Hemodynamic Improvement following a Single Dose of Oral Phentolamine

Hemodynamic Improvement followi,ng a Single Dose of Oral Phentolamine* Administration in Patients with Chronic Low Output Cardiac Failure Ronald Schreiber, M.D.; Paul T. Maier, M.D.; Rolf M. Gunnar, M.D., F.C.C.P.;oo and Henry S. Loeb, M.D.t

[i;emodYnamiC studies were made in ]5 patients with chronic low output cardiac: fajlore before and foUmyjPI a sinal' dose of oral phentolamjne (150 rna) After two hours significant

Recent interest in pharmacologic afterload reduction for management of patients with advanced refractory cardiac failure has made it desirable to investigate the hemodynamic responses to a variety of orally active vasodilators in order to identify those agents most likely to be of value when taken chronically. Because intravenous phentolamine had been shown to significantly reduce elevated ventricular filling pressure and increase cardiac output in patients with severe chronic heart failure, we undertook a study designed to see if similar hemodynamic improvement could be achieved utilizing phentolamine in the oral form. Our results suggest that oral phentolamine given as a single dosage of 150 mg results in significant hemodynamic improvement qualitatively similar to that achieved by administration of intravenous phentolamine. METHODS

The study group consisted of 15 male patients with chronic congestive heart failure, a cardiac index under 2.6 L/min/M2 and a left ventricular filling pressure above 12 mm Hg, Their mean age was 55.1 years (range 46-60) years. Eleven patients were felt to have ischemic heart disease, two had o From

the Section of Cardiology, Department of Medicine, University Stritch School of Medicine, Maywood, --an
car

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caody reduced (-18 percent) and cardiac indo: sipift. *t '1J11, cantly increased (+19 percent) from control values. Oral phentolamine resqlg in sjpificant hemodynamic im· grovement ig gatie...., with seyere heart faUgEr. Duration of etled for at least four hoon after a. sinlle dose

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hypertensive heart disease and two had cardiomyopathy of undetermined cause. Seven patients had cardiac catheterization and coronary arteriography, each showing inoperable, diffuse multivessel coronary artery disease and generalized hypokinesia of the left ventricle. Mitral regurgitation, when present, was mild and considered to be secondary to left ventricular dysfunction. No patient had sustained a myocardial infarction within the preceding three months, and none had significant angina pectoris at the time of the study. All patients had previously been treated with digitalis and diuretics and all were considered to be class 3 or 4 (New York Heart Association classification). On the morning of the study, the patient was brought to the special hemodynamic research unit in the fasting state without specific pre-medication. A No. 7F thermal dilution Swan-Ganz catheter was inserted in an antecubital vein and advanced under fluoroscopic control until the catheter tip was situated in the right or left pulmonary artery. The tip was positioned to yield a reliable wedge pressure (WP) waveform when the balloon was Inflated and pulmonary artery systolic and diastolic pressure waveform when the balloon was deflated. Right atrial pressure (RAP) was measured from the proximal lumen. Cardiac output (CO) was determined by averaging three or more thermal dilution curves obtained by injecting 10 ml of 0° C saline solution into the right atrium. A model 9500 cardiac output computer (Edwards Laboratories) was used to give on-line readout of cardiac output. Systemic arterial pressure was measured from an indwelling cannula in the radical or brachial artery. Pressures were measured from Statham 23DB transducers leveled at the midchest position. Mean pulmonary (MPAP ) and mean systemic arterial (MAP) pressures were determined by electrical dampening. Heart rate (HR) was determined from a standard ECG lead which was monitored continuously. Pressures and ECGs were recorded on a multichannel photographic recorder run at various paper speeds. Arterial (A0 2 ) and pulmonary (PA0 2) 'oxygen saturations were determined by oximetry using an American Optical oximeter. The following calculations were made: Cardiac index (CI) CO/body surface area; Stroke index (SI) CI/HR; Left

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HEMODYNAMIC IMPROVEMENT AFTER ORAL PHENTOLAMINE 511

Table I-MEAN ± SEM lor Each, Parameter a' Con'rol and 120 Minu'e.lollOU1ing Admini.'ration 01 Oral Phentolanaine in 15 Pa'ien'.·

