Table 1. lnitial Data on Both Study Groupsarb

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1 The Hemodynamic Effect of Phentolamine and Dobutamine after 0 enheart Operations in Children: Influence of the Un cp erlying Heart Defect M. Berner, M.D., J. C. Rouge, M.D., and B. Friedli, M.D. ABSTRACT The hemodynamic effects of phentolamine alone and in combination with dobutamine were studied in the immediate postoperative period in two groups of children. Group 1 (N = 6; mean age, 152 months) had openheart operation for acquired mitral valve disease. Group 2 (N = 6; mean age, 60 months) had intracardiac repair for tetralogy of Fallot. Before drug administration, cardiac index did not differ between groups, but patients with tetralogy of Fallot had a higher heart rate and smaller stroke volume index; systemic vascular resistance was high in both groups. With phentolamine (10 pg/kg/min), cardiac index and stroke volume index increased similarly in both groups ( + 13% for cardiac index in Group 1, + 9% in Group 2), while systemic vascular resistance, pulmonary vascular resistance, and pulmonary wedge pressure decreased. When dobutamine (5 pg/kg/min) was added, there was a further increase in cardiac index in both groups, but it was greater in Group 1 (+17% vs +12%, p < 0.01, compared with phentolamine alone; +33% vs +22%, p < 0.01, compared with control). Systemic vascular resistance remained unchanged and heart rate increased in both groups, so that the left ventricular stroke work index increased. Although stroke volume index increased significantly with dobutamine in Group 1 (+ll%, p < 0.01), it remained unchanged in Group 2 (+3%, not significant). Thus in Group 2, dobutamine increased cardiac index only by increasing heart rate. This suggests that the relatively small, noncompliant left ventricle in patients with tetralogy of Fallot cannot further respond to inotropic drugs by increasing stroke volume index. From the Departments of Pediatrics and Genetics, and Anesthesiology, University of Geneva Medical School, Geneva, Switzerland. Accepted for publication July 23, Address reprint requests to Dr. Berner, Clinique de P6diatne, HGpital Cantonal Universitaire, 30 boulevard de la Clue, 1205 Geneva, Switzerland. The combination of vasodilators to reduce afterload and inotropic agents to increase myocardial contractility is now widely used after intracardiac operations in adults; it is successful in treating low cardiac output syndrome [l31. The choice of a specific drug has to take into account that certain peripheral vasodilators affect preload by modifying venous tone and that some may induce secondary inotropic and chronotropic effects [I, 4, 51. On the other hand, most inotropic drugs also increase heart rate and consistently show vasoactive properties [691. In children, too, these drugs are employed after cardiac operations. They are used either alone or in combination [lo161 because the underlying heart defects, optimal heart rate, preload, and afterload may vary from patient to patient [ The need for a specific drug depends on the defect repaired. In this report, we studied the hemodynamic response to specific PI cardiac stimulation by dobutamine [22] after peripheral ablockade by phentolamine [23, 241 and immediately after intracardiac repair of two distinct cardiac defects in children. Materials and Methods Twelve children were studied during a period ranging from four to six hours following intracardiac operation. Six of them (Group l), with a mean age of 152 k 32 months, had been operated on for mitral valve disease. The other 6 (Group 2), with a mean age of 60 k 34 months, had tetralogy of Fallot and underwent operation to repair this condition. Table 1 shows clinical data, type of operation, and basic hemodynamic data in both groups. Each operation was performed during extracorporeal circulation with moderate hypothermia (24" to 28 C) in Group 1 and deep hypothermia (20" to 24 C) in Group 2. At the end of extracorporeal circulation, blood was reinfused to the patient until blood volume was judged clinically adequate. A single dose of furosemide (0.5 to 1.0 mg 643

