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Afterload reduction with hydralazine following valve replacement
J
THORAC CARDIOVASC SURG
80:50-53, 1980
Afterload reduction with hydralazine following valve replacement Impedance reduction with hydralazine was evaluated in 23 patients I to 3 hours after aortic or mitral valve replacement. Patients were randomly assigned to Group l (0.25 mg/kg) or Group 2 (0.5 mg/kg) and responses at 20, 60, and 120 minutes compared with control (paired t test) and mean values for each group compared (t test). In Group 1 significant responses were the fail in mean arterial pressure (78.3 ± 3.0 to 66.7 ± 2.2 mm Hg) and systemic vascular resistance (2,808 ± 264 to 1,823 ± 164 dynes-seclcm"]; the increase in cardiac index (2.07 ± 0./3 to 2.71 ± 0.21 Llminlm"), stroke volume index (26.9 ± 2.3 to 34.0 ± 3.3 mllbeat], and heart rate (80.8 ± 5.8 to 84.2 ± 6.6 beats/min). Central venous pressure did not change and left atrial pressure decreased at 120 minutes. Group 2 responses were similar except for higher central venous pressure at 20 minutes, higher left atrial pressures at control, 20, and 60 minutes, and lower left ventricular stroke work at control, 20, and 60 minutes. By selectively dilating the arterial system, hydralazine reduces mean arterial pressure and systemic vascular resistance and increases cardiac output with stable filling pressures.
Joseph D. Marco, M.D., John W. Standeven, Ph.D., and Hendrick B. Barner, M.D., St. Louis, Mo.
Vasodilation therapy as a means to enhance cardiac output in low-output states has been widely applied since its introduction in 1971. 1 Drugs acting on the arterial system influence afterload and venoactive drugs alter preload, although a venodilator that reduces preload may lower afterload by reducing ventricular volume without altering systemic vascular resistance. 2 In the postoperative patient it may be desirable to use an arterial dilator which will reduce left ventricular impedance without altering preload. Many of the vasoactive agents evaluated postoperativelyv" or intraoperatively" have dilated the arterial as well as the venous system. Although the desired effect is to increase cardiac output with a minimal increase in cardiac work, there may be some value in the selective use of venous and arterial dilators, depending on whether the preload is elevated or not. Vigorous use of a vasodilator with a dual action to achieve optimal afterload reduction may reduce preload inappropriately so that inordinate volume replacement is required to maintain cardiac filling. From the Department of Surgery, St. Louis University School of Medicine, St. Louis, Mo. Received for publication Sept. 4, 1979. Accepted for publication Dec. 12, 1979. Address for reprints: Dr. Hendrick B. Barner, 1325 S. Grand Blvd. 51. Louis, Mo. 63104.
50
Table I. Patient data
I
Group 1 (0.25 mg/kg)
No. of patients Mean age ± I SEM Male patients Female patients MVR AVR
12 53±2.7 3 9 7 5
I
Group 2 (0.5 mg/kg)
II 57±2.8 2 9 7 4
Legend: SEM, Standard error of the mean. MVR, Mitral valve replacement. AVR, Aortic valve replacement.
For these reasons we chose to evaluate hydralazine, which can be administered either intravenously or orally. The latter route may occasionally be advantageous in the postoperative patient for longer term therapy, as first described by Chatterjee and associates" for management of chronic heart failure. Methods
Mitral or aortic valve replacement was performed on 23 patients who were randomly assigned to one of two groups (Table I) receiving hydralazine, 0.25 or 0.5 mg/kg. All patients had undergone preoperative right and left heart cardiac catheterization without measurement of cardiac output. They were classified in functional Class III or IV on the basis of criteria of the New York Heart Association. None had a history of myo-
0022-5223/80/070050+04$00.40/0 © 1980 The C. V. Mosby Co.
