- Email: [email protected]
Dobutamine increases oxygen consumption during constant flow cardiopulmonary bypass
British Journal of Anaesthesia 1996; 76: 5–8
CLINICAL INVESTIGATIONS
Dobutamine increases oxygen consumption during constant flow cardiopulmonary bypass W. KARZAI, A. LÖTTE, M. GÜNNICKER, U. M. VORGRIMLER-KARZAI AND H.-J. PRIEBE
Summary We have studied the effects of flow and dobutamine on systemic haemodynamic variables, oxygen delivery (DO2) and oxygen consumption (VO2) in 20 patients during cardiopulmonary bypass (CPB) with mild hypothermia (34 C). In a subgroup of seven patients, we also studied the effects on gastric microcirculatory blood flow (MCF) using laser Doppler flowmetry. During CPB, measurements were made before and after two interventions: the first consisted of increasing flow from 2.4 to 3.0 litre min91 m92 for 10 min; the second consisted of an infusion of dobutamine at a rate of 6 g kg91 min91 for 10 min during constant flow CPB. There were no significant differences in DO2 VO2 or haemodynamic variables between the two baseline measurements. The increase in flow raised DO2 (27%, P : 0.001), mean arterial pressure (P : 0.01) and MCF (P : 0.01), but failed to increase VO2. In contrast, dobutamine infusion increased VO2 (11%, P : 0.001) during constant flow CPB without significant changes in DO2 systemic haemodynamic variables or MCF. These results indicate that increases in VO2 during dobutamine may be flow-independent. (Br. J. Anaesth. 1996; 76: 5–8) Key words Heart, dobutamine. Heart, cardiopulmonary bypass. Oxygen, consumption.
The synthetic catecholamine, dobutamine, is frequently used in critically ill patients to increase cardiac output and oxygen delivery (DO2) [1, 2]. Normally, changes in cardiac output or DO2 only minimally influence systemic oxygen consumption (VO2) [3]. However, in pathological states, VO2 is presumed to become delivery-dependent [3], possibly because of an increase in flow and DO2 to less well perfused areas of the circulation. Dobutamine infusion has been used in critically ill patients, not only diagnostically to uncover delivery-dependent VO2, but also therapeutically to increase perfusion to less well perfused areas of the organism [1, 2, 4]. Several studies have reported an increase in metabolic rate during various catecholamine infusions [5–8]. These studies suggest that at least part of the increase in VO2 infusion may be explained by the calorigenic effect of the catecholamine, unrelated to increases in flow or DO2. In healthy humans,
dobutamine has been shown to increase VO2 [8, 9]. However, the increase in VO2 was accompanied by an increase in cardiac output, thus not conclusively demonstrating flow-independent increases in VO2. Accordingly, the aim of this study was to study the flow-independent effects of dobutamine on VO2 and contrast them with the effects of flow on VO2. This was done using cardiopulmonary bypass (CPB) which, as we and others have shown [10–13], provides a means of studying the flow-independent effects of various interventions during constant flow without compromising patient safety. As redistribution of blood flow to metabolically active but underperfused areas of the circulation may increase VO2, even in the presence of unchanged flow, in addition we studied the effects of flow and dobutamine on the gastric microcirculation to uncover possible redistribution of blood to this area of the circulation.
Patients and methods We studied 20 patients requiring CPB during cardiac surgery. The Ethics Committee of Essen University approved the study and all patients gave informed consent. All patients received flunitrazepam 2 mg approximately 1 h before arriving in the operating room. An arterial catheter and a flow-directed pulmonary artery catheter were inserted under local anaesthesia. General anaesthesia was induced with etomidate 0.15–0.30 mg kg91, and fentanyl 5–7 g kg91, followed by pancuronium 0.1 mg kg91 and was maintained with 0.4–0.6 vol % isoflurane and 50 % nitrous oxide in oxygen. During operation and before CPB, increments of fentanyl 0.25 mg, pancuronium 2 mg and flunitrazepam 0.2 mg were given as needed. Fentanyl 0.25 mg and pancuronium 4 mg were added to the prime, and 0.4 vol % isoflurane was maintained during CPB. Extracorporeal circulation was maintained using non-pulsatile pump flow (Stöckert, Munich, Germany) at a standard flow rate of 2.4 litre min91 m92. Oxygenation was provided
WAHEEDULLAH KARZAI*, MD, HANS-JOACHIM PRIEBE, MD, Department of Anaesthesiology, University Hospital of Freiburg, Freiburg, Germany. ANKE LÖTTE, MD, MICHAEL GÜNNICKER, MD, UTA MARIA VORGRIMLER-KARZAI, Department of Anaesthesiology, University Hospital of Essen, Essen, Germany. Accepted for publication: August 10, 1995. *Address for correspondence: Anaesthesiologische Universitaetsklinik, Hugstetterstr. 55, 79106 Freiburg, Germany.
