atrium over 5 s, and the same haemodynamic measurements made. The anaemia and anaemia acidosis groups were treated similarly to the control and metabolic acidosis groups except that normovolaemic haemodilution was produced to obtain haemoglobin concentrations of g dl 1. Normovolaemia was produced by phlebotomy and simultaneous exchange with lactated Ringer s solution at 37 C in a ratio of approximately 1:3 aided by the stability of pulmonary artery occlusion pressure (PAOP). In the anaemia acidosis group, haemodilution preceded metabolic acidosis. All values are expressed as mean (SD). Both mean arterial pressure (MAP) and mean pulmonary artery pressure (MPAP) were obtained by electronic integration of pulse pressure. Right ventricular stroke volume (RVSV) was calculated as PBF divided by HR. Analysis of changes in haemodynamic variables from baseline (30 s, 1 and 3 min) and comparison of data between the four groups (baseline values and maximum changes from baseline) were performed using one-way and two-way ANOVA, respectively, followed by the Student s t test with Bonferroni s correction. P 0.05 was considered the minimum level of statistical significance. Results One dog from the anaemia acidosis group died before completing the study and only data from the remaining 31 dogs were analysed. Mean values of pha and base excess in the metabolic acidosis and anaemia acidosis groups were significantly lower than those in the control and anaemia groups, whereas there were no differences in P a CO, and P a O values between the groups (table 1). Haemoglobin concentrations in the anaemia and anaemia acidosis groups were significantly lower than those in the control and metabolic acidosis groups (table 1). There were no differences in plasma electrolyte concentrations between the groups (table 1). There were no differences in PAOP values before and after haemodilution, immediately before administration of sodium bicarbonate in the anaemia group (6.5 (3.) vs 6.7 (3.3) mm Hg, respectively) and in the anaemia acidosis group (5.4 (0.9) vs 5. (1.3) mm Hg, respectively). Before administration of sodium bicarbonate, PBF in the anaemia acidosis group was significantly greater than in the control group (P 0.05, table ). Similarly, RVSV in the anaemia acidosis group was significantly greater than that in the control and metabolic acidosis groups (P 0.05, table ). Compared with baseline values, administration of 7% sodium bicarbonate 1. ml kg 1 produced consistent but transient increases in RAP in all groups (P 0.05, table ). Transient but signifi-

3 410 British Journal of Anaesthesia Table 1 Arterial blood-gas values are electrolyte and haemoglobin concentrations (mean (SD)). *P 0.05 vs control and anaemia groups. P 0.05 vs control and metabolic acidosis groups Group Control (n 8) Metabolic acidosis (n 8) Anaemia (n 8) Anaemia acidosis (n 7) Arterial blood-gas pha 7.39 (0.03) 7.1 (0.05)* 7.40 (0.04) 7. (0.04)* P a CO (kpa) 5. (0.4) 5.4 (0.4) 5.3 (0.3) 5. (0.1) P a O (kpa) 15.8 (3.7) 14. (4.1) 19.7 (4.9) 17.3 (5.3) Base-excess (mmol litre 1 ) 1.0 (1.6) 11. (.1)* 0.1 (.0) 11.0 (.)* Electrolytes Na (mmol litre 1 ) 147 (5) 146 (5) 144 (5) 145 (5) K (mmol litre 1 ) 3.0 (0.5) 3. (0.5) 3.4 (0.3) 3.4 (0.7) Ca + (mmol litre 1 ) 1. (0.1) 1. (0.1) 1.1 (0.1) 1.1 (0.1) Haemoglobin (g dl 1 ) 13.9 (.5) 13.4 (.6) 7. (0.) 