MAPmm Hg MPAP mm Hg Wedge mm Hg RAP mm Hg CI L/min/M2 HR beats/min SI ml/beat LVSWI J!:m/~12 SAR mm Hg/L/min PAR mm Hg /Lyrnin A02 % P02 % A02-1">.-\():! %

Control

120 Minutes

89±4 39±2 26±2 10±4 1.8±0.1 91 ±3 19±2 19±3 25±2 4.3±0.4 93±1 48±3 44±3

83±5 35±3 19±2 7±2 2.5±0.2 99±4 25±4 23±3 18±1 3.9±0.4 92±1 56±3 37±3

P

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ventricular stroke work index (LVSWI) (MAP - WP) X 51 X 13.6/1000; Systemic arteriolar resistance (SAR) = (MAP-RAP)/CO; Pulmonary arteriolar resistance (PAR) (MPAP-WP)/CO. Commercially available 50 mg tablets of oral phentolamine were administered. The first two patients studied were given only two tablets (100 mg ) which resulted in negligible hemodynamic effect. Data from these two patients have not been included in the present series. Of the 15 patients whose data are presented, 14 received three phentolamine tablets ( 150 mg ) as a single dose. In the remaining patient who was a double amputee, only 100 mg was given. In each of the 15 patients, (excluding a measurement omitted at 90 minutes in one patient) hemodynamic measurements were made every 30 minutes for 2 hours following administration of phentolamine. In 12 patients, measurements were also made at three hours and in ten patients, measurements were extended for four hours after drug administration.

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REsULTS

Table 1 lists mean + SEM for control values and values obtained two hours after phentolamine administration in all 15 patients. The control values

represent the average of two measurements obtained 15 minutes apart. Differences between the two control measurements were not significant for any parameter. The time course of phentolamine action is illustrated in Figures 1 through 5. Since not all patients were studied at 180 and 240 minutes, the effects of phentolamine are presented as percentage of change from control with means + SEM calculated for only those patients studied at the time indicated. Mean arterial pressure (Fig 1) was insignificantly reduced, averaging only - 6 percent at 120 minutes with only three patients showing a fall in MAP of greater than -15 percent at any time. Symptomatic hypotension was not observed. Mean Pulmonary Arterial Pressure was likewise little effected following oral phentolamine; however, reductions of - 12 percent seen at 90 and 120 minutes were significant (P < .05). Wedge Pressure (Fig 2) was significantly reduced at 30 minutes (P < .05) reaching a maximal reduction of - 26 percent at 90 and 120 minutes (P < .01) and remaining - 18 percent below control at four hours (P < .01). At 120 minutes, 13 of the 15 patients had a reduced wedge pressure and in 7, the reduction was 6 mm Hg or greater. Right atrial pressure was reduced by - 13 percent at 30 minutes (NS) to a maximum reduction of - 41 percent at 90 minutes (P < .01). At 240 minutes, RAP was still - 27 percent below control (P < .05). Cardiac Index (Fig 3) was significantly increased at 30 minutes (P < .01) with a maximal effect seen at 120 minutes at which time the increase averaged + 36 percent (P < .(01). At this time, all 15 patients showed increases in CI and in 11 patients, the increase was greater than + 25 percent from control.

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FIGURE 1. This and the following figures show the percentage of change from control (± SEM) from 30 to 240 minutes following administration of oral phentolamine. The number of patients studied and the significance of the change determined by Student's t test for paired data (P .05 NS) is shown for each time period. Mean arterial pressure was not significantly changed during the study.

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CHEST, 76: 5, NOVEMBER, 1979

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At four hours, CI had fallen, but still averaged + 19 percent above control (P < .01) for the ten patients having measurements made at this time. Heart rate (Fig 4) tended to increase progressively through the four-hour study period becoming significantly increased at 60 minutes with a maximal increase of + 12 percent at four hours (P < .01). At 120 minutes, 12 of the 15 patients had increases in HR with the largest increase of + 29 percent occurring in the only patient who had atrial fibrillation; the remaining patients were in normal sinus rhythm. Although ventricular ectopic beats were present in a few patients prior to and during the study, no significant arrhythmias were noted during the four hours following administration of phentolamine. Stroke index (SI) was significantly increased at 30 minutes (P < .05) reaching a maximal increase of + 24 percent at 120 minutes (P < .001) and remaining above control at four hours (P < .02). In spite of the increased heart rate, all but one patient showed an increase in SI at 120 minutes with 9 of lIJ

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2. Wedge pressure was significantly reduced at 30 minutes with a peak reduction of -26 percent at 90 and 120 minutes.