2 644 The Annals of Thoracic Surgery Vol 35 No 6 June 1983 Table 1. lnitial Data on Both Study Groupsarb Group 1 Group 2 Value Data (N = 6) (N = 6) of P Operation performed Carpentier's ring Reparative (1); StanEdwards procedure (6) prostheses (4); commissurotomy (1) Age (mo) 152 f <0.01 Duration of bypass (min) 77 f t 23 NS Cardiac index ( L/min/m2) 3.52 t NS Stroke volume index (ml/m2) 38.2 f f 6.1 <0.01 Heart rate (beatdmin) 92 f t 20 <0.05 Central venous pressure (mm Hg) 8 f f 1.5 <0.01 Pulmonary wedge pressure (mm Hg) 15 f f 4.5 NS Mean systemic arterial pressure (mm Hg) 88 t <0.05 Systemic vascular resistance NS (mm Hg/L/min/m2 = RU) Pulmonary vascular resistance 3.69 f f 1.3 NS (mm Hg/L/min/m2 = RU) 'Data are shown as mean f standard deviation where applicable. bgroup 1 underwent operation for mitral valve disease; Group 2 had tetralogy of Fallot. NS = not significant; RU = resistance units. per kilogram of body weight) was then given. After the operation, a 5F thermodilution Swan Ganz catheter was introduced percutaneously through the subclavian or jugular vein and floated into the pulmonary artery under oscilloscopic control of the pressure. During the study, each patient was ventilated without positive endexpiratory pressure. No digitalis was used in the immediate postoperative period. Individual temperature variations did not exceed 0.3"C during the study. Blood loss through drains was carefully compensated, but no attempt was made to maintain the same filling pressure throughout the study by additional volume loading. In the intensive care Fig 1. Study protocol. (C, = control measure before drug administration; PI = first measure with phentolamine; P + D = measure with phentolamine and dobutamine; P2 = second measure with phentolamine after removal of dobutamine; C2 = control measure after removal of drugs. ) unit, the following protocol, approved by the ethical committee of the department of pediatrics, was started (Fig 1). Five successive measurements of cardiac output and pressures were made at thirtyminute intervals. The first was made before drugs were given. The second was taken after infusion of phentolamine (10 p.g/kg/min) was begun. The third measurement was taken after dobutamine (5 p.g/kg/min) was added to phentolamine for thirty minutes, and served to evaluate the combined action of dobutamine and phentolamine. Thereafter, dobutamine was stopped and another measurement was made under phentolamine alone. A fifth and final determination was made after both drugs were stopped. The first and fifth measurements were averaged to yield a mean control value as were the second and fourth measurements when phentolamine was the sole drug. This was done in order to take into account any spontaneous improvement during the time of the study. Each

3 645 Bemer, Rouge, and Friedli: Phentolamine and Dobutamine after Pediatric OpenHeart Operations measurement was taken three times at short intervals, and the results were averaged. Cardiac output by thermodilution was assessed with a Kimray 3500 computer. Simultaneously, mean systemic arterial pressure, mean pulmonary arterial pressure, and pulmonary wedge pressure were recorded with a Statham P23Db strain gauge from a radial arterial cannula and the SwanGanz catheter. Various hemodynamic variables, including systemic and pulmonary vascular resistances and right and left ventricular stroke work indices, were calculated with the usual formulas [25]. For statistical analysis, the two control values as well as the two measurements involving phentolamine alone were averaged. Effects of drugs were compared with control values by means of an analysis of variance and when significant, the effect of each drug was determined by means of three nonorthogonal comparisons [26]. For each computed F value, significance level was assessed only for a p value less than 0.05 or a p value less than Differences in hemodynamic data between Groups 1 and 2 were analyzed through a Student t test. Results The results of the hemodynamic measurements and the changes in each group of patients are shown in Tables 2 through 4 and in Figure 2. Cardiac index was somewhat decreased in the two control periods in both groups. With phentolamine, a significant increase was noted (+ 13% in Group 1, +9% in Group 2). When dobutamine was added, there was a further significant increase, the final increase being +33% in Group 1 and +22% in Group 2. The difference in response to phentolamine between groups was not significant. With dobutamine, however, Group 1 achieved a significantly higher cardiac output (p < 0.01). Heart rate was significantly faster in Group 2 during control periods. It did not change significantly with phentolamine. With dobutamine, a significant rise was observed in both groups. Stroke volume index was significantly smaller in Group 2 at any time during the study. A significant increase was noted in both groups with phentolamine. Adding dobutamine resulted in a further increase in Group 1 only (+ 11%, p < 0.01). Central venous pressure was significantly higher in Group 2 during control periods. No change was noted in either group with phentolamine. Pulmonary wedge pressure showed no statistical difference between groups during control periods. A slight but significant fall was observed in both groups with phentolamine. When dobutamine was added, a further fall was noted only in Group 2. Control values for mean systemic arterial pressure showed a significant difference between groups. Group 1 had higher values, probably because of the older age of the patients. With phentolamine, a significant decrease was noted in both groups. When dobutamine was added, a rise in mean arterial pressure was observed in both groups, but it was significant only in Group 1. However, arterial pressures during administration of both drugs were not statistically different from controls in either group. Systemic vascular resistance was abnormally high and was similar in both groups during control periods. With phentolamine, a significant fall was recorded. Adding dobutamine produced a slight further decrease, which was not significant. Pulmonary vascular resistance was within the normal range throughout the study. However, a significant fall was observed with phentolamine in both groups. Left ventricular stroke work index was not significantly affected by phentolamine in either group. When dobutamine was added, a significant increase was noted. Comment The risk of death in the immediate postoperative period after cardiac operation in children appears to be inversely related to cardiac index during this period [ll, 19, 271. To increase cardiac output, various drugs are used, especially vasodilators to decrease afterload [I, 10, 11, 141 and sympathomimetic drugs to increase myocardial contractility [12, 13, 15, 161. Choice and combination of these drugs in children have been empirical and based mostly on experience gathered in adults. However, in children, the hemodynamic setting (i.e., heart rate, afterload, and preload) may vary markedly according to

4 646 The Annals of Thoracic Surgery Vol 35 No 6 June 1983 Table 2. Results of Hemodynamic Measurementsaib GROUP 1 Phentolamine Control Phentolamine + Dobutamine Phentolamine Control CI (L/min/m2) 3.54 f f f f 0.48 HR (beatdmin) loo f f 6 94 f 8 88 f 7 CVP (mm Hg) 7.8 f f f f PWP (mm Hg) 15.3 f f f f SAP(mm Hg) 88.5 f f f f f 4.7 PAP(mm Hg) 29.5 f f f f f 6.2 GROUP 2 CI (L/min/m2) ~~ 3 f f f f f 0.25 HR(beats/min) 121 f f f f f 8 CVP (mm Hg) 12 f f f f PWP (mm Hg) 16.5 f f f f f 1.4 SAP (mm Hg) 79.3 f f f 6.7 PAP (mm Hg) 23.1 f f f f f 2.3 'Data are shown as mean C standard deviation. %ee Materials and Methods section for discussion of times of measurement. CI = cardiac index; HR = heart rate; CVP = central venous pressure; PWP = pulmonary wedge pressure; SAP = mean systemic arterial pressure; PAP = mean pulmonary arterial pressure. Table 3. Hemodynamic Changes with Phentolamine Alone and with Phen tolamine and Dobutamine in Group 1 Difference Difference Difference from Phentolamine from from Variables Control' Phentolamineb Control (%) + Dobutamine Phentolamine (%) Control (%) CI (L/min/m2) 3.52 f f ' 4.67 f T + 33' SVI (d/m2) 38.2 f f ' 45.6 f c + 19' HR (beatslmin) 92 k 5 98 f f 6 + 6' + 13' m(mm Hg) 88f3 81 f 4 % 91 f ' +3 PAP (mm Hg) 29 f 4 28 f f ' +9 CVP (mm Hg) 8 f f f ' PWP (mm Hg) 15 f 3 13 f 3 13d 14.4 f SVR (RU) 26.8 e k C 20.5 f ' PVR (RU) 3.69 f f d 2.88 f d RVSWI (gmrn/beat/m2) 11.2 k f e c + 45c RVWI (gmm/min/m2 x 10.4 f k f ' + 63' LVSWI (gmm/beat/m2) 39.2? f f c + 22' LVWI (gmmlmin/m2 x 37.3 f f f oc + 36c "Control values = the mean of the two control measurements shown in Table 2. See Materials and Methods section for details. bphentolamine values = the mean of the two phentolamine measurements shown in Table 2. See Materials and Methods section for details. 'p < dp < C1 = cardiac index; SVI = stroke volume index; HR = heart rate; SAP = mean systemic arterial pressure; PAP = mean pulmonary arterial pressure; CVP = central venous pressure; PWP = pulmonary wedge pressure; SVR = systemic vascular resistance; PVR = pulmonary vascular resistance; RVSWI = right ventricular stroke work index; RVWI = right ventricular work index; LVSWl = left ventricular stroke work index; LVWI = left ventricular work index; RU = resistance units.