7.4 (0.3) Table Baseline haemodynamic values and percentage change in haemodynamic responses to bolus injection of sodium bicarbonate 1 mmol kg 1 (mean (SD)). *P 0.05 vs control and metabolic acidosis groups. P 0.05 vs control, anaemia and anaemia acidosis groups. P 0.05 vs control group. P 0.05 vs baseline values; MAP Mean arterial pressure (mm Hg); HR Heart rate (beat min 1 ); MPAP Mean pulmonary artery pressure (mm Hg); RAP Right atrial pressure (mm Hg); RV dp/dtmax Maximum rate of change of pressure in the right ventricle (mm Hg s 1 ); PBF Pulmonary blood flow (litre min 1 ); RVSV Right ventricular stroke volume (ml) Time after injection Baseline 30 s 1 min 3 min Control group (n=8) MAP 97 (3) 13.5 (5.5) 1.1 (4.7).8 (.3) HR 119 (4).9 (6.0).8 (.4).0 (3.7) MPAP 14.3 (3.4) 0.9 (6.0) 5.9 (6.7) 3.8 (5.) RAP 1.3 (1.0) 185 (169) 10 (13) 31 (41) RV dp/dtmax 590 (117) 1.5 (9.8) 8.9 (5.7) 3.3 (6.0) PBF 1.41 (0.1) 8.4 (7.9) 8.4 (6.0) 10.1 (5.9) RVSV 1. (.4) 5.6 (4.6) 6.5 (5.8) 8.0 (7.1) Metabolic acidosis group (n=8) MAP 80 (19) 9.7 (7.9) 1. (14.4) 6.7 (5.4) HR 131 (0) 0.3 (4.) 0. (.0) 0.9 (.7) MPAP 16.6 (9.5) 0.7 (13.8) 4.3 (11.0) 1.0 (1.8) RAP.3 (.3) 101 (59) 71 (167) 18 (7) RV dp/dtmax 586 (110) 1.8 (1.8) 11.0 (13.5) 0. (6.5) PBF 1.46 (0.46) 5.8 (1.1). (14.6) 9. (8.0) RVSV 11.3 (3.) 1.6 (5.5) 5.6 (4.3) 3.9 (4.9) Anaemia group (n=8) MAP 84 (13) 11.1 (5.6) 4.1 (4.1) 1.3 (1.8) HR 1 (13) 4.0 (6.0).9 (3.7).3 (.3) MPAP 1.9 (3.7) 1.8 (5.9) 4.5 (4.0) 0.8 (6.8) RAP 1.3 (1.5) 150 (190) 96 (19) 16 (6) RV dp/dtmax 535 (88) 16.9 (10.0) 7.0 (9.) 1.1 (5.1) PBF 1.7 (0.3) 8.7 (8.3) 7.4 (7.1) 9. (5.1) RVSV 14. (3.1) 4.6 (6.5) 4.4 (6.4) 6.9 (5.9) Anaemia acidosis group (n=7) MAP 85 (10) 6.7 (7.9) 7.8 (10.3) 5.6 (6.4) HR 11 (15) 1.1 (3.9) 0.8 (.6) 0.8 (0.9) MPAP 15.4 (3.4) 0.4 (7.1) 4.3 (10.0) 1.9 (3.7) RAP.3 (1.5) 66 (79) 47 (47) 0 (14) RV dp/dtmax 609 (158) 10.5 (7.8).8 (9.) 1.0 (9.) PBF 1.91 (0.38) 1.0 (1.1).0 (9.0) 4.8 (5.5) RVSV 16.1 (3.6)* 3.3 (4.7) 1. (5.0) 4.1 (6.) cant decreases in MAP and RV dp/dtmax occurred in all groups except for the anaemia acidosis group. In the non-acidosis groups (the control and anaemia groups), PBF and RVSV increased significantly from baseline values at the end of the observation period. PBF and RVSV values in the metabolic acidosis group decreased significantly for a period of 1 min after administration of sodium bicarbonate. The percentage reduction in RVSV in the metabolic acidosis group at 30 s after administration of bicarbonate was significantly more than in the three other groups (P 0.05, table ). HR was unchanged after administration of sodium bicarbonate in all groups. The mean times at which maximum changes in MAP, RV

4 Haemodilution, acidosis and bicarbonate 411 dp/dtmax and PBF occurred were all within 0 s of bicarbonate administration: MAP: 18 (7), 19 (11), 17 (4), 13 (4) s; RV dp/dtmax: 16 (), 0 (4), 14 (3), 16 (4) s; PBF: 17 (3), 0 (6), 15 (6), 17 (6) s in the control, metabolic acidosis, anaemia and anaemia acidosis groups, respectively. Discussion We have observed cardiodepressant effects associated with rapid administration of sodium bicarbonate 1 mmol kg 1 in control, metabolic acidosis and anaemia groups, demonstrated by significant depression of RV dp/dtmax, and this response was attenuated in the anaemia acidosis group. It is not explained simply by dilution, as depression of RV dp/dtmax was also observed in the anaemia group. Maximum reductions in RV dp/dtmax, PBF and MAP occurred within 0 s of administration of bicarbonate, but the changes were transient. Although the extent and duration of these changes may not be clinically important, they may be significant