Infusion for Afterload Reduction

Continuous Hydralazine Infusion for Afterload Reduction Marc T. Swartz, B.A., George C. Kaiser, M.D., Vallee L. Willman, M.D., John E. Codd, M.D., Denis H. Tyras, M.D., and Hendrick B. BaAer, M.D. ABSTRACT Impedance reduction with a continuous infusion of hydralazine was evaluated in 0 patients following cardiopulmonary bypass. Patients were selected for therapy when the cardiac index (CI) was less than. L/m/min, when the systemic vascular resistance index (SVRI) was greater than,500 dyne sec ~ m-~, or when both conditions were present. No other vasoactive or cardiotonic drugs were uqed intraoperatively or postoperatively. Responses were measured at 5, 30, 60, 0, 80, and 40 minutes and compared with control measurements. Significant responses appeared by 5 minutes in the mean arterial pressure, CI, and SVRI, which were maximal by hours. At 4 hours, the SVRI was,50 f 76 dyne sec ~ m(control, - ~ 3,35 f ) and pulmonary vascular resistance index, 365 f 0 dyne sec cm-5 (control, 59 f 7). The CI was 3.0 f 0.9 L/ m/min (control,.96 f 0.6) and mean arterial pressw, 75 k.3 mm Hg (control, 9 &.4). Left atrial, pulmonary artery diastolic, and right atrial pressures increased from control but not significantly:.4 f 0.8 to 3.3 *. mm Hg, 3.6 f.6 to 7. +_.5 mm Hg, and 6 k.6 to 9.4 f.7 mm Hg, respectively. In 6 patients, hydralazine was continued for 4 hours and in, the transition to oral therapy was made. Hydralazine by infusion effectively reduces afterload, avoids the fluctuations of bolus therapy, and allows the transition to oral therapy if needed. In the past decade, treatment of low cardiac output with vasodilators has been used with increasing frequency and success. Drugs acting on the arterial system influence afterload while venoactive drugs alter preload, although a ve- From the Department of Surgery, St. Louis University School of Medicine, St. Louis, MO. Presented at the Twenty-seventh Annual Meeting of the Southern Thoracic Surgical Association, Nov 3-5, 980, White Sulphur Springs, W. Address reprint requests to Dr. Bamer, Department of Surgery, St. Louis University, 35 Grand Blvd, St. Louis, MO 6304. nodilator that reduces preload may decrease afterload by reducing ventricular volume without altering systemic vascular resistance [ll. Following cardiopulmonary bypass it may be desirable to use a vasodilator that decreases afterload without altering preload. It has been shown that arterial resistance can be reduced with little change in filling pressures with bolus intravenous infusion of hydralazine []. Because of the limitations of bolus therapy, we report here our experience with continuous intravenous infusion of hydralazine. Material and Methods Open-heart procedures were performed on 0 patients (Table ). Intraoperatively, catheters were placed in the radial artery and left atrium. A triple-lumen, balloon-tipped, thermodilution Swan-Ganz catheter was inserted through the innominate vein into the pulmonary artery. Pressures were measured by Trantec Model 800 transducers (Bentley) and an Electronics for Medicine amplifying system. Cardiac output determinations were obtained by the thermodilution method with a thermodilution cardiac output computer (Edwards Model F59E). Measurements included heart rate, mean arterial pressure, right atrial pressure, mean left atrial pressure, pulmonary artery mean and pulmonary artery diastolic pressures, cardiac output, and temperature. Standard formulas were used to calculate cardiac index (CI), stroke volume index, left ventricular stroke work, pulmonary vascular resistance index, and systemic vascular resistance index (SVRI). The pulmonary vascular resistance index was obtained by subtracting mean left atrial pressure from pulmonary artery mean pressure, multiplying that result by 80, and dividing by the CI. The SVRI was calculated by subtracting right atrial pressure from mean arterial pressure, multiplying that by 80, and dividing by the CI. 88 0003-4975/8/08088-05$0.5 @ 98 by The Society of Thoracic Surgeons