Volume 80
Afterload reduction with hydralazine
Number 1
51
July, 1980
Table II. Hemodynamic data, Group J Hydralazine 0.25 mglkg Control HR (beats/min) MAP(mm Hg) CI (Lzrnin/mt) SVI (ml/beat) LVSW (gm-rn) PVRI (dynes-sec/em') SVRI (dynes-sec/ern") CVP(mm Hg) LAP (mm Hg)
80.8 78.3 2.07 26.9 43.6 551.8 2,808 12.3 10.0
± 5.8 ± 3.0 ± 0.13 ± 2.3 ± 3.7 ± 90.3 ± 264 ± 1.4 ± 0.6
20 min 84.2 66.7 2.69 34.0 45.8 517.3 1,826 12.2 10.1
± 6.6* ± 2.2:1: ± 0.20:1: ± 3.3:1: ± 4.3 ± 92.9 ± 189:1: ± 2.0 ± 0.8
60 min 84.6 68.3 2.71 34.2 48.6 577.5 1,823 14.3 9.9
± 7.4 ± 2.6t ± 0.2l:j: ± 3.l:j: ± 5.3 ± 103.8 ± 164:1: ± 2.4 ± 1.2
120 min 91.3 72.3 2.50 29.7 40.3 524.3 2,109 11.1 12.5
± 10.1 ± 2.6 ± 0.30* ± 4.3* ± 5.8 ± 106.4 ± 318:1: ± 2.0 ± 1.2*
Legend: HR, Hean rate. MAP, Mean anerial pressure. CI, Cardiac index. SVI, Stroke volume index. LVSW, Left ventricular stroke work. PVRI, Pulmonary
vascular resistance index. SVRI, Systemic vascular resistance index. CVP, Central Venous pressure. LAP, Left atrial pressure. *p < 0.05. tp < 0.01. :j:p < 0.001.
Table III. Hemodynamic data, Group 2 Hydralazine 0.25 mglkg 20 min
Control HR (beats/min) MAP (mm Hg) CI (Lzrnin/m-) SVI (rnl/beat) LVSW (gm-m) PVRI (dynes-sec/em") SVRI (dynes-sec/em") CVP (mm Hg) LAP (mm Hg)
82.8 76.2 1.87 23.1 33.9 830.5 2,788 16.5 14.1
± 4.2 ± 3.3 ± 14 ± 1.7 ± 2.1 ± 163.4 ± 278 ± 2.0 ± 1.6
94.0 64.3 2.62 28.2 30.4 695.7 1,437 16.6 15.2
± 4.5:1: ± 2.2t ± 0.13:1: ± 1.5:1: ± 2.5 ± 143.2* ± 69:1: ± 1.6 ± 2.0
60 min 98.3 64.2 2.76 28.9 34.4 774.2 1,535 17.3 15.3
± 6.4t
± ± ± ± ±
3.2* 0.17:1: 1.5t 3.1 116.5 ± 94:1: ± 1.3 ± 1.8
120 min 97.1 71.0 2.57 26.9 35.1 709.3 1,730 15.2 12.0
± .54t
± ± ± ± ± ± ± ±
3.lt 0.15:1: 1.7* 2.9 108.1 137:1: 1.5 0.9*
Forlegend see Table II. 'p < 0.05. tp < 0.01 :j:p < 0.001.
cardial infarction and coronary angiography did not demonstrate significant coronary disease. All patients were receiving digitalis and diuretics prior to operation. Intraoperatively, catheters were placed in the radial artery, right atrium, and left atrium. A triple-lumen, balloon-tipped, thermodilution Swan-Ganz catheter was inserted via the innominate vein into the pulmonary artery. Pressures were measured with Bentley, Trantec Model 800 transducers and an Electronics for Medicine amplifying system coupled to a Gould, Brush 260 pen-tipped chart recorder. Cardiac output determinations were obtained by the thermodilution technique with an Edwards Laboratories, Inc., thermodilution cardiac output computer (Model 9510-A). Measurements included heart rate, mean arterial pressure (MAP), central venous pressure (CVP), mean pulmonary arterial pressure (PAP), mean left atrial
pressure (LAP), and cardiac output. Standard formulas were used to calculate cardiac index, stroke volume index, left ventricular stroke work (LVSW), pulmonary vascular resistance index (PVRI), and systemic vascular resistance index (SVRI). PVRI and SVRI were calculated as PAP - CVP or MPA - LAP multiplied by 80 and the body surface area and divided by the cardiac output. One to 3 hours after the patient arrived in the intensive care area the study was initiated. At this time cardiotonic or vasoactive drugs were not being utilized, although they may have been intraoperatively. The intra-aortic balloon pump was not employed. Baseline measurements were obtained and hydralazine (0.25 or 0.5 mg/kg) was given as an intravenous bolus. Measurements were repeated at 20, 60, and 120 minutes. Blood was infused to replace measured loss.