in patients undergoing cardiopulmonary bypass where normovolaemic haemodilution is practised, and also after massive bleeding and haemodilution complicated by metabolic acidosis. The cardiodepressant effect of bicarbonate is considered to be caused by a rapid decrease in the intracellular ph of the myocardium caused by free diffusion of carbon dioxide liberated from bicarbonate, rather than a result of volume expansion 13. The fact that such a detrimental effect of bicarbonate is more pronounced during metabolic acidosis suggests that a further reduction in intramyocardial ph occurs with pre-existing extracellular acidosis at pha 7.. A marginally reduced intracellular ph is not cardiodepressant in itself, as evidenced by comparable haemodynamic variables between the control and metabolic acidosis groups in our study and previous experiments It is not clear from our study why the haemodynamic response to sodium bicarbonate was more pronounced during metabolic acidosis but less marked when there was coexisting normovolaemic haemodilution. Clinical 8 9 and experimental 10 1 studies have observed typical responses to normovolaemic haemodilution characterized by an increase in stroke volume and cardiac index, and a decrease in systemic vascular resistance, with essentially no changes in arterial pressure and HR. One possible explanation is that these underlying haemodynamic changes induced by haemodilution may have counteracted the cardiodepressant effect of bicarbonate. There are three possible shortcomings to our study. First, this was not a dose response study, and interpretation of the results should be confined to the doses studied. Most importantly, bicarbonate was given over a brief period of time. A smaller dose of bicarbonate or slower speed of injection could have resulted in less depression of the myocardium 4. The dose of bicarbonate in our study has been used in previous studies and is recommended in some circumstances during cardiopulmonary resuscitation In addition, the degree of metabolic acidosis studied would not be expected to produce significant cardiovascular depression With more profound acidosis where myocardial depression caused by aci- dosis per se is apparent, cardiac depression induced by bolus administration of bicarbonate may be more aggravated. Second, we did not determine circulating blood volume. In previous experiments, a ratio of 1:.5 of bleeding and exchange crystalloid infusion resulted in a constant blood volume estimated by 15 I-labelled albumin in dogs 11. In contrast, exchange transfusion with a ratio of 1:3 has been reported to produce progressive metabolic acidosis, hypovolaemia and eventually death 19. These previous conflicting results may be attributed in part to the differences in time for equilibration. Our study has confirmed that an equilibration period of at least h is required after surgical preparation, establishment of acidosis or haemodilution, during which lactated Ringer s solution was infused continuously. A significant amount of extravasation of plasma, had it occurred during this period, must have been replaced, as indicated by the unchanged PAOP before and after haemodilution, before administratin of bicarbonate in the anaemia and anaemia acidosis groups. Third, administration of hydrochloric acid effectively induced extracellular acidosis, but we did not measure intracellular ph. However, greater depression of cardiac performance with administration of bicarbonate in the metabolic acidosis