6 by a Cobe CML membrane oxygenator (Laboratories GmbH, Heimstetten, Germany). An asanguineous prime containing 1000 ml of lactated Ringer’s solution, 10 % hydroxyethylstarch 500 ml, 20 % mannitol 100 ml and 8.4 % sodium bicarbonate 100 ml was used. Packed cell volume was maintained above 20 %. Blood temperature was kept at 34 C. Measurements were made after CPB was commenced, the aorta was cross-clamped, the heart was in hypothermic cardioplegic arrest, and rectal and nasopharyngeal temperatures were within 0.8 C of each other. In seven of the 20 patients, gastric microcirculatory blood flow was studied using laser Doppler flowmetry (LDF) (MBF 3D, Moors Instruments Ltd, Devon, England). The measurement probe (fibreoptic wire :3 mm ) was inserted through the lumen of a nasogastric tube. The correct position of the nasogastric tube was confirmed by auscultation and aspiration of gastric contents. The correct position of the probe was verified by observing typical pulse synchronous oscillations. LDF uses the size and amount of the frequency shift caused by the back-scattered laser beam to calculate microcirculatory blood flow (MBF) [14]. LDF has been used experimentally to measure intestinal mucosal blood flow and has been found to correlate with mucosal blood flow, as measured by standard techniques [15]. Initial measurements were made at a flow rate of 2.4 litre min91 m92 (baseline 1). Flow was then increased to 3.0 litre min91 m92 (intervention 1), and repeat measurements were made 10 min later. Flow was then returned to and maintained at 2.4 litre min91 m92, and measurements were repeated 5 min later (baseline 2). Subsequently, at unchanged flow, dobutamine 6 g kg91 min91 was started (intervention 2), and repeat measurements were made 10 min later. At each of these times, samples were obtained for blood-gas analysis, and electrolyte and blood glucose concentrations from sampling ports of the CPB cannulae, and haemodynamic variables were recorded. Samples for blood-gas analysis were analysed immediately at 37 C. DO2 and VO2 were calculated according to the Fick method. A repeated measures analysis of variance was used to test for differences between times. Paired t tests, corrected for multiple comparisons (Bonferroni), were used to test for differences between each baseline and subsequent intervention, and between the two baseline values [16]. Statistical significance was based on P values less than 0.05. Results are presented as mean SD. The statistical program used was SAS SAS Institute Inc., Cary, NC, USA, on an Accel (486DX33) Notebook computer (Accel Computers, Rockville, MD, USA).
Results Patient data are summarized in table 1. The increase in CPB flow rate from 2.4 to 3.0 litre min1 m2 significantly increased DO2, mean arterial pressure (MAP) and gastric MCF, and decreased oxygen extraction (table 2). VO2 did not change significantly. In contrast, dobutamine
British Journal of Anaesthesia Table 1 Patient characteristics (mean (SD or range) or number). CABG : Coronary artery bypass grafting; ACE : angiotensin-converting enzyme Age (yr) Weight (kg) Sex (M/F) Operation CABG Valve replacement Preoperative medication Blockers Nitrates ACE inhibitors Calcium antagonist Digitalis glycosides Diuretics
65 (53–75) 70 (11) 12/8 16 4 — 13 7 8 4 4
6 g kg91 min91 for 10 min increased VO2 and oxygen extraction but MBF remained unchanged (table 2). Plasma concentrations of glucose and potassium were not affected by the two interventions. There were no significant differences in rectal temperature during the procedure (table 3).
Discussion In this study, we found that dobutamine, in clinical doses, increased VO2. This increase occurred in the presence of unchanged global and regional gastric mucosal flow and DO2. This finding of an increase in VO2 during dobutamine is in agreement with previous studies. In healthy volunteers, dobutamine 5–10 g kg91 min91 was found to increase energy expenditure or VO2 by 20–33 % [8, 9]. However, in these studies cardiac output (flow) presumably or measurably increased, whereas in our study flow was controlled. The smaller increase in VO2 (11 %) found in our study may have been caused by a lack of increase in myocardial oxygen consumption, a lack of increase in total body blood flow in response to dobutamine, a higher basal catecholamine concentration during CPB [17] or by hypothermia. We cannot explain why dobutamine increased VO2 without changing global blood flow. Flow-independent increases in VO2 in response to catecholamines may be caused by direct effects on effector cells, indirect effects on humoral factors (insulin and glucagon) or redistribution of blood flow, resulting in increased perfusion of metabolically active tissues [18]. The effects of catecholamines on metabolism are frequently accompanied by an increase in glucose and a decrease in potassium concentration [18]. This did not occur in our study. Redistribution of flow to less well perfused regions of the circulation could have been responsible for the increase in VO2. However, whereas the increase in flow (i.e. first intervention) increased MBF to one area of the circulation but failed to increase VO2, dobutamine failed to increase gastric MBF. These findings would suggest that redistribution of blood flow is unlikely to be a major cause of the increase in VO2 with dobutamine. In contrast, in a previous study using a similar design, dopamine increased gastric MBF without increasing VO2 [13]. However, some of the observed differences between dobu-
Dobutamine and oxygen consumption
7
Table 2 Haemodynamic variables, oxygen delivery and oxygen consumption during the two interventions (mean (SD)). VO2 : Oxygen consumption; DO2 : oxygen delivery; O2-Ext : oxygen extraction; MAP : mean arterial pressure; SVRI : systemic vascular resistance index; CVP : central venous pressure; and MCF : microcirculatory gastric blood flow expressed in arbitrary units. *** P 0.001, †† P 0.01 compared with preceding value Flow Intervention
min91
Flow rate (1 litre VO2 (ml min91 m92) DO2 (ml min91 m92) O2-Ext MAP (kPa) SVRI (dyn s cm95 m92) CVP (kPa) MCF (u.) (n : 7)
m92)
Dobutamine (6 g kg91 min91)
Before
After
Before
After
2.4 66 (14) 250 (40) 0.27 (0.05) 9.2 (1.5) 2180 (347) 0.4 (0.3) 107 (29)
3.0 70 (12) 319 (47)*** 0.22 (0.04)*** 10.1 (2.3)†† 1948 (432) 0.7 (0.6) 196 (92)††
2.4 2.4 66 (12) 73 (13)*** 261 (35) 269 (38) 0.25 (0.05) 0.28 (0.06)*** 9.3 (2.3) 9.7 (2.3) 2173 (551) 2285 (533) 0.6 (0.5) 0.6 (0.6) 126 (65) 132 (58)
Table 3 Potassium and glucose concentrations, and rectal temperature during the two interventions (mean (SD)) Flow Intervention
min91
m92)
Flow rate (1 litre Glucose (mmol litre91) Potassium (mmol litre91) Temperature (C)
Dobutamine (6 g kg91 min91)
Before
After
Before
2.4 6.4 (1.1) 4.1 (0.4) 34.3 (0.8)
3.0 7.1 (1.2) 4.1 (0.4) 34.3 (0.6)
2.4 2.4 7.4 (1.4) 7.8 (1.4) 4.1 (0.4) 4.2 (0.5) 34.1 (0.7) 34.1 (0.8)
tamine and dopamine on gastric blood flow may be caused by different receptor activities of these catecholamines on regional and systemic vasculature. Randomization of the sequence of interventions (i.e. flow variation and dobutamine infusion) might have been preferable. However, as there are no data on the clearance of dobutamine during hypothermia, we chose not to randomize the sequence of interventions. The similar values before flow intervention and before dobutamine infusion are evidence of the stability of this model and return to baseline conditions after flow intervention. As neuromuscular block is known to decrease VO2 [19], a possible decrease in block during the study might have affected the changes in VO2. However, as hypothermic CPB has been shown to reduce requirements [20] and increase the duration of action of pancuronium [21], and as pancuronium 4 mg was added to the prime of the extracorporeal circuit, it is highly unlikely that a decrease in neuromuscular block occurred during the study. Even acknowledging the limitations of this study (i.e. hypothermia and surgical procedure with humoral activation), our finding may have implications for the diagnostic and therapeutic uses of dobutamine. Dobutamine has been used diagnostically in critically ill patients to increase DO2 and uncover delivery-dependent VO2 [4]. As we have observed that dobutamine increased VO2, independent of DO2, this diagnostic test may be of limited value. Furthermore, dobutamine has been used therapeutically to increase DO2 and achieve supranormal values of VO2 in haemodynamically stable but critically ill patients in the hope of possibly increasing survival [22]. Our findings suggest caution in using dobutamine for this purpose. Dobutamine may further
After
increase VO2, independent of increases in DO2 or cardiac output (flow), and thus unnecessarily increase heart work and VO2, and possibly endanger the patient. A recent study suggested that increasing VO2 with dobutamine to achieve supranormal values in critically ill patients may increase mortality [23].
Acknowledgements This study was performed in the Department of Thoracic and Cardiovascular Surgery, University Hospital Essen. We acknowledge the support of Horst Schmidt, Josef Graban and Helmut Hees, Perfusionists, Department of Thoracic and Cardiovascular Surgery, and Susanne Spitzer, Regine Pohl and Beate LehnenLutzke, Department of Anaesthesiology, University Hospital Essen, Essen, Germany.
References 1. Vincent J-L, Roman A, Backer de D, Kahn RJ. Oxygen uptake/supply dependency: Effects of short-term dobutamine infusion. American Review of Respiratory and Critical Care Medicine 1990; 142: 2–8. 2. Vincent J-L, Roman A, Kahn RJ. Dobutamine administration in septic shock: Addition to a standard protocol. Critical Care Medicine 1990; 18: 689–693. 3. Cain SM, Curtis SE. Experimental models of pathologic oxygen supply dependency. Critical Care Medicine 1991; 19: 603–612. 4. de Backer D, Moraine J-J, Berre J, Kahn RJ, Vincent J-L. Effects of dobutamine on oxygen consumption in septic patients. American Journal of Respiratory and Critical Care Medicine 1994; 150: 95–100. 5. Blaak EE, van Baak MA, Kempen KPG, Saris WHM. Role of alpha- and beta-adrenoreceptors in sympathetically mediated thermogenesis. American Journal of Physiology 1993; 264: E11–E17. 6. Ruttimann Y, Chioléro R, Jéquier E, Breitenstein E, Schutz Y. Effects of dopamine on total oxygen consumption and oxygen delivery in healthy men. American Journal of Physiology 1989; 257: E541–E546. 7. Abdul-Rasool IH, Chamberlain JH, Swan PC, Ward DS.
8
8. 9. 10.
11. 12.
13.
14. 15.
16.
British Journal of Anaesthesia Cardiorespiratory and metabolic effects of dopamine and dobutamine infusions in dogs. Critical Care Medicine 1987; 15: 1044–1050. Bhatt S, Hutchinson R, Tomlinson B, Oh T, Mak M. Effects of dobutamine on oxygen supply and uptake in healthy volunteers. British Journal of Anaesthesia 1992; 69: 298–303. Green CJ, Frazer RS, Underhill S, Maycock P, Fairhurst JA, Campbell IT. Metabolic effects of dobutamine in normal man. Clinical Science 1992; 82: 77–83. Videcoq M, Desmonts J-M, Marty J, Hazebroucq J, Langlois J. Effects of droperidol on peripheral vasculature: Use of cardiopulmonary bypass as a study model. Acta Anaesthesiologica Scandinavica 1987; 31: 370–374. Evans PJD, Ruygrok P, Seelye ER, Harris EA. Does sodium nitroprusside improve oxygenation during cardiopulmonary bypass? British Journal of Anaesthesia 1977; 49: 799–803. Karzai W, Günnicker M, Vorgrimler-Karzai U-M, Freund U, Zerkowski H-R. The effects of beta-adrenoreceptor blockade on oxygen consumption during cardiopulmonary bypass. Anesthesia and Analgesia 1994; 79: 19–22. Karzai W, Scharbert G, Günnicker M, Vorgrimler-Karzai U-M, Freund U, Doetsch N, Kox WJ. Dopamine increases gastric microcirculatory blood flow during constant flow cardiopulmonary bypass. Clinical Intensive Care 1994; 5 (Suppl.): 22. Stern MD. In vivo evaluation of microcirculation by coherent light scattering. Nature (London) 1975; 254: 56–58. Ahn H, Lindhagen J, Nilsson GE, Salerud EG, Jodal M, Lundgren O. Evaluation of laser flowmetry in the assessment of intestinal blood flow in cat. Gastroenterology 1985; 88: 951–957. Ludbrook J. Repeated measurements and multiple compari-
17.
18. 19.
20.
21.
22.
23.
sons in cardiovascular research. Cardiovascular Research 1994; 28: 303–311. Wallach R, Karp RB, Reves JG, Smith LR, James TN. Pathogenesis of paroxysmal hypertension developing during and after coronary bypass surgery: A study of hemodynamic and humoral factors. American Journal of Cardiology 1980; 46: 559–565. Macdonald IA, Bennet T, Fellows IW. Catecholamines and control of metabolism in man. Clinical Science 1985; 68: 613–619. Irish CL, Murkin JM, Cleland A, Macdonald JL, Mayer R. Neuromuscular blockade significantly decreases systemic oxygen consumption during hypothermic cardiopulmonary bypass. Journal of Cardiothoracic and Vascular Anesthesia 1991; 5: 132–134. D’Hollander AA, Duvaldestin P, Henzel D, Nevelsteen M, Bomblet JP. Variations in pancuronium requirement, plasma concentration, and urinary excretion induced by cardiopulmonary bypass with hypothermia. Anesthesiology 1983; 58: 505–509. Buzello W, Schluermann D, Schindler M, Spillner G. Hypothermic cardiopulmonary bypass and neuromuscular blockade by pancuronium and vecuronium. Anesthesiology 1985; 62: 201–204. Shoemaker WC, Appel PL, Kram HB, Waxman K, Lee T. Prospective trial of supernormal values of survivors as therapeutic goals in high-risk surgical patients. Chest 1988; 94: 1176–1186. Hayes MA, Timmins AC, Yau EHS, Palazzo M, Hinds CJ, Watson D. Elevation of systemic oxygen delivery in the treatment of critically ill patients. New England Journal of Medicine 1994; 330: 1717–1722.
CLINICAL INVESTIGATIONS
Dobutamine increases oxygen consumption during constant flow cardiopulmonary bypass W. KARZAI, A. LÖTTE, M. GÜNNICKER, U. M. VORGRIMLER-KARZAI AND H.-J. PRIEBE
Summary We have studied the effects of flow and dobutamine on systemic haemodynamic variables, oxygen delivery (DO2) and oxygen consumption (VO2) in 20 patients during cardiopulmonary bypass (CPB) with mild hypothermia (34 C). In a subgroup of seven patients, we also studied the effects on gastric microcirculatory blood flow (MCF) using laser Doppler flowmetry. During CPB, measurements were made before and after two interventions: the first consisted of increasing flow from 2.4 to 3.0 litre min91 m92 for 10 min; the second consisted of an infusion of dobutamine at a rate of 6 g kg91 min91 for 10 min during constant flow CPB. There were no significant differences in DO2 VO2 or haemodynamic variables between the two baseline measurements. The increase in flow raised DO2 (27%, P : 0.001), mean arterial pressure (P : 0.01) and MCF (P : 0.01), but failed to increase VO2. In contrast, dobutamine infusion increased VO2 (11%, P : 0.001) during constant flow CPB without significant changes in DO2 systemic haemodynamic variables or MCF. These results indicate that increases in VO2 during dobutamine may be flow-independent. (Br. J. Anaesth. 1996; 76: 5–8) Key words Heart, dobutamine. Heart, cardiopulmonary bypass. Oxygen, consumption.
The synthetic catecholamine, dobutamine, is frequently used in critically ill patients to increase cardiac output and oxygen delivery (DO2) [1, 2]. Normally, changes in cardiac output or DO2 only minimally influence systemic oxygen consumption (VO2) [3]. However, in pathological states, VO2 is presumed to become delivery-dependent [3], possibly because of an increase in flow and DO2 to less well perfused areas of the circulation. Dobutamine infusion has been used in critically ill patients, not only diagnostically to uncover delivery-dependent VO2, but also therapeutically to increase perfusion to less well perfused areas of the organism [1, 2, 4]. Several studies have reported an increase in metabolic rate during various catecholamine infusions [5–8]. These studies suggest that at least part of the increase in VO2 infusion may be explained by the calorigenic effect of the catecholamine, unrelated to increases in flow or DO2. In healthy humans,
dobutamine has been shown to increase VO2 [8, 9]. However, the increase in VO2 was accompanied by an increase in cardiac output, thus not conclusively demonstrating flow-independent increases in VO2. Accordingly, the aim of this study was to study the flow-independent effects of dobutamine on VO2 and contrast them with the effects of flow on VO2. This was done using cardiopulmonary bypass (CPB) which, as we and others have shown [10–13], provides a means of studying the flow-independent effects of various interventions during constant flow without compromising patient safety. As redistribution of blood flow to metabolically active but underperfused areas of the circulation may increase VO2, even in the presence of unchanged flow, in addition we studied the effects of flow and dobutamine on the gastric microcirculation to uncover possible redistribution of blood to this area of the circulation.
Patients and methods We studied 20 patients requiring CPB during cardiac surgery. The Ethics Committee of Essen University approved the study and all patients gave informed consent. All patients received flunitrazepam 2 mg approximately 1 h before arriving in the operating room. An arterial catheter and a flow-directed pulmonary artery catheter were inserted under local anaesthesia. General anaesthesia was induced with etomidate 0.15–0.30 mg kg91, and fentanyl 5–7 g kg91, followed by pancuronium 0.1 mg kg91 and was maintained with 0.4–0.6 vol % isoflurane and 50 % nitrous oxide in oxygen. During operation and before CPB, increments of fentanyl 0.25 mg, pancuronium 2 mg and flunitrazepam 0.2 mg were given as needed. Fentanyl 0.25 mg and pancuronium 4 mg were added to the prime, and 0.4 vol % isoflurane was maintained during CPB. Extracorporeal circulation was maintained using non-pulsatile pump flow (Stöckert, Munich, Germany) at a standard flow rate of 2.4 litre min91 m92. Oxygenation was provided
WAHEEDULLAH KARZAI*, MD, HANS-JOACHIM PRIEBE, MD, Department of Anaesthesiology, University Hospital of Freiburg, Freiburg, Germany. ANKE LÖTTE, MD, MICHAEL GÜNNICKER, MD, UTA MARIA VORGRIMLER-KARZAI, Department of Anaesthesiology, University Hospital of Essen, Essen, Germany. Accepted for publication: August 10, 1995. *Address for correspondence: Anaesthesiologische Universitaetsklinik, Hugstetterstr. 55, 79106 Freiburg, Germany.
6 by a Cobe CML membrane oxygenator (Laboratories GmbH, Heimstetten, Germany). An asanguineous prime containing 1000 ml of lactated Ringer’s solution, 10 % hydroxyethylstarch 500 ml, 20 % mannitol 100 ml and 8.4 % sodium bicarbonate 100 ml was used. Packed cell volume was maintained above 20 %. Blood temperature was kept at 34 C. Measurements were made after CPB was commenced, the aorta was cross-clamped, the heart was in hypothermic cardioplegic arrest, and rectal and nasopharyngeal temperatures were within 0.8 C of each other. In seven of the 20 patients, gastric microcirculatory blood flow was studied using laser Doppler flowmetry (LDF) (MBF 3D, Moors Instruments Ltd, Devon, England). The measurement probe (fibreoptic wire :3 mm ) was inserted through the lumen of a nasogastric tube. The correct position of the nasogastric tube was confirmed by auscultation and aspiration of gastric contents. The correct position of the probe was verified by observing typical pulse synchronous oscillations. LDF uses the size and amount of the frequency shift caused by the back-scattered laser beam to calculate microcirculatory blood flow (MBF) [14]. LDF has been used experimentally to measure intestinal mucosal blood flow and has been found to correlate with mucosal blood flow, as measured by standard techniques [15]. Initial measurements were made at a flow rate of 2.4 litre min91 m92 (baseline 1). Flow was then increased to 3.0 litre min91 m92 (intervention 1), and repeat measurements were made 10 min later. Flow was then returned to and maintained at 2.4 litre min91 m92, and measurements were repeated 5 min later (baseline 2). Subsequently, at unchanged flow, dobutamine 6 g kg91 min91 was started (intervention 2), and repeat measurements were made 10 min later. At each of these times, samples were obtained for blood-gas analysis, and electrolyte and blood glucose concentrations from sampling ports of the CPB cannulae, and haemodynamic variables were recorded. Samples for blood-gas analysis were analysed immediately at 37 C. DO2 and VO2 were calculated according to the Fick method. A repeated measures analysis of variance was used to test for differences between times. Paired t tests, corrected for multiple comparisons (Bonferroni), were used to test for differences between each baseline and subsequent intervention, and between the two baseline values [16]. Statistical significance was based on P values less than 0.05. Results are presented as mean SD. The statistical program used was SAS SAS Institute Inc., Cary, NC, USA, on an Accel (486DX33) Notebook computer (Accel Computers, Rockville, MD, USA).
Results Patient data are summarized in table 1. The increase in CPB flow rate from 2.4 to 3.0 litre min1 m2 significantly increased DO2, mean arterial pressure (MAP) and gastric MCF, and decreased oxygen extraction (table 2). VO2 did not change significantly. In contrast, dobutamine
British Journal of Anaesthesia Table 1 Patient characteristics (mean (SD or range) or number). CABG : Coronary artery bypass grafting; ACE : angiotensin-converting enzyme Age (yr) Weight (kg) Sex (M/F) Operation CABG Valve replacement Preoperative medication Blockers Nitrates ACE inhibitors Calcium antagonist Digitalis glycosides Diuretics
65 (53–75) 70 (11) 12/8 16 4 — 13 7 8 4 4
6 g kg91 min91 for 10 min increased VO2 and oxygen extraction but MBF remained unchanged (table 2). Plasma concentrations of glucose and potassium were not affected by the two interventions. There were no significant differences in rectal temperature during the procedure (table 3).
Discussion In this study, we found that dobutamine, in clinical doses, increased VO2. This increase occurred in the presence of unchanged global and regional gastric mucosal flow and DO2. This finding of an increase in VO2 during dobutamine is in agreement with previous studies. In healthy volunteers, dobutamine 5–10 g kg91 min91 was found to increase energy expenditure or VO2 by 20–33 % [8, 9]. However, in these studies cardiac output (flow) presumably or measurably increased, whereas in our study flow was controlled. The smaller increase in VO2 (11 %) found in our study may have been caused by a lack of increase in myocardial oxygen consumption, a lack of increase in total body blood flow in response to dobutamine, a higher basal catecholamine concentration during CPB [17] or by hypothermia. We cannot explain why dobutamine increased VO2 without changing global blood flow. Flow-independent increases in VO2 in response to catecholamines may be caused by direct effects on effector cells, indirect effects on humoral factors (insulin and glucagon) or redistribution of blood flow, resulting in increased perfusion of metabolically active tissues [18]. The effects of catecholamines on metabolism are frequently accompanied by an increase in glucose and a decrease in potassium concentration [18]. This did not occur in our study. Redistribution of flow to less well perfused regions of the circulation could have been responsible for the increase in VO2. However, whereas the increase in flow (i.e. first intervention) increased MBF to one area of the circulation but failed to increase VO2, dobutamine failed to increase gastric MBF. These findings would suggest that redistribution of blood flow is unlikely to be a major cause of the increase in VO2 with dobutamine. In contrast, in a previous study using a similar design, dopamine increased gastric MBF without increasing VO2 [13]. However, some of the observed differences between dobu-
Dobutamine and oxygen consumption
7
Table 2 Haemodynamic variables, oxygen delivery and oxygen consumption during the two interventions (mean (SD)). VO2 : Oxygen consumption; DO2 : oxygen delivery; O2-Ext : oxygen extraction; MAP : mean arterial pressure; SVRI : systemic vascular resistance index; CVP : central venous pressure; and MCF : microcirculatory gastric blood flow expressed in arbitrary units. *** P 0.001, †† P 0.01 compared with preceding value Flow Intervention
min91
Flow rate (1 litre VO2 (ml min91 m92) DO2 (ml min91 m92) O2-Ext MAP (kPa) SVRI (dyn s cm95 m92) CVP (kPa) MCF (u.) (n : 7)
m92)
Dobutamine (6 g kg91 min91)
Before
After
Before
After
2.4 66 (14) 250 (40) 0.27 (0.05) 9.2 (1.5) 2180 (347) 0.4 (0.3) 107 (29)
3.0 70 (12) 319 (47)*** 0.22 (0.04)*** 10.1 (2.3)†† 1948 (432) 0.7 (0.6) 196 (92)††
2.4 2.4 66 (12) 73 (13)*** 261 (35) 269 (38) 0.25 (0.05) 0.28 (0.06)*** 9.3 (2.3) 9.7 (2.3) 2173 (551) 2285 (533) 0.6 (0.5) 0.6 (0.6) 126 (65) 132 (58)
Table 3 Potassium and glucose concentrations, and rectal temperature during the two interventions (mean (SD)) Flow Intervention
min91
m92)
Flow rate (1 litre Glucose (mmol litre91) Potassium (mmol litre91) Temperature (C)
Dobutamine (6 g kg91 min91)
Before
After
Before
2.4 6.4 (1.1) 4.1 (0.4) 34.3 (0.8)
3.0 7.1 (1.2) 4.1 (0.4) 34.3 (0.6)
2.4 2.4 7.4 (1.4) 7.8 (1.4) 4.1 (0.4) 4.2 (0.5) 34.1 (0.7) 34.1 (0.8)
tamine and dopamine on gastric blood flow may be caused by different receptor activities of these catecholamines on regional and systemic vasculature. Randomization of the sequence of interventions (i.e. flow variation and dobutamine infusion) might have been preferable. However, as there are no data on the clearance of dobutamine during hypothermia, we chose not to randomize the sequence of interventions. The similar values before flow intervention and before dobutamine infusion are evidence of the stability of this model and return to baseline conditions after flow intervention. As neuromuscular block is known to decrease VO2 [19], a possible decrease in block during the study might have affected the changes in VO2. However, as hypothermic CPB has been shown to reduce requirements [20] and increase the duration of action of pancuronium [21], and as pancuronium 4 mg was added to the prime of the extracorporeal circuit, it is highly unlikely that a decrease in neuromuscular block occurred during the study. Even acknowledging the limitations of this study (i.e. hypothermia and surgical procedure with humoral activation), our finding may have implications for the diagnostic and therapeutic uses of dobutamine. Dobutamine has been used diagnostically in critically ill patients to increase DO2 and uncover delivery-dependent VO2 [4]. As we have observed that dobutamine increased VO2, independent of DO2, this diagnostic test may be of limited value. Furthermore, dobutamine has been used therapeutically to increase DO2 and achieve supranormal values of VO2 in haemodynamically stable but critically ill patients in the hope of possibly increasing survival [22]. Our findings suggest caution in using dobutamine for this purpose. Dobutamine may further
After
increase VO2, independent of increases in DO2 or cardiac output (flow), and thus unnecessarily increase heart work and VO2, and possibly endanger the patient. A recent study suggested that increasing VO2 with dobutamine to achieve supranormal values in critically ill patients may increase mortality [23].
Acknowledgements This study was performed in the Department of Thoracic and Cardiovascular Surgery, University Hospital Essen. We acknowledge the support of Horst Schmidt, Josef Graban and Helmut Hees, Perfusionists, Department of Thoracic and Cardiovascular Surgery, and Susanne Spitzer, Regine Pohl and Beate LehnenLutzke, Department of Anaesthesiology, University Hospital Essen, Essen, Germany.