5 647 Bemer, Rouge, and Friedli: Phentolamine and Dobutamine after Pediatric OpenHeart Operations Table 4. Hemodynamic Changes with Phentolamine Alone and with Phen tolamine and Dobutamine in Group 2 Difference Difference Difference from Phentolamine from from Index Control" Phentolamineb Control (I) + Dobutamine Phentolamine (%) Control (%) CI (L/min/m') 2.93 f c 3.57 f c + 22c SVI (d/m2) 24.6 f f c 27.6 f l2c HR (beatslmin) 121? 6 121? ? 10 +IF + 11' SAP (mm Hg) f 4 lld 73? (mm Hg) f f CVP (mm Hg) 12 f f PWP (mm Hg) '4 13.3? ' 2' SVR (RU) 23.1 f f ' PVR (RU) 2.8 f f d 2.5 f RVSWI (gmmlbeatlm') 4.2 f f ? RVWl (gmmlminlm' x 4.9 f f f LVSWl (gmm/beat/m2) 22.3 f f IT d + 12 LVWI (gmmlminlm' x lo') f f 6 + 2T + 21' 'Control values = the mean of the two control measurements shown in Table 2. See Materials and Methods section for details. bphentolamine values = the mean of the two phentolamine measurements shown in Table 2. See Materials and Methods section for details. 'p < "p < C1 = cardiac index; SVI = stroke volume index; HR = heart rate; SAP = mean systemic arterial pressure; PAP = mean pulmonary arterial pressure; CVP = central venous pressure; PWP = pulmonary wedge pressure; SVR = systemic vascular resistance; PVR = pulmonary vascular resistance; RVSWI = right ventricular stroke work index; RVWI = right ventricular work index; LVSWl = left ventricular stroke work index; LVWI = left ventricular work index; RU = resistance units. the underlying cardiac defect that has been repaired. Our two groups of patients differed in mean age as well as in hemodynamic situation at the onset of the study. Whereas cardiac index and pulmonary vascular resistance (right heart afterload) were not statistically different between the two groups, central venous pressure was significantly higher in the patients with tetralogy of Fallot. This may be related to some right ventricular dysfunction, low right ventricular compliance, or pulmonary regurgitation [20, 211. With regard to the left heart, pulmonary wedge pressure (left ventricular preload) and systemic vascular resistance (left ventricular afterload), although abnormally high, were not statistically different between the two groups, nor was cardiac index. However, in patients with tetralogy of Fallot, cardiac index was maintained at a significantly higher heart rate with a smaller stroke volume index [17, 28, 291. As far as the choice of drugs is concerned, the administration of a vasodilator has been advocated as a first step [I, 11, 191 because of the abnormally high vascular resistances usually present after cardiopulmonary bypass [lo, 121. We selected phentolamine, an ablocking vasodilator, active mainly at the arteriolar level [4, 5, 24, 301 and considered safe for use in children Ill, 181. Dobutamine, the inotropic agent tested, is said to be the most specific PI cardiac agonist [6, 3134] with less chronotropic or arrhythmogenic effects than dopamine or isoproterenol [8, 22, 3539]. Furthermore, unlike dopamine, epinephrine, or isoproterenol, no direct effect on vascular tone was expected with dobutamine at the dosage used [7, 9,131. It was less than the 10 to 15 pg/kg/min, at which levels p2 stimulation might be expected [36, 381. The hemodynamic response to phentolamine was remarkably similar in both groups. Cardiac output rose because of an increased stroke volume, while heart rate was not significantly affected. In this respect children differ from adults, in whom a tachycardia of variable degree is commonly observed after administration of phentolamine [23, 24, 30, 401. It is explained by a release of endogenous catecholamines from sympathetic nerve endings through inhibition of both presynaptic and postsynaptic a receptors by phentolamine [ In our patients this phenomenon did not seem to play a major role, perhaps because the initial heart rate was faster or because the level of circulating cate

6 648 The Annals of Thoraac Surgery Vol 35 No 6 June 1983 ** T B MSAP mmhg kfi il +++ T 1 3 *+* 20 T r : I I I n m I r I I I I. I I fi PCD E P PtD E P P H ) m Fig 2. Hemodynamic effects of phentolarnine and of phentolamine and dobutamine on (A) cardiac index (CI), stroke volume index (SVI), and heart rate (HR) and on (B) mean systemic arterial pressure (MSAP), systemic vascular resistance (SVR), and left Ventricular stroke work index (LVSWI) immediately after cardiac operation. Data are shown as mean & standard error of the mean. The squares represent patients in Group 1, who underwent operation for mitral valve disease, and the closed circles represent patients in Group 2, whohd tetralogy of Fallot. (C = mean of both control values; P = mean of both phentolamine values; P + D = phentolamine and dobutamine values; * = significant versus ct = significant versus cand P; *** = significant versus P.) cholamines was already high. As expected, the improvement in cardiac output was secondary to a decrease in systemic vascular resistance (left ventricular afterload reduction). As a result, a decrease in pulmonary wedge pressure and pulmonary vascular resistance was observed (right ventricular afterload reduction). The similarly good response to phentolamine in both groups demonstrated the usefulness of a vasodilator in the postoperative phase, regardless of the underlying heart defect and hemodynamic setting. It must be emphasized that in spite of a better stroke volume, right and left ventricular stroke work indices were not increased. The cost of oxygen demand for this hemodynamic improvement was therefore minimal [24, 441. However, it must be remembered that the fall in left ventricular filling pressure below a critical level could also result in a drop in cardiac output [4, 10, 451. Dobutamine, added to phentolamine, produced a further increase in cardiac index in both groups. However, this increase was significantly greater in Group 1. Dobutamine,