group than in the control group suggests marginally disturbed intracellular environment by maintenance of extracellular ph at 7. for h or longer. In an in vivo experiment using rabbits, i.v. infusion of hydrochloric acid followed by an equilibration period of 1 h produced dose-dependent linear decreases in intracellular ph of the left ventricular myocardium 0. References 1. Arieff AI. Indications for use of bicarbonate in patients with metabolic acidosis. British Journal of Anaesthesia 1991; 67: Planta M, Weil MH, Gazmuri RJ, Bisera J, Rackow EC. Myocardial acidosis associated with CO production during cardiac arrest and resuscitation. Circulation 1989; 80: Clancy RL, Cingolani HE, Taylor RR, Graham TP, Gilmore JP. Influence of sodium bicarbonate on myocardial performance. American Journal of Physiology 1967; 1: Huseby JS, Gumprecht DG. Hemodynamic effect of rapid bolus hypertonic sodium bicarbonate. Chest 1981; 79: Graf H, Leach W, Arieff AI. Evidence for a detrimental effect of bicarbonate therapy in hypoxic lactic acidosis. Science 1985; 7: Bersin RM, Chatterjee K, Arieff AI. Metabolic and hemodynamic consequences of sodium bicarbonate administration in patients with heart disease. American Journal of Medicine 1989; 87: Tanaka M, Nishikawa T. Acute hemodynamic changes by sodium bicarbonate in respiratory or metabolic acidosis in dogs. Anesthesiology 1994; 81: A Mouren S, Baron JF, Hag B, Arthaud M, Viars P. Normovolemic hemodilution and lumbar extradural anesthesia. Anesthesia and Analgesia 1989; 69: Catoire P, Saada M, Liu N, Delaunay L, Rauss A, Bonnet F. Effect of preoperative normovolemic hemodilution on left ventricular segmental wall motion during abdominal aortic surgery. Anesthesia and Analgesia 199; 75: Estafanous FG, Smith CE, Selim WM, Tarazi RC. Cardiovascular effects of acute normovolemic hemodilution in rats with disopyramide-induced myocardial depression. Basic Research of Cardiology 1990; 85: Geha AS. Coronary and cardiovascular dynamics and oxygen availability during acute normovolemic anemia. Surgery 1976; 80:

5 41 British Journal of Anaesthesia 1. Wilkerson DK, Rosen AL, Sehgal LR, Gould SA, Sehgal HL, Moss GS. Limits of cardiac compensation in anemic baboons. Surgery 1988; 103: Nishikawa T. Acute haemodynamic effects of sodium bicarbonate in canine respiratory or metabolic acidosis. British Journal of Anaesthesia 1993; 70: Downing SE, Talner NS, Gardner TH. Cardiovascular responses to metabolic acidosis. American Journal of Physiology 1965; 08: Wildenthal K, Mierzwiak DS, Myers RW, Mitchell JH. Effects of acute lactic acidosis on left ventricular performance. American Journal of Physiology 1968; 14: Andersen MN, Border JR, Mouritzen CV. Acidosis, catecholamines and cardiovascular dynamics: when does acidosis require correction? Annals of Surgery 1967; 166: Standards and guidelines for cardiopulmonary resuscitation and emergency cardiac care. Journal of the American Medical Association 1986; 55: Guerci AD, Chandra N, Johnson E, Rayburn B, Wurmb E, Tsitlik J, Halperin HR, Siu C, Weisfeldt ML. Failure of sodium bicarbonate to improve resuscitation from ventricular fibrillation in dogs. Circulation 1986; 74 (Suppl. IV): Cervera AL, Moss G. Progressive hypovolemia leading to shock after continuous hemorrhage and 3:1 crystalloid replacement. American Journal of Surgery 1975; 19: Poole-Wilson PA, Cameron IR. Intracellular ph and K of cardiac and skeletal muscle in acidosis and alkalosis. American Journal of Physiology 1975; 9: