A Comparison of the Hemodynamic Effects of Inotropic Agents

Transcription

1 A Comparison of the Hemodynamic Effects of Inotropic Agents Louis C. Argenta, M.D., Marvin M. Kirsh, M.D., Edward L. Bove, M.D., Vincent M. Cimmino, M.D., Benedict Lucchesi, M.D., John Straker, B.S., Robert Baker, B.S., Robert Lee, B.S., and Herbert Sloan, M.D. ABSTRACT This experimental study was con- tance, restoration of systemic arterial pressure and ducted to compare and contrast the cardiovascular consequent improved coronary flow, absence of effects of the drugs most commonly used to alleviate tachycardia, and augmented renal blood flow. low-cardiac-output syndrome. Twenty-five adult mongrel dogs were infused with sodium pentobarbi- A major cause of death in patients following tal(60 mglmin) until their cardiac output fell to 50 k open-heart operations is low-cardiac-output 5% of the average values determined by syndrome. This complex is characterized hemothermodilution technique prior to pentobarbital in- dynamically by a decreased cardiac index, fusion. The dogs were then divided into six groups, increased peripheral vascular resistance, and and one of the following agents or combinations redistribution of blood flow to vital organs. Deof agents was administered to each group: iso- spite advances in mechanical support systems proterenol, glucagon, dopamine, dobutamine, levar- such as the intraaortic balloon and membrane terenol and phentolamine, or levarterenol and ni- oxygenator, inotropic drugs are still the troprusside. mainstay of treatment for low-cardiac-output All drugs, except for glucagon and the combination syndrome. The most commonly used drugs of levarterenol and nitroprusside, produced an in- are isoproterenol, glucagon, dopamine, dobucrease in cardiac output above the nonfailure baseline tamine, and norepinephrine either alone or values. However, this increase was accompanied by in combination with phentolamine. However, an undesirable, pronounced tachycardia except when the therapeutic benefits achieved with the use of levarterenol was used simultaneously with phen- these drugs are frequently offset by certain adtolamine. Both dopamine and the combined infusion verse cardiovascular effects that accompany of levarterenol and phentolamine proved the most their administration. The purpose of this study effective in restoring systemic arterial pressure to was to compare and contrast the cardiovascular near baseline values, and both were able to increase effects of the most commonly used drugs in renal blood flow above the failure baseline values. animals subjected to a low-cardiac-output state. While renal blood flow remained elevated with all dosages of levarterenol and phentolamine, it tended to decrease with larger doses of dopamine. These experiments demonstrate that there are major advantages in the use of simultaneously infused levarterenol and phentolamine for of low-cardiac-output syndrome: increased cardiac output without elevated peripheral vascular resis- From the Department of Surgery, Section of Thoracic Surgery, The University of Michigan Medical Center, Ann Arbor, MI. Supported in part by Michigan Heart Association Grant No Presented at the Twelfth Annual Meeting of The Society of Thoracic Surgeons, Jan 26-28, 1976, Washington, DC. Address reprint requests to Dr. Kirsh, Section of Thoracic Surgery, University of Michigan Medical Center, Ann Arbor, MI Methods Twenty-five adult mongrel dogs weighing between 17 and 30 kg were anesthetized intravenously with Dialurethane* (0.6 ml per kilogram of body weight) and mechanically ventilated with room air through a cuffed endotracheal tube. A right femoral artery catheter was placed for continuous systemic arterial pressure monitoring. A left ventricular catheter was passed retrograde through the left carotid artery to measure the first derivative of the left ventricular pressure curve (dpldt) and ventricular pressures. A Swan-Ganz catheter was posi- *Allobarbital, 100 mglml; urethane, 400 mg/ml; monoethylurea, 400 mglml in water. 50