89 Swartz et al: Hydralazine Infusion for Afterload Reduction After operation, patients were selected for hydralazine therapy when the CI was less than. L/m/min, when the SVRI was greater than,500 dyne sec ~ m-~, or when both conditions were present. A loading dose of hydralazine, 0. mg per kilogram of body weight, was given intravenously and a continuous infusion ( mg per milliliter in 5% dextrose and water) of.5 pglkglmin was started. In most patients this dosage was adequate to raise the CI above.5 L/m/min while SVRI was reduced to less than,000 dyne sec cmp5. In a few patients the infusion was increased to as much as 5.0 pglkglmin to obtain the desired response. Measurements were obtained after 5/30! 60, 0, 80, and 40 minutes of therapy in all patients. In 4 patients, hydralazine was discontinued between 4 and 4 hours when it was no longer necessary for afterload reduction (SVRI <,500 dyne sec cmv5). The 6 patients who continued to require hydralazine were studied at 4 hours. In patients it was necessary to use orally administered hydralazine (5 or 50 mg every 4 hours) in order to discontinue intravenous therapy without deterioration of hemodynamic variables. No patients required oral administration of hydralazine at the time of dismissal from the hospital. The intraaortic balloon pump was employed in patients, and 3 required atrial pacing (see Table ). No other Table. Operative Procedure, Patient Sex, and the Need for Mechanical or Electrical Support Male Female Atrial Procedure Patients Patients IABP Pacing DVG TVG SVG + LVA MVR AVR AVR + SVG AVR + TVG AVR + MVR Total 3 IABP = intraaortic balloon pump; DVG = double yein graft; TVG = triple vein graft; SVG = single vein graft; LVA = left ventricular aneurysm; MVR = mitral valve replacement; AVR = aortic valve replacement. vasoactive or cardiotonic drugs were utilized. Infusion of blood to replace measured loss was accomplished precisely over the initial 4 hours of treatment. During the next 0 hours there was infusion of excess blood over measured loss for a hematocrit of less than 30%. Diuretics in the form of Lasix (furosemide), 0 to 40 mg administered intravenously, were given in the morning of the first postoperative day and daily for three to four days. During the study period intravenous fluids were infused at the rate of 50 ml per hour. Results Hemodynamic data are presented in Table and Figures through 3. Data for each time interval are compared with control using the paired t test. By 5 minutes there were significant (p < 0.05) changes in mean arterial pressure, CI, and SVRI, which progressed to maximal responses (p < 0.00) by hours. These responses persisted at 4 hours at the same level of significance. The stroke volume index was significantly increased (p < 0.05) at and 4 hours only. At 4 hours (6 patients), the SVRI remained low, but the CI had declined to.8 L/m/min ( p < 0.05) and mean arterial pressure had risen to 8 mm Hg ( p < 0.05). Filling pressures increased slightly but insignificantly during the observation period. The increase in heart rate was not significant nor was the decline in the pulmonary vascular resistance index. Left ventricular stroke work was stable. Comment The -hour responses to continuous infusion of hydralazine following a loading dose of 0. mg per kilogram are of similar magnitude to those obtained with bolus intravenous therapy of 0.5 or 0.5 mg per kilogram [. However, with bolus therapy the CI and SVRI were returning to control by hours, whereas with continuous therapy there was steady improvement in cardiac output and a further decline in the SVRI, which were maximal by hours. Despite these favorable responses, it can be argued that our therapy was suboptimal in that SVRI re-

90 The Annals of Thoracic Surgery Vol 3 No August 98 Table. Hemodynamic Dataa Control 5 Min 30 Min Hr Hr 3 Hr 4 Hr 4 Hr (N= 0) (N= 0) (N= 0) (N= 0) (N= 0) (N= 0) (N= 0) (N= 6) HR (beats/ 90 f 6. 90.6 f 6.4 9. f 5.9 9.6 f 6. 98.8 f 6. 97.4 f 6.3 97.0 f 5.7 9.0 f 5. min) MAP (mm 9 f.4 83 f.6' 79f 3.e 77 f.5' 76 f.6' 74 f.' 75f.3' 8.0 f 4.Zb Hg) CI (UmY l.% f 0.6.9 f 0.W.5 f 0.6d.76 f 0.3' 3.4 f 0.7' 3.05 f 0.' 3.0 f 0.9'.83 f 0.3lC min) SVI (mu.3 f 3. 5.8 f.9 6 + 4. 9.9 f.6 3. f.9 3.4 f 3.4 33 f 3.7b 3.6 f 3.4 beat) LVSW 48 f 3.5 48 f 3.9 49.8 f 4.0 48. f 4.3 55.6f 4.9 5. f 5. 54. 