The Journal of
52
Marco, Standeven, Barner
Thoracic and Cardiovascular Surgery
Results The hemodynamic data for Group I (0.25 mg/kg) are contained in Table II and for Group 2 (0.5 mg/kg) in Table III. Data for each time interval were compared with control data by means of the paired t test. In Group I there was a significant fall in MAP and SVRI, whereas cardiac index and stroke volume index rose and PVRI and filling pressures were unchanged except for a fall in left atrial pressure at 120 minutes. Left ventricular work rose slightly (p = ns) as the increase in cardiac output was relatively greater than the decline in S VRI. Heart rate increased slightly, but the increase was significant at 20 minutes only. Group 2 patients had a decrease in mean arterial pressure, left ventricular work, and S VRI as heart rate, cardiac index and stroke volume index increased and filling pressures were unchanged except for the late fall in left atrial pressure noted in Group I. The PVRI did fall significantly at 20 minutes but not at later time intervals. Two sample t tests were used to compare the corresponding control, 20, 60, and 120 minute mean values of the two groups. Significant differences (p < 0.05) were found in L VSW at control, 20, and 60 minutes, in SVRI at 20 minutes, in LAP at control, 20, and 60 minutes, and in CVP at 20 minutes. Thus the two groups were quite similar in control values and responses to hydralazine. Group 2 did have slightly higher filling pressures, particularly on the left side. The SVRI was lower in Group 2 at 20 minutes only. The heart rate increase after hydralazine was significant (paired t test) in Group 2 at all time intervals, but on comparison with Group I the differences were not significant.
Discussion We have evaluated intravenous hydralazine for afterload reduction with two dosage schedules (0.25 and 0.5 mg/kg) following aortic or mitral valve replacement. That the responses to both doses were comparable suggests that a near-maximal response was obtained with the lesser amount of medication. Cardiac output (cardiac index and stroke volume index) increased and SVRI declined, heart rate increased mildly, and MAP declined at 20 and 60 minutes but was returning to control at 120 minutes. Filling pressures (CVP, LAP) did not change. These data indicate a prompt response to hydralazine, with slight diminution of the response at 2 hours. These responses to hydralazine were similar to those obtained in a small group of patients following cardiac operations who were treated by Sladen and Rosenthal?
with smaller doses (2.5 to 7.5 mg intravenously every 4 to 6 hours) and concurrently with dopamine, nitroprusside, or the intra-aortic balloon. In their? patients heart rate declined slightly after hydralazine, but it was at a much higher initial level than in our patients, in whom heart rate rose slightly. MAP declined in our patients at 20 and 60 minutes while in theirs the change was minimal, although starting at the same level. The differences in response can be related to the dosage of hydralazine, the associated therapy, and the fact that their patients had greater cardiac impairment on the basis of a greater initial heart rate (98 versus 82 beats/min) and left ventricular filling pressure which was nearly twice as great (pulmonary artery wedge of 23.6 versus left atrial pressure of IO to 14), although control cardiac indices were comparable. Nitroprusside is widely employed intraoperatively and postoperatively for treatment of hypertension, low-output states, and elevated preload. 4. 8. 9 Nitroprusside dilates both resistance and capacitance vessels to achieve the dual decrease in preload and afterload. Some low-output states are associated with high filling pressures, and it is appropriate to lower preload to reduce left ventricular end-diastolic pressures, improve coronary flow, and favorably alter the determinants of myocardial oxygen need as well as diminishing pulmonary hydrostatic pressure and secondary pulmonary edema. If filling pressures are normal or mildly elevated, then impedance control with nitroprusside may result in an appropriate fall in preload with a resultant decline in cardiac output despite the diminished impedance." Under such conditions volume expansion is necessary to restore preload to optimal levels and achieve a maximal increase in cardiac output. 9 Although this usually can be readily accomplished when the clinician is aware of the potential for a fall in filling pressures, there is some merit in having pure arteriolar vasodilitation without venous dilatation. Hydralazine has a reflex sympathetic effect (heart rate) and an inotropic effect. When used as an oral antihypertensive agent, hydralazine commonly increases heart rate. to This response is absent or minimal in the postoperative patient or the patient with chronic heart failure, where sympathetic activity is frequently maximal. 6. 7. 11 It has recently been reported that hydralazine has a direct inotropic effect in the dog, which is blocked by propranolol. 12 Our data indicate that hydralazine, 0.25 mg/kg intravenously, will effectively reduce afterload and improve cardiac output without alteration of normal filling pressures over a 2 hour interval. When the dose of hydralazine was doubled in a group of patients with
Volume 80
Afterload reduction with hydralazine
Number 1
53
July, 1980
minimally elevated filling pressures, the hemodynamic responses were similar to those with the smaller dose. Heart rate increase to the smaller dose was minimal and it was highly significant with the larger dose, whereas MAP and cardiac index responses were similar. Although afterload is a prime determinant of myocardial oxygen consumption, increases in heart rate and possibly inotropic state may have increased total developed wall tension and oxygen demands so that supply/demand discrepancies could occur. This consideration would lead to the recommendation of using the smaller dose of hydralazine to decrease the likelihood of an increase in heart rate and these secondary effects. REFERENCES Majid PA, Sharma B, Taylor SH: Phentolamine for vasodilator treatment of severe heart failure. Lancet 2 :719723, 1971 2 Braunwald E: Vasodilator therapy. A physiologic approach to the treatment of heart failure. N Engl J Med 297:331-332, 1977 3 Kouchoukos NT, Sheppard LC, Kirklin JW: Effect of alterations in arterial pressure on cardiac performance early after open cardiac operations. J THoRAc CARDIOVASC SURG 64:563-572, 1972 4 Stinson EB, Holloway EL, Derby A, Oyer PE, Hollingsworth J, Griepp RB, Harrison DC: Comparative hemodynamic responses to chlorpromazine, nitroprusside,
5
6
7
8 9
10 11
12