2 51 Argenta et al: Hernodynamic Effects of Inotropic Agents tioned in the pulmonary artery by way of the right femoral vein for cardiac output, central venous pressure, and pulmonary arterial wedge pressure determinations. Drug-infusion catheters were placed in the right and left jugular veins. The bladder was drained with a Foley catheter. A splenectomy was then performed through a midline abdominal incision. All animals were given sodium heparin, 1 mglkg intravenously, at two-hour intervals. Left renal vein blood was then shunted to the left femoral vein using a catheter with a sampling side-arm for measurement of renal blood flow. Cardiac output was determined by the thermodilution technique. Instantaneous dpldt was measured during peak inspiration. Systemic vascular resistance, expressed in arbitrary units, was calculated from the pressure and flow data (mean systemic arterial pressure minus right atrial pressure divided by cardiac output). Lactated Ringer's solution was given in all animals to maintain the central venous pressure between 6 and 8 mm Hg. Following a stabilization period of 30 minutes, three sets of data were recorded at 10-minute intervals. The previously described pressures were recorded continuously throughout the experiment. Sodium pentobarbital* was then infused at a rate of 60 mglmin until the cardiac output fell to 50 f 5% of the average value. This level of myocardial depression was maintained with a constant rate of infusion for each animal that varied between 6 and 11 mglmin. A second set of baseline data was then recorded at 10-minute intervals for 30 minutes. The animals were then divided into six groups: Group 1 (4 dogs) received isoproterenol at 0.01, 0.02, and 0.05 pglkglmin; Group 2 (4 dogs) received an infusion of glucagon at 0.5, 1.0, and 2.0 pglkglmin; Group 3 (4 dogs) received dopamine at 5.0, 10.0, and 20.0 pglkgl min; Group 4 (4 dogs) received dobutamine at 1.0, 2.0, and 5.0 pglkglmin; Group 5 (5 dogs) received simultaneous infusion of levarterenol and phentolamine at equal doses of 0.2,0.5, and 1.0 pglkglmin; and Group 6 (4 dogs) received a Tentobarbital sodium, 6%; propylene glycol, 20%; 95% ethyl alcohol, looh. simultaneous combination of levarterenol and nitroprusside at 0.5 pglkglmin each, 1.0 pglkgl min each, and 1.Opglkglmin of levarterenol with 2.0 pglkglmin of nitroprusside. The drugs were administered so as to produce a progressive increase in cardiac output. The maximum dose in each group was that which elevated the cardiac output above baseline values. At each dose level the physiological variables were measured for 10 minutes after a 30-minute stabilization period. Upon completion of inotropic drug infusion, physiological measurements were again recorded to ensure that the cardiac output was not significantly different from the original failure baseline. Each dog therefore served as its own. Data are presented as mean values for each group plus or minus the standard error about the mean (SEM). Statistical analyses were determined by the Student paired t-test. Results Pentobarbital lnfusion The infusion of sodium pentobarbital produced a fall in cardiac output from a baseline value of 2.70 f 0.12 to 1.34 f 0.06 Llmin (p < 0.001), representing a 49% decline. Heart rate was reduced to 116 f 4 beatslmin from a value of 147 f 6 ( p < 0.001). The mean systemic pressure decreased to 36 '$0 of, from 139 _+ 4 to 50 f 3 mm Hg ( p < 0.001), and dpldt fell from a value of 4,000 f 380 mm Hglsec to 1,100 k 51 ( p < 0.001). The systemic vascular resistance was consistently reduced in all animals to 67% of baseline (52 f 3 units), to 35 f 2 units ( p < 0.001). blood flow fell to 85 f 3 mllmin, representing a 47% decline from the value of 180 * 7 ( p < 0.001). No significant variation from values was seen in left ventricular end-diastolic pressure. After cessation of inotropic drug infusion, no change from the original failure baseline values was noted for mean systemic pressure, dpldt, systemic vascular resistance, or cardiac output. Heart rate remained significantly above the failure baseline at 126 f 5 beatslmin (p < 0.05). blood flow fell further, to 70 k 3 mllmin ( p < 0.001).