References 1. Vincent J-L, Roman A, Backer de D, Kahn RJ. Oxygen uptake/supply dependency: Effects of short-term dobutamine infusion. American Review of Respiratory and Critical Care Medicine 1990; 142: 2–8. 2. Vincent J-L, Roman A, Kahn RJ. Dobutamine administration in septic shock: Addition to a standard protocol. Critical Care Medicine 1990; 18: 689–693. 3. Cain SM, Curtis SE. Experimental models of pathologic oxygen supply dependency. Critical Care Medicine 1991; 19: 603–612. 4. de Backer D, Moraine J-J, Berre J, Kahn RJ, Vincent J-L. Effects of dobutamine on oxygen consumption in septic patients. American Journal of Respiratory and Critical Care Medicine 1994; 150: 95–100. 5. Blaak EE, van Baak MA, Kempen KPG, Saris WHM. Role of alpha- and beta-adrenoreceptors in sympathetically mediated thermogenesis. American Journal of Physiology 1993; 264: E11–E17. 6. Ruttimann Y, Chioléro R, Jéquier E, Breitenstein E, Schutz Y. Effects of dopamine on total oxygen consumption and oxygen delivery in healthy men. American Journal of Physiology 1989; 257: E541–E546. 7. Abdul-Rasool IH, Chamberlain JH, Swan PC, Ward DS.
8
8. 9. 10.
11. 12.
13.
14. 15.
16.
British Journal of Anaesthesia Cardiorespiratory and metabolic effects of dopamine and dobutamine infusions in dogs. Critical Care Medicine 1987; 15: 1044–1050. Bhatt S, Hutchinson R, Tomlinson B, Oh T, Mak M. Effects of dobutamine on oxygen supply and uptake in healthy volunteers. British Journal of Anaesthesia 1992; 69: 298–303. Green CJ, Frazer RS, Underhill S, Maycock P, Fairhurst JA, Campbell IT. Metabolic effects of dobutamine in normal man. Clinical Science 1992; 82: 77–83. Videcoq M, Desmonts J-M, Marty J, Hazebroucq J, Langlois J. Effects of droperidol on peripheral vasculature: Use of cardiopulmonary bypass as a study model. Acta Anaesthesiologica Scandinavica 1987; 31: 370–374. Evans PJD, Ruygrok P, Seelye ER, Harris EA. Does sodium nitroprusside improve oxygenation during cardiopulmonary bypass? British Journal of Anaesthesia 1977; 49: 799–803. Karzai W, Günnicker M, Vorgrimler-Karzai U-M, Freund U, Zerkowski H-R. The effects of beta-adrenoreceptor blockade on oxygen consumption during cardiopulmonary bypass. Anesthesia and Analgesia 1994; 79: 19–22. Karzai W, Scharbert G, Günnicker M, Vorgrimler-Karzai U-M, Freund U, Doetsch N, Kox WJ. Dopamine increases gastric microcirculatory blood flow during constant flow cardiopulmonary bypass. Clinical Intensive Care 1994; 5 (Suppl.): 22. Stern MD. In vivo evaluation of microcirculation by coherent light scattering. Nature (London) 1975; 254: 56–58. Ahn H, Lindhagen J, Nilsson GE, Salerud EG, Jodal M, Lundgren O. Evaluation of laser flowmetry in the assessment of intestinal blood flow in cat. Gastroenterology 1985; 88: 951–957. Ludbrook J. Repeated measurements and multiple compari-
17.
18. 19.
20.
21.
22.
23.
sons in cardiovascular research. Cardiovascular Research 1994; 28: 303–311. Wallach R, Karp RB, Reves JG, Smith LR, James TN. Pathogenesis of paroxysmal hypertension developing during and after coronary bypass surgery: A study of hemodynamic and humoral factors. American Journal of Cardiology 1980; 46: 559–565. Macdonald IA, Bennet T, Fellows IW. Catecholamines and control of metabolism in man. Clinical Science 1985; 68: 613–619. Irish CL, Murkin JM, Cleland A, Macdonald JL, Mayer R. Neuromuscular blockade significantly decreases systemic oxygen consumption during hypothermic cardiopulmonary bypass. Journal of Cardiothoracic and Vascular Anesthesia 1991; 5: 132–134. D’Hollander AA, Duvaldestin P, Henzel D, Nevelsteen M, Bomblet JP. Variations in pancuronium requirement, plasma concentration, and urinary excretion induced by cardiopulmonary bypass with hypothermia. Anesthesiology 1983; 58: 505–509. Buzello W, Schluermann D, Schindler M, Spillner G. Hypothermic cardiopulmonary bypass and neuromuscular blockade by pancuronium and vecuronium. Anesthesiology 1985; 62: 201–204. Shoemaker WC, Appel PL, Kram HB, Waxman K, Lee T. Prospective trial of supernormal values of survivors as therapeutic goals in high-risk surgical patients. Chest 1988; 94: 1176–1186. Hayes MA, Timmins AC, Yau EHS, Palazzo M, Hinds CJ, Watson D. Elevation of systemic oxygen delivery in the treatment of critically ill patients. New England Journal of Medicine 1994; 330: 1717–1722.