nitroglycerin, and trimethaphan immediately after openheart operations. Circulation 51,52:Suppl 2:26-33, 1975 Lappas DG, Lowenstein E, Waller J, Fahmy NR, Daggett WM: Hemodynamic effects of nitroprusside infusion during coronary artery operation in man. Circulation 54: Suppl 3:4-10, 1976 Chatterjee K, Parmley WW, Massie B, Greenberg B, Werner J, Klausner S. Norman A: Oral hydralazine therapy for chronic refractory heart failure. Circulation 54:879-883, 1976 Siaden RN, Rosenthal MY: Specific afterload reduction with parenteral hydralazine following cardiac surgery. J THORAC CARDIOVASC SURG 78: 195-202, 1979 Benzing GIll, Helmsworth J, Schreiber JT: Nitroprusside after open-heart surgery. Circulation 54:467-471, 1976 Stinson EB, Holloway EL, Derby GC, Copeland JG, Oyer PE, Buchler DL, Griepp RB: Control of myocardial performance early after open-heart operations by vasodilator treatment. J THORAC CARDIOV ASC SURG 73: 523530, 1977 Koch-Weser J: Drug therapy. Hydralazine. N Engl J Med 295:320-323, 1976 Franciosa JA, Pierpont G, Cohn IN: Hemodynamic improvement after oral hydralazine in left ventricular failure. Ann Intern Med 86:388-393, 1977 Khatri I, Uemura N, Notargiacomo A, Freis ED: Direct and reflex cardiostimulating effects of hydralazine. Am J Cardiol 40:38-42, 1977
THORAC CARDIOVASC SURG
80:50-53, 1980
Afterload reduction with hydralazine following valve replacement Impedance reduction with hydralazine was evaluated in 23 patients I to 3 hours after aortic or mitral valve replacement. Patients were randomly assigned to Group l (0.25 mg/kg) or Group 2 (0.5 mg/kg) and responses at 20, 60, and 120 minutes compared with control (paired t test) and mean values for each group compared (t test). In Group 1 significant responses were the fail in mean arterial pressure (78.3 ± 3.0 to 66.7 ± 2.2 mm Hg) and systemic vascular resistance (2,808 ± 264 to 1,823 ± 164 dynes-seclcm"]; the increase in cardiac index (2.07 ± 0./3 to 2.71 ± 0.21 Llminlm"), stroke volume index (26.9 ± 2.3 to 34.0 ± 3.3 mllbeat], and heart rate (80.8 ± 5.8 to 84.2 ± 6.6 beats/min). Central venous pressure did not change and left atrial pressure decreased at 120 minutes. Group 2 responses were similar except for higher central venous pressure at 20 minutes, higher left atrial pressures at control, 20, and 60 minutes, and lower left ventricular stroke work at control, 20, and 60 minutes. By selectively dilating the arterial system, hydralazine reduces mean arterial pressure and systemic vascular resistance and increases cardiac output with stable filling pressures.
Joseph D. Marco, M.D., John W. Standeven, Ph.D., and Hendrick B. Barner, M.D., St. Louis, Mo.
Vasodilation therapy as a means to enhance cardiac output in low-output states has been widely applied since its introduction in 1971. 1 Drugs acting on the arterial system influence afterload and venoactive drugs alter preload, although a venodilator that reduces preload may lower afterload by reducing ventricular volume without altering systemic vascular resistance. 2 In the postoperative patient it may be desirable to use an arterial dilator which will reduce left ventricular impedance without altering preload. Many of the vasoactive agents evaluated postoperativelyv" or intraoperatively" have dilated the arterial as well as the venous system. Although the desired effect is to increase cardiac output with a minimal increase in cardiac work, there may be some value in the selective use of venous and arterial dilators, depending on whether the preload is elevated or not. Vigorous use of a vasodilator with a dual action to achieve optimal afterload reduction may reduce preload inappropriately so that inordinate volume replacement is required to maintain cardiac filling. From the Department of Surgery, St. Louis University School of Medicine, St. Louis, Mo. Received for publication Sept. 4, 1979. Accepted for publication Dec. 12, 1979. Address for reprints: Dr. Hendrick B. Barner, 1325 S. Grand Blvd. 51. Louis, Mo. 63104.
50
Table I. Patient data
I
Group 1 (0.25 mg/kg)
No. of patients Mean age ± I SEM Male patients Female patients MVR AVR
12 53±2.7 3 9 7 5
I
Group 2 (0.5 mg/kg)
II 57±2.8 2 9 7 4
Legend: SEM, Standard error of the mean. MVR, Mitral valve replacement. AVR, Aortic valve replacement.
For these reasons we chose to evaluate hydralazine, which can be administered either intravenously or orally. The latter route may occasionally be advantageous in the postoperative patient for longer term therapy, as first described by Chatterjee and associates" for management of chronic heart failure. Methods
Mitral or aortic valve replacement was performed on 23 patients who were randomly assigned to one of two groups (Table I) receiving hydralazine, 0.25 or 0.5 mg/kg. All patients had undergone preoperative right and left heart cardiac catheterization without measurement of cardiac output. They were classified in functional Class III or IV on the basis of criteria of the New York Heart Association. None had a history of myo-
0022-5223/80/070050+04$00.40/0 © 1980 The C. V. Mosby Co.