3 52 The Annals of Thoracic Surgery Vol 22 No 1 July 1976 Group 1-lsoproterenol The infusion of isoproterenol at 0.05 pglkgl min produced an increase in the cardiac output of 117% above the baseline. Heart rate rose from a failure baseline of 109 to 131 beatslmin, just slightly above the value ( p < 0.01). The drop in systemic vascular resistance represented a 75% reduction from the original value of 52 f 5 units. The dpldt rose significantly from the failure baseline to 2,000 f 65 mm Hglsec ( p < 0.001), representing 57% of the normal. No significant change from the failure baseline was seen in mean systemic arterial pressure or renal blood flow. At lower doses isoproterenol showed the same trends, but to a lesser degree (Table 1). Group 2-Glucagon The infusion of glucagon produced similar but less marked changes than those seen with isoproterenolinfusion. The exception to this was the heart rate, which rose to 200 k 10 beatslmin at an infusion rate of 2.0 pglkglmin, a 31% increment over the nonfailure value. Systemic vascular resistance progressively decreased with each dosage increment in glucagon, falling to a minimum of 48% of value. The peak cardiac output was achieved at a glucagon dose of 2.0 pglkglmin (2.23 f 0.14 Llmin; p < 0.001); this value is 84% of the nonfailure baseline. As with isoproterenol, no significant changes from failure baseline were seen in mean arterial pressure or renal blood flow (Table 2). Table 1. Hemodynamic Effects of Isoproterenol Cardiac Blood Isoproterenol Heart Rate Mean SAP dpldt SVR output Flow Dose (beatslmin) (mm Hg) (mm Hg/sec) (units) (Llmin) (mumin) Nonfailure 129 f f 11 3,500 f f f f 17 Failure baseline 109 f 4 44f f f f f pglkglmin ,100 * f f f pglkglmin 123 f 2 41f 3 1,400 f f f f pglkglmin ,000 f f f f 1 All values given as mean f SEM. SAP = systemic arterial pressure; dpldt = first derivative of left ventricular pressure curve; SVR = systemic vascular resistance. Table 2. Hernodynamic Effects of Glucagon Cardiac Blood Glucagon Heart Rate Mean SAP dpldt SVR output Flow Dose (beatslmin) (mm Hg) (mm Hglsec) (units) (Llmin) (mumin) Nonfailure 153 f f 12 3,700 f f f Failure baseline 111 f 8 55f 7 1,000 f f f pglkg/min ,700 f f f f pglkglmin 182 f 16 53f 4 1,800 f f f pglkglmin f 8 1, f f f 8 All values are given as mean k SEM.

4 53 Argenta et al: Hemodynamic Effects of Inotropic Agents Group 3-Dopamine At a concentration of 20 pglkglmin, dopamine produced marked tachycardia representing 164% of the original. Systemic arterial pressure rose significantly (p < 0.1) to a level only 20% below the original value. The dpldt rose markedly (p < 0.01), representing 441% of the original baseline. The peak renal blood flow equaled 71% of the original value; larger doses resulted in a further decline to 111 f 13 ml/min. No significant change from failure baseline was seen in the systemic vascular resistance (Table 3). Group 4-Dobutamine The infusion of dobutamine at the lower dose ranges produced progressive increases in cardiac output. The increments were significantly above the failure baseline value of 1.31 f 0.29 Llmin ( p < 0.05). Systemic arterial pressure rose from 47 k 1 to 76 k 7 mm Hg ( p < 0.01), 53% of the original. Heart rate and dpldt were significantly elevated above the failure baseline (p < 0.05) and represented 97 and 98% of the original s, respectively. Systemic vascular resistance fell progressively but showed no significant change from failure baseline (Table 4). Group 5-Levarterenol and Phentolamine The simultaneous infusion of levarterenol and phentolamine in higher dose ranges produced significant ( p < 0.01) elevations in cardiac output, representing 115% of the nonfailure. The heart rate was increased to 162 f 13 beatslmin, 96% of the original value. The dpldt was significantly elevated above failure baseline (p < 0.01), representing 202% of. The mean systemic pressure rose significantly ( p < 0.01) and was only 25% below the Table 3. Hernodynamic Effects of Dopamine" Cardiac Blood Dopamine Heart Rate Mean SAP dpldt SVR output Flow Dose (beatslmin) (mm Hg) (mm Hglsec) (units) (Wmin) (mumin) Nonfailure 136 f f 7 2,900 f f f f 16 Failure baseline 126 f 18 55f 6 1,300 f f f f 8 5 pglkglmin 118 f 7 68f 9 1,700 f f f f pglkglmin 167 f 7 95f 6 5,600 f 1, f f f pglkglmin 223 f f 23 12,800 f 1, f f f 13 "All values are given as mean f SEM. Table 4. Hemodynamic Effects of Dobutamine" Cardiac Blood Dobutamine Heart Rate Mean SAP dpldt SVR output Flow Dose (beatslmin) (mm Hg) (mm Hglsec) (units) (Llmin) (mumin) Nonfailure Failure baseline 138 f f f 14 47f 1 4,200 k 753 1,200 f f f f f f 14 75f 6 1 pglkglmin 117 f 8 59f 3 1,900 f f f f 10 2 pglkglmin 119 f 4 68f 4 2,500 f f f f 7 5 pglkglmin 134f 3 76f 7 4,100 f f f f 10 "All values are given as mean? SEM.

5 54 The Annals of Thoracic Surgery Vol 22 No 1 July 1976 original value of 157 k 5 mm Hg. Likewise, renal blood flow rose significantly ( p < 0.05) and represented a return to within 23% of the nonfailure level. Systemic vascular resistance showed no significant change from failure baseline (Table 5). Group 6-Levarterenol and Nitroprusside The simultaneous administration of levarterenol and nitroprusside produced marked tachycardia with a peak value of 199 f 7 beatslmin at concentrations of 1.0 and 2.0 pglkglmin, respectively. This is a significant elevation above the failure baseline of 124 f 6 beatslmin (p < 0.001) and represents 125% of the nonfailure. Cardiac output rose significantly at the higher dose concentrations ( p < 0.05). This increment repre- sents 98% of the nonfailure value. blood flow rose to 120 f 12 mllmin at the lower dose range from the failure baseline of 92 f 5 ( p < 0.1). When the concentrations of both drugs were increased, a further decline in renal blood flow was noted (Table 6). Comment This experiment was designed to compare the cardiovascular effects of the various inotropic agents used to treat low-cardiac-output syndrome after open-heart operations. We employed a continuous infusion of sodium pentobarbital in dogs to produce a hernodynamic state resembling that of low cardiac output. In addition to its negative inotropic effect, sodium pentobarbital causes a marked slowing of the Table 5. Hemodynamic Effects of LevarterenollPhentolamine" Levarterenoll Cardiac Blood Phentolamine Heart Rate Mean SAP dpldt SVR output Flow Dose (beatslmin) (mm Hg) (mm Hglsec) (units) (Llmin) (mllmin) Nonfailure 168 f f 5 4,800 f f k k 17 Failure baseline 122 f 6 52f 5 1,100 f f k f pg/kglmin 125 f 9 77 f 17 2,200 k f k f 15 each 0.5 pglkglmin 144 f 10 89f 5 3,900 f f f k 11 each 1.0 pglkglmin 162 f f 14 9,700 f 1, k f f 20 each "All values are given as mean f SEM. Table 6. Hemodynamic Effects of LevarterenollNitroprusside" Levarterenoll Cardiac Blood Nitroprusside Heart Rate Mean SAP dpldt SVR output Flow Dose (beatslmin) (mm Hg) (mm Hglsec) (units) (Llmin) (mllmin) Nonfailure 159 f k 8 5,200 f f f k 14 Failure baseline 124 f 6 47 f 3 1,100 f k k f pglkglmin 164 f f 5 4,500 f f f f l f 7 66 f 6 6,200 f 1, % f f 10 pglkglmin aall values are given as mean k SEM.

