Continuous Hydralazine 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., a n d Hendrick B. BaAer, M.D. ABSTRACT Impedance reduction with a continuous infusion of hydralazine was evaluated in 20 patients following cardiopulmonary bypass. Patients were selected for therapy when the cardiac index (CI) was less than 2.2 L/m2/min,when the systemic vascular resistance index (SVRI) was greater than 2,500 dyne sec ~ m - or ~ ,when both conditions were present. N o other vasoactive or cardiotonic drugs were uqed intraoperatively or postoperatively. Responses were measured at 15, 30, 60, 120, 180, and 240 minutes and compared with control measurements. Significant responses appeared by 15 minutes in the mean arterial pressure, CI, and SVRI, which were maximal by 2 hours. At 4 hours, the SVRI was 1,520 f 276 dyne sec ~ m (control, - ~ 3,235 f 222) and pulmonary vascular resistance index, 365 f 102 dyne sec cm-5 (control, 592 f 71). The CI was 3.20 f 0.29 L/ m2/min(control, 1.96 f 0.16) and mean arterial press w , 75 k 2.3 mm Hg (control, 92 & 2.4). Left atrial, pulmonary artery diastolic, and right atrial pressures increased from control but not significantly: 11.4 f 0.8 to 13.3 1.2 mm Hg, 13.6 f 1.6 to 17.2 +_ 1.5 mm Hg, and 6 k 1.6 to 9.4 f 1.7 mm Hg, respectively. In 16 patients, hydralazine was continued for 24 hours and in 11, 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.

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 [ 2 ] . 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 20 patients (Table 1). 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 F259E). Measurements included heart rate, mean arterial pressure, right atrial pressure, mean left atrial pressure, pulmonary artery mean and In the past decade, treatment of low cardiac pulmonary artery diastolic pressures, cardiac output with vasodilators has been used with output, and temperature. Standard formulas increasing frequency and success. Drugs acting were used to calculate cardiac index (CI), stroke on the arterial system influence afterload while volume index, left ventricular stroke work, venoactive drugs alter preload, although a ve- pulmonary vascular resistance index, and systemic vascular resistance index (SVRI). The pulmonary vascular resistance index was obFrom the Department of Surgery, St. Louis University tained by subtracting mean left atrial pressure School of Medicine, St. Louis, MO. from pulmonary artery mean pressure, multiPresented at the Twenty-seventh Annual Meeting of the Southern Thoracic Surgical Association, Nov 13-15, 1980, plying that result by 80, and dividing by the CI. White Sulphur Springs, W. The SVRI was calculated by subtracting right Address reprint requests to Dr. Bamer, Department of Surgery, St. Louis University, 1325 Grand Blvd, St. Louis, atrial pressure from mean arterial pressure, multiplying that by 80, and dividing by the CI. MO 63104.

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188 0003-4975/81/080188-05$01.25 @ 1981 by The Society of Thoracic Surgeons

189 Swartz et al: Hydralazine Infusion for Afterload Reduction

After operation, patients were selected for hydralazine therapy when the CI was less than 2.2 L/m2/min,when the SVRI was greater than 2,500 dyne sec ~ m - or ~ , when both conditions were present. A loading dose of hydralazine, 0.1 mg per kilogram of body weight, was given intravenously and a continuous infusion (1mg per milliliter in 5% dextrose and water) of 1.5 pglkglmin was started. In most patients this dosage was adequate to raise the CI above 2.5 L/m2/minwhile SVRI was reduced to less than 2,000 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 15/30! 60, 120, 180, and 240 minutes of therapy in all patients. In 4 patients, hydralazine was discontinued between 4 and 24 hours when it was no longer necessary for afterload reduction (SVRI < 1,500 dyne sec cmV5).The 16 patients who continued to require hydralazine were studied at 24 hours. In 11 patients it was necessary to use orally administered hydralazine (25 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 2 patients, and 3 required atrial pacing (see Table 1).No other