5.5 49.6 f 4.9 (P-M) (dyne 59 f 7 56 f 75 493 f 83 474 f 8 443 f 83 440 f 97 365 f 0 39 f 90 sec SVRI (dyne 3,35 f,48 f l%c,970 f 80',84 f 9',60 f 93',569 f 303',50 f 76',690 f 344' sec LAP.4 k 0.8. f..9 f 0.7 3.7 f 0.9 3. f 0.9.3 f.4 3.3 f..8 f.4 RAP 6 f.6 6.5 f.9 6.7 f.7 7.8 f.0 7.8 f.8 8.6 f.9 9.4 f.7 0.4 f.9 PADP 3.6 f.6 4.8 f.9. f.7 7.0 f.0 7.5 f.6 7.9 f. 7. f.5 5. f.6 =Shown as f standard error of the mean. p < 0.05. "p < 0.05. "p < 0.0. "p < 0.005. < 0.00. HR = heart rate; MAP = mean arterial pressure; CI = cardiac index; SVI = stroke volume index; LVSW = left ventricular stroke work; PVRl = pulmonary vascular resistance index; SVRI = systemic vascular resistance index; LAP = left atrial pressure; RAP = right atrial pressure; PADP = pulmonary artery diastolic pressure. Heart Rate MAP 00 00 BeatslMinute mmhg 50 50 p<.005.00-00.00.w.w' 0 0 3 Fig. Heart rate and mean arterial pressure (MAP) with infusion of hydralazine. Values for heart rate (solid line) are shown on the left vertical axis and for mean arterial pressure (broken line) on the right vertical axis, and are given as mean k standard error for the 4.. 4 0 entire group (N = 0 at 4 hours; N = 6 at 4 hours). All data points are compared with control (zero time) using the paired t test, and p values are depicted for changes in mean arterial pressure. Changes in heart rate were not significant. mained above normal (<,500 dyne sec ~ m-~) patients a smaller dose is adequate and avoids [3. In some of our patients (not included in this the risk of excessive hemodynamic alterations. study), it was necessary to repeat the loading When infusion was continued beyond 4 dose at 30 minutes to obtain an adequate re- hours, we did not note a greater dosage response, and occasibnally a third loading dose quirement or a diminution in the response to a has been required. This shortcoming could be stable dose. This observation is not surprising managed by a larger initial bolus, but in most in view of the absent tachyphylaxis with six

9 Swartz et al: Hydralazine Infusion for Afterload Reduction Cardiac Index SVRI I I I I p<.ql.00.w.w.00.05 I Umin/mz seclcm' p<.ool.w.w.00.00 I I 3 I 4 0 I Ii' 4 Fig. Cardiac index and systemic vascular resistance index (SVRI) with infusion of hydralazine. Values for cardiac index (broken line) are shown on the left vertical axis and for SVRI (solid line) on the right vertical axis, and are given as mean f standard error for the entire group (N = 0 at 4 hours; N = 6 at 4 hours). All data points are compared with control (zero time) using the paired t test, and p values are shown along the top for cardiac index and along the bottom for SVRI. E E I=.. 5-0 LA 0 3 4 4 Fig 3. Atrial pressures with hydralazine infusion (mean f standard error) for the entire group (N = 0 at 4 hours; N = 6 at 4 hours) are shown for right atrial (RA) and left atrial (LA) pressure. All data points have been compared with control (zero time) using the paired t test with p = ns. months of orally administered hydralazine for heart failure [4. When weaning the patient from continuous therapy is associated with unfavorable hemodynamics, oral therapy is initiated and the intravenous route abruptly discontinued after two oral doses of 5 mg or, if needed, multiples thereof. Although none of our patients required long-term therapy for management of heart failure, this is a well-known indication for oral administration of hydralazine [4, 5. In the postoperative interval, transient impairment of left ventricular function secondary to intraoperative myocardial injury, which may be superimposed on preexisting myocardial impairment, can benefit from afterload reduction. Peripheral vascular resistance is frequently elevated during operation and the interval following, which reflects heightened sympathetic activity. Two of these conditions (operative impairment of left ventricular function and elevated arterial resistance) tend to improve in the postoperative interval, which abrogates the necessity for continued afterload reduction. However, there are patients with persistent left ventricular dysfunction and secondary enhancement of sympathetic activity who will benefit from continued vasodilator therapy. Despite the increase in cardiac output, there