6 55 Argenta et al: Hernodynamic Effects of Inotropic Agents heart rate. These effects resulted in a consistently reproducible model of low cardiac output [2, 3, 171 which, being anatomically intact, lent itself to evaluation of the response to sympathetic stimulating and blocking drugs. Each of the drugs studied has distinct pharmacological properties. Isoproterenol exerts its action by stimulating the beta-adrenergic receptors in the myocardium and in the peripheral arterial bed. Dopamine increases cardiac contractility by excitation of the myocardial betaadrenergic receptor sites. Peripherally it exerts alpha-adrenergic activity in all except the splanchnic and renal vascular beds, where it appears to stimulate a specific dopamine receptor site to produce vasodilatation [l, 6, 11, 131. Dobutamine, a new synthetic catecholamine, exerts a direct action on the myocardial betaadrenergic receptors and on both alpha and beta receptor sites in the peripheral arterial bed [9]. Glucagon manifests its effects on the heart and arterial bed through mechanisms that are unknown and apparently do not involve stimulation of either alpha- or beta-adrenergic receptor sites [4, 5, 10, 12, 161. Levarterenol exerts its action on the heart by stimulating the myocardial beta-receptor sites to produce an increase in heart rate, stroke volume, and cardiac output. The positive chronotropic effects of the drug, however, are masked by reflex vagal tone as a result of the increase in arterial pressure. Its effect on stroke volume is often masked by an increase in afterload brought about largely by its peripheral effect (vasoconstriction). This adverse peripheral vasoconstrictive effect may be minimized through the simultaneous use of an alpha-adrenergic blocking agent, phentolamine (Regitine), without altering levarterenol's positive inotropic actions on the heart. Nitroprusside, a direct vasodilator with inotropic properties, was administered with levarterenol to determine whether it would counteract the adverse peripheral vasoconstrictive effects of levarterenol [15]. Each drug produced an increase in cardiac output in a dose-dependent fashion. Except for glucagon and simultaneously infused levarterenol and nitroprusside, all the drugs were able to raise cardiac output above the nonfailure baseline value (Fig 1). However, this increase in I I I I I Control Foilue dose dose dose Baseline I 2 3 Fig I. Effect of the various drugs and drug combinations on cardiac output (CO). All except glucagon and simultaneously administered levarterenol and nitroprusside raised cardiac output above the value. (L = levarterenol; NP = nitroprusside; P = phentolamine.) 4 DoDamine cardiac output was accompanied by pronounced tachycardia with the infusion of dopamine, glucagon, and levarterenohitroprusside. Since heart rate is one of the most powerful determinants of myocardial oxygen demand, this tachycardia might be detrimental, as it would further increase the myocardial oxygen requirements already raised by the improved inotropic state [7, 81. When levarterenol was used simultaneously with phentolamine, however, this marked tachycardia did not occur. At the peak dose range (lpuglkglmin each) the heart rate did not exceed prefailure baseline rates. A similar increase in cardiac output unaccompanied by pronounced tachycardia occurred with the infusion of dobutamine and isoproterenol. All drugs except glucagon and isoproterenol produced a rise in systemic arterial pressure (Fig 2). Dopamine and simultaneously infused levarterenol and phentolamine were the drugs most effective in restoring systemic pressure to near prefailure baseline values (80 and 75% of, respectively). The increase in pressure occurred without a statistically significant rise in peripheral vascular resistance and was secondary to the elevation in cardiac output. Glucagon and isoproterenol failed to raise systemic pressure because these drugs markedly decreased peripheral vascular resistance [4, 5, 7, 101. Theoretically this could tend to counteract, at least in part, the increase in myocardial oxy-

7 56 The Annals of Thoracic Surgery Vol 22 No 1 July 1976 k40t 8, mglucagon lsuprel administered in combination with phentola-! a Y o Control Failure dose dose dose Baseline I 2 3 Fig2. Effect of the various drugs and combinations on systemic arterial pressure (SAP). Glucagon and isoproterenolfailed to raisesystemic pressure, while dopamine and concomitantly infused levarterenol and phentolamine elevated it nearly to level without raising peripheral vascular resistance. (L = levarterenol; NP = nitroprusside; P = phentolamine.) I z 80 8 loo w 60-2 $ 40 0 t Control Failure dose dose dose Baseline I 2 3 Land P GI u c a g o n lsuprel Fig3. Effect of the various drugs and combinations on renal blood flow (RBF). Only dopamine and simultaneously infused leuarterenol and phentolamine raised renal flow above the failure baseline level. (L = levarterenol; NP = nitroprusside; P = phentolamine.) gen requirements produced by the augmentation of the inotropic state. In addition to their varying effects on total peripheral vascular resistance, these drugs also manifested different effects on renal blood flow. Of the