Table 1. Operative Procedure, Patient Sex, and the Need for Mechanical or Electrical Support Procedure

Male Patients

Female Patients

IABP

Atrial Pacing

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 20 hours there was infusion of excess blood over measured loss for a hematocrit of less than 30%. Diuretics in the form of Lasix (furosemide), 20 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 2 and Figures 1 through 3. Data for each time interval are compared with control using the paired t test. By 15 minutes there were significant ( p < 0.025) changes in mean arterial pressure, CI, and SVRI, which progressed to maximal responses ( p < 0.001) by 2 hours. These responses persisted at 4 hours at the same level of significance. The stroke volume index was significantly increased ( p < 0.05) at 2 and 4 hours only. At 24 hours (16 patients), the SVRI remained low, but the CI had declined to 2.8 L/m2/min( p < 0.025) and mean arterial pressure had risen to 82 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 1-hour responses to continuous infusion of 3 hydralazine following a loading dose of 0.1 mg + LVA 2 per kilogram are of similar magnitude to those 1 MVR obtained with bolus intravenous therapy of 2 AVR 0.25 or 0.5 mg per kilogram [21. However, with 1 AVR + SVG bolus therapy the CI and SVRI were returning 1 AVR + TVG to control by 2 hours, whereas with continAVR + MVR 1 uous therapy there was steady improvement 12 Total in cardiac output and a further decline in the IABP = intraaortic balloon pump; DVG = double yein graft; SVRI, which were maximal by 2 hours. Despite TVG = triple vein graft; SVG = single vein graft; LVA = left ventricular aneurysm; MVR = mitral valve replacement; these favorable responses, it can be argued that our therapy was suboptimal in that SVRI reAVR = aortic valve replacement. DVG TVG SVG

1

190 The Annals of Thoracic Surgery Vol 32 No 2 August 1981

Table 2 . Hemodynamic Dataa Control ( N = 20) HR (beats/ min) MAP (mm Hg) CI (UmY min) SVI (mu beat) LVSW (P-M) (dyne sec SVRI (dyne sec LAP (mm Hg) RAP (mm Hg) PADP (mm Hg)

15 Min ( N = 20)

90 f 6.2

90.6 f 6.4

92 f 2.4

83 f 2.6'

l.%f 0.16

2.29 f 0.W

22.3 f 3.2

25.8 f 2.9

48 f 3.5

48 f 3.9

592 f 71 3,235 f 222

526 f 75

30 Min ( N = 20)

1Hr ( N = 20)

91.2 f 5.9

2 Hr ( N = 20)

3 Hr ( N = 20)

4 Hr

(N= 20)

24 Hr

( N = 16) 92.0 f 5.1

92.6 f 6.1

98.8 f 6.1

97.4 f 6.3

97.0 f 5.7

7 9 f 3.1e

77 f 2.5'

76 f 2.6'

74 f 2.2'

7 5 f 2.3'

82.0 f 4.Zb

2.51 f 0.16d

2.76 f 0.23'

3.14 f 0.27'

3.05 f 0.21'

3.20 f 0.29'

2.83 f 0.3lC

+ 4.1

29.9 f 2.6

32.2 f 2 . 9

31.4 f 3.4

49.8 f 4.0

48.1 f 4.3

55.6f 4.9

51.2 f 5.2

54.2 2 5.5

49.6 f 4.9

493 f 83

474 f 81

443 f 83

440 f 97

365 f 102

392 f 90

1,824 f 191'

1,610 f 293'

1,569 f 303'

1,520 f 276'

1,690 f 344'

26

2,481 f l%c 1,970 f 180'

33 f 3.7b

31.6 f 3.4

11.4 k 0.8

12.1 f 1.1

11.9 f 0.7

13.7 f 0.9

13.1 f 0.9

12.3 f 1.4

13.3 f 1.2

12.8 f 1.4

6 f 1.6

6.5 f 1.9

6.7 f 1.7

7.8 f 2.0

7.8 f 1.8

8.6 f 1.9

9.4 f 1.7

10.4 f 1.9

13.6 f 1.6

14.8 f 1.9

11.2 f 1.7

17.0 f 2.0

17.5 f 1.6

17.9 f 1.2

17.2 f 1.5

15.1 f 1.6

=Shown as f 1standard error of the mean. p < 0.05. "p < 0.025. "p < 0.01. "p < 0.005.