9 The Annals of Thoracic Surgery Vol 3 No August 98 was a favorable effect on myocardial work. It can be reasoned that myocardial oxygen requirements did not increase and were probably reduced. The double product (heart rate X mean arterial pressure) declined from 8,80 to 7,75 mm Hglmin at 4 hours and rose to 7,544 at 4 hours. Wall tension is the prime determinant of myocardial oxygen need and is a function of mean arterial pressure, which declined, and ventricular volume, according to Laplace s law. Since filling pressures were not changed, ventricular volume was probably unchanged or perhaps decreased in view of the reduced afterload, improved stroke volume, and probable improved emptying of the left ventricle. Contractility was not measured, but it is likely that any changes were mild [6 and not of importance. In addition, hydralazine has a favorable effect on coronary flow and resistance [7]. We noted a gradual rise in right- and left-sided filling pressures over the interval of the study, which undoubtedly represents gradual volume expansion due to infusion of blood products and perhaps mobilization of tissue fluid, which formed during cardiopulmonary bypass. The filling pressure changes in the first hour paralleled those observed during bolus infusion of hydralazine []. In the previous study, there was a nonsignificant decline in filling pressures by hours when the effect of the drug was declining. The filling pressures are notable in that they changed minimally. This is particularly noteworthy in the previous study [] with 0.5 mg per kilogram of hydralazine, which reduced SVRI from,788 to,437 dyne sec and increased CI from.87 to.6 L/m/min in 0 minutes while left atrial pressure rose from 4. to 5. mm Hg. This represents the pure arteriolar effect of hydralazine without a trace of venous pooling. Had filling pressures been elevated in this or the previous study, we would anticipate a fall toward normal with improved ventricular performance through afterload reduction. Based on these and unreported observations on patients receiving hydralazine, we have a simplistic notion of the blood circulating through the arterial system more easily and returning to the heart without pooling or delay so that filling pressures are maintained with hydralazine. Mean arterial pressure fell from a control of 9 to a low of 74 and ended at 8 mm Hg in this study. With bolus infusion there was a greater fall to 64 mm Hg with 0.5 mg per kilogram and 66 mm Hg with 0.5 mg per kilogram [. In the current study, the final mean pressure (at 4 hours) of 8 mm Hg is considered relatively ideal as we believe that higher pressure is frequently associated with elevated systemic vascular resistance and a reduced cardiac output. Coronary perfusion is adequate at this pressure and higher perfusion pressures only increase myocardial oxygen requirements as wall tension rises. We treat even mild hypertension throughout the postoperative interval with appropriate orally administered antihypertensive agents. Although the maximal decline in WRI of 38% was not significant, this observation may be worthy of emphasis in view of the recent use of hydralazine for the management of primary pulmonary hypertension [8. References. Braunwald E: Vasodilator therapy: a physiologic approach to the treatment of heart failure. N Engl J Med 97:33-33, 977. Marco JD, Standeven JW, Bamer HB: Afterload reduction with hydralazine following valve replacement. J Thorac Cardiovasc Surg 80:50, 980 3. Barratt-Boyes BG, Wood EH: Cardiac output and related measurements and pressure values in the right heart and associated vessels, together with an analysis of the hemodynamic response to the inhalation of high oxygen mixtures in healthy subjects. J Lab Clin Med 5:7, 958 4. Mathey D, Hanrath P, Polster J, et al: Acute and chronic effects of oral hydralazine on left ventricular pump function and renal hernodynamics in chronic left heart failure. Eur Heart J :5,980 5. Chatterjee K, Parmley WW, Massie B, et al: Oral hydralazine therapy for chronic refractory heart failure. Circulation 545379, 976 6. Khatri I, Uemura N, Notargiacomo A, et al: Direct and reflex cardiostimulating effects of hydralazine. Am J Cardiol40:38, 977 7. Barner HB, Jellinek M: Effect of hydralazine on coronary flow and resistance. Clin Res 0:63, 97 8. Rubin LJ, Peten RH: Oral hydralazine therapy for primary pulmonary hypertension. N Engl J Med 30~69-73, 980