Volume 80
Afterload reduction with hydralazine
Number 1
51
July, 1980
Table II. Hemodynamic data, Group J Hydralazine 0.25 mglkg Control HR (beats/min) MAP(mm Hg) CI (Lzrnin/mt) SVI (ml/beat) LVSW (gm-rn) PVRI (dynes-sec/em') SVRI (dynes-sec/ern") CVP(mm Hg) LAP (mm Hg)
80.8 78.3 2.07 26.9 43.6 551.8 2,808 12.3 10.0
± 5.8 ± 3.0 ± 0.13 ± 2.3 ± 3.7 ± 90.3 ± 264 ± 1.4 ± 0.6
20 min 84.2 66.7 2.69 34.0 45.8 517.3 1,826 12.2 10.1
± 6.6* ± 2.2:1: ± 0.20:1: ± 3.3:1: ± 4.3 ± 92.9 ± 189:1: ± 2.0 ± 0.8
60 min 84.6 68.3 2.71 34.2 48.6 577.5 1,823 14.3 9.9
± 7.4 ± 2.6t ± 0.2l:j: ± 3.l:j: ± 5.3 ± 103.8 ± 164:1: ± 2.4 ± 1.2
120 min 91.3 72.3 2.50 29.7 40.3 524.3 2,109 11.1 12.5
± 10.1 ± 2.6 ± 0.30* ± 4.3* ± 5.8 ± 106.4 ± 318:1: ± 2.0 ± 1.2*
Legend: HR, Hean rate. MAP, Mean anerial pressure. CI, Cardiac index. SVI, Stroke volume index. LVSW, Left ventricular stroke work. PVRI, Pulmonary
vascular resistance index. SVRI, Systemic vascular resistance index. CVP, Central Venous pressure. LAP, Left atrial pressure. *p < 0.05. tp < 0.01. :j:p < 0.001.
Table III. Hemodynamic data, Group 2 Hydralazine 0.25 mglkg 20 min
Control HR (beats/min) MAP (mm Hg) CI (Lzrnin/m-) SVI (rnl/beat) LVSW (gm-m) PVRI (dynes-sec/em") SVRI (dynes-sec/em") CVP (mm Hg) LAP (mm Hg)
82.8 76.2 1.87 23.1 33.9 830.5 2,788 16.5 14.1
± 4.2 ± 3.3 ± 14 ± 1.7 ± 2.1 ± 163.4 ± 278 ± 2.0 ± 1.6
94.0 64.3 2.62 28.2 30.4 695.7 1,437 16.6 15.2
± 4.5:1: ± 2.2t ± 0.13:1: ± 1.5:1: ± 2.5 ± 143.2* ± 69:1: ± 1.6 ± 2.0
60 min 98.3 64.2 2.76 28.9 34.4 774.2 1,535 17.3 15.3
± 6.4t
± ± ± ± ±
3.2* 0.17:1: 1.5t 3.1 116.5 ± 94:1: ± 1.3 ± 1.8
120 min 97.1 71.0 2.57 26.9 35.1 709.3 1,730 15.2 12.0
± .54t
± ± ± ± ± ± ± ±
3.lt 0.15:1: 1.7* 2.9 108.1 137:1: 1.5 0.9*
Forlegend see Table II. 'p < 0.05. tp < 0.01 :j:p < 0.001.
cardial infarction and coronary angiography did not demonstrate significant coronary disease. All patients were receiving digitalis and diuretics prior to operation. Intraoperatively, catheters were placed in the radial artery, right atrium, and left atrium. A triple-lumen, balloon-tipped, thermodilution Swan-Ganz catheter was inserted via the innominate vein into the pulmonary artery. Pressures were measured with Bentley, Trantec Model 800 transducers and an Electronics for Medicine amplifying system coupled to a Gould, Brush 260 pen-tipped chart recorder. Cardiac output determinations were obtained by the thermodilution technique with an Edwards Laboratories, Inc., thermodilution cardiac output computer (Model 9510-A). Measurements included heart rate, mean arterial pressure (MAP), central venous pressure (CVP), mean pulmonary arterial pressure (PAP), mean left atrial
pressure (LAP), and cardiac output. Standard formulas were used to calculate cardiac index, stroke volume index, left ventricular stroke work (LVSW), pulmonary vascular resistance index (PVRI), and systemic vascular resistance index (SVRI). PVRI and SVRI were calculated as PAP - CVP or MPA - LAP multiplied by 80 and the body surface area and divided by the cardiac output. One to 3 hours after the patient arrived in the intensive care area the study was initiated. At this time cardiotonic or vasoactive drugs were not being utilized, although they may have been intraoperatively. The intra-aortic balloon pump was not employed. Baseline measurements were obtained and hydralazine (0.25 or 0.5 mg/kg) was given as an intravenous bolus. Measurements were repeated at 20, 60, and 120 minutes. Blood was infused to replace measured loss.