7 649 Berner, Rouge, and Friedli: Phentolamine and Dobutamine after Pediatric OpenHeart Operations unlike phentolamine, had a dissimilar hemodynamic effect in Groups 1 and 2, although some of the variables changed in the same way. A response common to both groups was an increase in cardiac index, heart rate, and mean systemic arterial pressure. Accordingly, peripheral vascular resistance was not lowered further. Consequently, left ventricular work indices increased in both groups. Whether the final balance between work (oxygen demand) and rise in cardiac output (oxygen supply) is beneficial or not to the left ventricle cannot be answered from this study. In contrast, the response to dobutamine with regard to stroke volume was different between the two groups. In Group 1 (mitral valve disease) only, dobutamine increased cardiac output further by a significant rise in stroke volume index. Stroke volume did not change in Group 2 (tetralogy of Fallot), the increased output being explained by the higher heart rate only (see Fig 2). Several hypotheses can be put forth to explain this diminished response. As the mean age in Group 2 was lower (60 months versus 152 months), this response could be simply an agerelated phenomenon. Driscoll and colleagues [46], comparing hemodynamic effects of various catecholamines in puppies and adult dogs, found that tachycardia was the only response to dobutamine in immature dogs. However, no newborns or infants were included in our study. Therefore, although some effects of age cannot be excluded, we do not believe that this is the main factor. We favor another hypothesis: the relatively small left ventricle in patients with tetralogy of Fallot has limited capacity [17, 281 and may have reached its maximum potential for increasing stroke volume index once afterload had been reduced by phentolamine. In another study, successive echocardiographic determinations demonstrated that two to four weeks are necessary for the left ventricle to increase to normal dimensions after a corrective operation [27]. As long as the left ventricle is of low capacity, cardiac output must be dependent chiefly on heart rate. It can be concluded from this study that phentolamine is primarily indicated after openheart operation whatever the underlying cardiac defect. When inotropic support is required as well, dobutamine appears to be a good choice for chil dren with valve disease, but a drug that has a more chronotropic effect may be preferable for patients who have undergone repair of tetralogy of Fallot. References 1. Cohn JN, Franciosa JA: Vasodilator therapy of cardiac failure. N Engl J Med 29727, Meretoja OA: Influence of sodium nitroprusside and dobutamine on the haemodynamic effects produced by each other. Acta Anaesthesiol Scand 24:195, Mikulic E, Cohn JN, Franciosa JA: Comparative hemodynamic effects of inotropic and vasodilator drugs in severe heart failure. Circulation 56:528, Miller RR, Vismara LA, Williams DO, et al: Pharmacological mechanisms for left ventricular unloading in clinical congestive heart failure. Circ Res 39:127, Williams DO, Hilliard GK, Cantor SA, et al: Comparative mechanism of ventricular unloading by systemic vasodilator agents in therapy of cardiac failure: nitroprusside versus phentolamine. Am J Cardiol 35:177, Berkowitz C, McKeever L, Croke RP, et al: Comparative responses to dobutamine and nitroprusside in patients with chronic low output cardiac failure. Circulation 56:918, Chamberlain JH, Pepper JR, Yates AK: Dobutamine, isoprenaline and dopamine in patients after open heart surgery. Intensive Care Med 75, Lewis GRJ, Poole Wilson PA, Angerpointer TA, et al: Measurement of the circulatory effects of dobutamine, a new inotropic agent, in patients following cardiac surgery. Am Heart J 95:301, Steen PA, Tinker JH, Pluth JR, et al: Efficacy of dopamine, dobutamine, and epinephrine during emergence from cardiopulmonary bypass in man. Circulation 57:378, Appelbaum A, Blackstone EH, Kouchoukos NT, Kirklin JW: Afterload reduction and cardiac output in infants early after intracardiac surgery. Am J Cardiol39:445, Benzing G 111, Helmsworth JA, Schreiber JT, et al: Nitroprusside after openheart surgery. Circulation 54:467, Benzing G 111, Helmsworth JA, Schreiber JT, Kap Ian S: Nitroprusside and epinephrine for treatment of low output in children after openheart surgery. Ann Thorac Surg 27:523, Bohn DJ, Poirier CS, Edmonds JF, Barker GA: Hemodynamic effects of dobutamine after cardiopulmonary bypass in children. Crit Care Med 8:367, 1980

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