drugs used, only dopamine and simultaneous levarterenol and phentolamine increased renal flow above the failure baseline values (Fig 3). flow remained elevated with all the dosages of levarterenol and phentolamine but tended to decrease with the larger dosages of dopamine. The larger dopamine doses noticeably stimulated the alpha receptor sites in the renal and peripheral vascular bed [141, resulting in increased cardiac output, peripheral vascular resistance, and pulse rate but a fall in renal blood flow. A similar decrease in renal flow with the larger dosage of dopamine has been reported by Glick and associates [5]. Since adrenergic receptor sites have been shown to exist in the kidney, the maintenance of renal blood flow achieved when levarterenol is mine is secondary, in part, to the ability of phentolamine to block the renal vasoconstrictive effect of levarterenol. The improved renal flow was also due to the increase in cardiac output that occurred with simultaneous administration of the drugs. At times the changes in renal blood flow did not parallel fluctuations in cardiac output, indicating that local autoregulation within the kidney predominates over systemic factors in ling renal blood flow. No statistically significant increase in renal blood flow occurred with the infusion of glucagon, dobutamine, levarterenol with nitroprusside, or isoproterenol. The decrease in renal flow that occurs with isoproterenol infusion has also been reported by Glick and co-workers [5] and others [81. Although isoproterenol dilates the cutaneous and skeletal vascular bed, it has no direct action on the renal bed. The dilation that occurs in the other vascular beds causes blood to be preferentially shunted away from the kidneys to these areas, thereby decreasing renal blood flow [61. The results of this study demonstrate the advantages or usefulness of simultaneous infusion of levarterenol and phentolamine, compared with the other commonly used drugs, in treatment of the low-cardiac-output state. There is an increase in cardiac output without a change in peripheral vascular resistance. The rise in systemic pressure that results from the improved cardiac output leads to increased coronary blood flow. This, in conjunction with the absence of tachycardia, causes a reduction in myocardial oxygen consumption and therefore an improvement in myocardial oxygenation and left ventricular function. The simultaneous administration of these two drugs in optimal ratios has no deleterious effect upon renal blood flow. Finally, the improvement in cardiac output occurs without producing tachycardia. Since heart rate is an important determinant of myocardial oxy-

8 57 Argenta et al: Hemodynamic Effects of Inotropic Agents gen demands, the absence of tachycardia would increase myocardial oxygen consumption to a lesser degree than occurs with drugs that increase the heart rate. From these considerations, simultaneously administered levarterenol and phentolamine, in our opinion, are the preferable agents for use in patients who develop low cardiac output following open-heart operations. References 1. Black WL, Rolett EL: Dopamine induced alterations in left ventricular performance. Circ Res 19:71, Cox R: Influence of pentobarbital anesthesia on cardiovascular function in trained dogs. Am J Physiol 223:651, Daniel EE, Fulton JB, Hiddleston M, et al: An analysis of the mechanism of barbiturate induced cardiovascular depression and its antagonism by sympathomimetic amines. Arch Int Pharmacodyn Ther 108:457, Glick G, Parmley WW, Wechsler AS, et al: Glucagon: its enhancement of cardiac performance in the cat and dog and persistence of its inotropic action despite beta receptor blockade with propanolol. Circ Res 22:789, Glick G, Segal M, Lewis R: Peripheral vascular effects of glucagon, norepinephrine, dopamine, and isoproterenol in acute myocardial infarction in dogs. Circ Shock 1:153, Goldberg L: The treatment of cardiogenic shock. Am Heart J 75:416, Gunnar R, Loeb H: Use of drugs in cardiogenic shock due to acute myocardial infarction. Circulation 45:1111, Gunnar R, Loeb H, Pietras R, et al: Ineffectiveness of isoproterenol in shock due to acute myocardial infarction. JAMA 202:1124, Holloway GA, Frederickson EL: Dobutamine, a new beta agonist. Anesth Analg (Cleve) 53:616, Koch N, Tibblin S, Schenk W: Hemodynamic responses to glucagon. Ann Surg 171:373, Lipp H, Falicou R, Resnekov L, et al: The effects of dopamine on depressed myocardial function following coronary embolization in the closed chest dog. Am Heart J 84:208, Lucchesi BR: Cardiac actions of glucagon. Circ Res 22:777, McDonald RH, Goldberg LI: Analysis of the cardiovascular effects of dopamine in the dog. J Pharmacol Exp Ther 140:60, McNay JL, McDonald RH, Goldberg LI: Direct renal vasodilatation produced by dopamine in the dog. Circ Res 16:510, Palmer RF, Lasseter KC: Sodium nitroprusside. N Engl J Med 292:294, Puri P, Bing R: Effects of glucagon on myocardial contractility and hemodynamics in acute experimental myocardial infarction. Am Heart J 78:660, Urthaler F, Kramer B, James T: Selective effects of pentobarbital on automaticity and conduction in the intact canine heart. Cardiovasc Res 8:46,1974