The Journal of
52
Marco, Standeven, Barner
Thoracic and Cardiovascular Surgery
Results The hemodynamic data for Group I (0.25 mg/kg) are contained in Table II and for Group 2 (0.5 mg/kg) in Table III. Data for each time interval were compared with control data by means of the paired t test. In Group I there was a significant fall in MAP and SVRI, whereas cardiac index and stroke volume index rose and PVRI and filling pressures were unchanged except for a fall in left atrial pressure at 120 minutes. Left ventricular work rose slightly (p = ns) as the increase in cardiac output was relatively greater than the decline in S VRI. Heart rate increased slightly, but the increase was significant at 20 minutes only. Group 2 patients had a decrease in mean arterial pressure, left ventricular work, and S VRI as heart rate, cardiac index and stroke volume index increased and filling pressures were unchanged except for the late fall in left atrial pressure noted in Group I. The PVRI did fall significantly at 20 minutes but not at later time intervals. Two sample t tests were used to compare the corresponding control, 20, 60, and 120 minute mean values of the two groups. Significant differences (p < 0.05) were found in L VSW at control, 20, and 60 minutes, in SVRI at 20 minutes, in LAP at control, 20, and 60 minutes, and in CVP at 20 minutes. Thus the two groups were quite similar in control values and responses to hydralazine. Group 2 did have slightly higher filling pressures, particularly on the left side. The SVRI was lower in Group 2 at 20 minutes only. The heart rate increase after hydralazine was significant (paired t test) in Group 2 at all time intervals, but on comparison with Group I the differences were not significant.
Discussion We have evaluated intravenous hydralazine for afterload reduction with two dosage schedules (0.25 and 0.5 mg/kg) following aortic or mitral valve replacement. That the responses to both doses were comparable suggests that a near-maximal response was obtained with the lesser amount of medication. Cardiac output (cardiac index and stroke volume index) increased and SVRI declined, heart rate increased mildly, and MAP declined at 20 and 60 minutes but was returning to control at 120 minutes. Filling pressures (CVP, LAP) did not change. These data indicate a prompt response to hydralazine, with slight diminution of the response at 2 hours. These responses to hydralazine were similar to those obtained in a small group of patients following cardiac operations who were treated by Sladen and Rosenthal?
with smaller doses (2.5 to 7.5 mg intravenously every 4 to 6 hours) and concurrently with dopamine, nitroprusside, or the intra-aortic balloon. In their? patients heart rate declined slightly after hydralazine, but it was at a much higher initial level than in our patients, in whom heart rate rose slightly. MAP declined in our patients at 20 and 60 minutes while in theirs the change was minimal, although starting at the same level. The differences in response can be related to the dosage of hydralazine, the associated therapy, and the fact that their patients had greater cardiac impairment on the basis of a greater initial heart rate (98 versus 82 beats/min) and left ventricular filling pressure which was nearly twice as great (pulmonary artery wedge of 23.6 versus left atrial pressure of IO to 14), although control cardiac indices were comparable. Nitroprusside is widely employed intraoperatively and postoperatively for treatment of hypertension, low-output states, and elevated preload. 4. 8. 9 Nitroprusside dilates both resistance and capacitance vessels to achieve the dual decrease in preload and afterload. Some low-output states are associated with high filling pressures, and it is appropriate to lower preload to reduce left ventricular end-diastolic pressures, improve coronary flow, and favorably alter the determinants of myocardial oxygen need as well as diminishing pulmonary hydrostatic pressure and secondary pulmonary edema. If filling pressures are normal or mildly elevated, then impedance control with nitroprusside may result in an appropriate fall in preload with a resultant decline in cardiac output despite the diminished impedance." Under such conditions volume expansion is necessary to restore preload to optimal levels and achieve a maximal increase in cardiac output. 