< 0.001.

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

100

100 BeatslMinute

mmHg

50 p<

0

0

.005 .001

1

-001

.001

2

3

50

.w1

4

.W'

..

24

0

HOURS

Fig 1. 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

entire group (N= 20 at 4 hours; N = 16 at 24 hours). All data points are compared with control (zero time)

mained above normal (< 1,500 dyne sec ~ m [31. In some of our patients (not included in this study), it was necessary to repeat the loading dose at 30 minutes to obtain an adequate response, and occasibnally a third loading dose has been required. This shortcoming could be managed by a larger initial bolus, but in most

a smaller dose is adequate and avoids ~ patients ) the risk of excessive hemodynamic alterations. When infusion was continued beyond 24 hours, we did not note a greater dosage requirement or a diminution in the response to a stable dose. This observation is not surprising in view of the absent tachyphylaxis with six

using the paired t test, and p values are depicted for changes in mean arterial pressure. Changes in heart rate were not significant.

191 Swartz et al: Hydralazine Infusion for Afterload Reduction

Cardiac Index

SVRI I

p<.Ql

I

.w1

.001

I

.w1

1

I

.025

.001

I

seclcm'

Umin/mz

p<.Ool

.w1

2

I

0

1

.w1

.001

.001

2I

3I

4I

Ii'

24

HOURS

Fig 2. 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= 20 at 4 hours; N = 16 at 24 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.

I=.

.

E E 5 -

0 LA

0

1

3

2

4

24

HOURS

Fig 3 . Atrial pressures with hydralazine infusion (mean f standard error) for the entire group (N= 20 at 4 hours; N = 26 at 24 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 [41. 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 25 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, 51. 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

192 The Annals of Thoracic Surgery Vol 32 No 2 August 1981

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 8,280 to 7,275 mm Hglmin at 4 hours and rose to 7,544 at 24 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 [61 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 [2]. In the previous study, there was a nonsignificant decline in filling pressures by 2 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 [2] with 0.5 mg per kilogram of hydralazine, which reduced SVRI from 2,788 to 1,437 dyne sec and increased CI from 1.87 to 2.62 L/m2/min in 20 minutes while left atrial pressure rose from 14.1 to 15.2 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 92 to a low of 74 and ended at 82 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 0.25 mg per kilogram [21. In the current study, the final mean pressure (at 24 hours) of 82 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 W R I 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 [81.

References

1. Braunwald E: Vasodilator therapy: a physiologic approach to the treatment of heart failure. N Engl J Med 297:331-332, 1977 2. Marco JD, Standeven JW, Bamer HB: Afterload reduction with hydralazine following valve replacement. J Thorac Cardiovasc Surg 80:50, 1980 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 51:72, 1958 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 1:25,1980 5. Chatterjee K, Parmley WW, Massie B, et al: Oral hydralazine therapy for chronic refractory heart failure. Circulation 545379, 1976 6. Khatri I, Uemura N, Notargiacomo A, et al: Direct and reflex cardiostimulating effects of hydralazine. Am J Cardiol40:38, 1977 7. Barner HB, Jellinek M: Effect of hydralazine on coronary flow and resistance. Clin Res 20:263, 1972 8. Rubin LJ, Peten RH: Oral hydralazine therapy for primary pulmonary hypertension. N Engl J Med 302~69-73, 1980