9 Although this usually can be readily accomplished when the clinician is aware of the potential for a fall in filling pressures, there is some merit in having pure arteriolar vasodilitation without venous dilatation. Hydralazine has a reflex sympathetic effect (heart rate) and an inotropic effect. When used as an oral antihypertensive agent, hydralazine commonly increases heart rate. to This response is absent or minimal in the postoperative patient or the patient with chronic heart failure, where sympathetic activity is frequently maximal. 6. 7. 11 It has recently been reported that hydralazine has a direct inotropic effect in the dog, which is blocked by propranolol. 12 Our data indicate that hydralazine, 0.25 mg/kg intravenously, will effectively reduce afterload and improve cardiac output without alteration of normal filling pressures over a 2 hour interval. When the dose of hydralazine was doubled in a group of patients with
Volume 80
Afterload reduction with hydralazine
Number 1
53
July, 1980
minimally elevated filling pressures, the hemodynamic responses were similar to those with the smaller dose. Heart rate increase to the smaller dose was minimal and it was highly significant with the larger dose, whereas MAP and cardiac index responses were similar. Although afterload is a prime determinant of myocardial oxygen consumption, increases in heart rate and possibly inotropic state may have increased total developed wall tension and oxygen demands so that supply/demand discrepancies could occur. This consideration would lead to the recommendation of using the smaller dose of hydralazine to decrease the likelihood of an increase in heart rate and these secondary effects. REFERENCES Majid PA, Sharma B, Taylor SH: Phentolamine for vasodilator treatment of severe heart failure. Lancet 2 :719723, 1971 2 Braunwald E: Vasodilator therapy. A physiologic approach to the treatment of heart failure. N Engl J Med 297:331-332, 1977 3 Kouchoukos NT, Sheppard LC, Kirklin JW: Effect of alterations in arterial pressure on cardiac performance early after open cardiac operations. J THoRAc CARDIOVASC SURG 64:563-572, 1972 4 Stinson EB, Holloway EL, Derby A, Oyer PE, Hollingsworth J, Griepp RB, Harrison DC: Comparative hemodynamic responses to chlorpromazine, nitroprusside,
5
6
7
8 9
10 11
12
nitroglycerin, and trimethaphan immediately after openheart operations. Circulation 51,52:Suppl 2:26-33, 1975 Lappas DG, Lowenstein E, Waller J, Fahmy NR, Daggett WM: Hemodynamic effects of nitroprusside infusion during coronary artery operation in man. Circulation 54: Suppl 3:4-10, 1976 Chatterjee K, Parmley WW, Massie B, Greenberg B, Werner J, Klausner S. Norman A: Oral hydralazine therapy for chronic refractory heart failure. Circulation 54:879-883, 1976 Siaden RN, Rosenthal MY: Specific afterload reduction with parenteral hydralazine following cardiac surgery. J THORAC CARDIOVASC SURG 78: 195-202, 1979 Benzing GIll, Helmsworth J, Schreiber JT: Nitroprusside after open-heart surgery. Circulation 54:467-471, 1976 Stinson EB, Holloway EL, Derby GC, Copeland JG, Oyer PE, Buchler DL, Griepp RB: Control of myocardial performance early after open-heart operations by vasodilator treatment. J THORAC CARDIOV ASC SURG 73: 523530, 1977 Koch-Weser J: Drug therapy. Hydralazine. N Engl J Med 295:320-323, 1976 Franciosa JA, Pierpont G, Cohn IN: Hemodynamic improvement after oral hydralazine in left ventricular failure. Ann Intern Med 86:388-393, 1977 Khatri I, Uemura N, Notargiacomo A, Freis ED: Direct and reflex cardiostimulating effects of hydralazine. Am J Cardiol 40:38-42, 1977