FiGURE

the 15 patients experiencing increases of greater than + 25 percent above control. Left ventricular stroke uiork: index was also increased at 30 minutes (P < .05) with a maximal increase averaging + 31 percent at 120 minutes (P < .001) and remaining + 18 percent above control at 4 hours (P < .02). At the time of maximal effect following phentolamine, all but 4 of the 15 patients had increases in LVSWI with 9 of the 15 patients showing increases more than + 25 percent above the control value. Systemic arteriolar resistance (Fig 5) was significantly reduced at 30 minutes (P < .05) and maximally reduced by - 22 percent at 120 minutes, at which time all 15 patients showed a reduction in SAR (P < .001). At four hours, SAR had increased and was only - 8 percent under the control (NS). Pulmonary arteriolar resistance showed variable changes after oral phentolamine and at no time was there a significant change from the control. At 120

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FIGURE 3. Maximum increase in cardiac index was present at 120 minutes, but at 240 minutes CI was significantly (+ 19 percent) above control.

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HEMODYNAMIC IMPROVEMENT AnER ORAL PHENTOLAMINE 573

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4. Heart rate increased progressively throughout the study with the peak increase of +12 percent present at 240 minutes.

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an effective agent for temporarily reversing the altered hemodynamics associated with severe acute and chronic cardiac failure.r" Although oral phentolamine has been available for several years, its acute hemodynamic effects in the setting of advanced chronic heart failure have not been described previously. From the present study, it is clear that oral phentolamine can quickly improve hemodynamics in such patients in a manner qualitatively similar to that observed during infusion of intravenous phentolamine. We observed the peak increase in CI (+36 percent) and decreases in wedge pressure ( - 26 percent) to occur two hours after phentolamine administration with some dissipation of effect over the next two hours. Nevertheless, at four hours, both CI and wedge pressure were still significantly changed from control values averaging + 19 percent and - 18 percent respectively.

minutes, PAR had decreased in eight patients, increased in flve patients and was unchanged in two patients. Oxygen Saturations A02 which was 90 percent or above in all but one patient before administration of phentolamine, was not significantly effected by the drug, increasing slightly in four patients, decreasing slightly in six patients and remaining unchanged in five patients. PA02, which was markedly reduced before phentolamine, had increased in 11 of the 15 patients at 120 minutes. The difference between A02 and PA02 had decreased significantly at 30 minutes (P < .05) with the maximal decrease of -19 percent at 60 minutes (P < .001) and remaining significantly reduced at 180 minutes (P < .02). DISCUSSION

Intravenous phentolamine has been shown to be

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FIGURE 5. Systemic arteriolar resistance was significantly reduced at 30 minutes and maximally reduced (-22 percent) at 120 minutes. By 240 minutes, changes in SAR were no longer significant.

CHEST, 76: 5, NOVEMBER, 1979

Sharpe and Long" reported hemodynamic improvement in eight patients with chronic heart failure studied four and 28 hours following administration of slow release oral phentolamine (150-200 mg every eight hours). At four hours, their patients showed an increase in mean cardiac index from 1.8 to 2.1 Lj min/M'' ( + 17 percent) and a drop in left ventricular filling pressure from 24 to 20 mm Hg ( - 17 percent). Although these changes are somewhat less than the changes we observed two hours following phentolamine administration, they are quite similar to what we observed in our ten patients studied after four hours. The mechanism whereby phentolamine improves hemodynamics in patients with heart failure is somewhat uncertain. As an alpha receptor blocking agent, phentolamine is thought to partially block adrenergic-mediated, increased vasoconstriction associated with low output states," however, a direct, nonadrenergic vasodilating effect or vasodilation resulting from stimulation of beta adrenergic receptors? has also been suggested. Any of these mechanisms could result in reduced impedance to ventricular ejection and improvement in ventricular performance. Although we observed significant reduction in ventricular filling pressure, the effect of phentolamine on preload via venodilatation appears to be less than with nitrates or nitroprusside." Another possible action of phentolamine which may play an important role on cardiac function is its effect on cardiac beta receptors, possibly by release of myocardial norepinephrine stores." The consistent increase in heart rate observed by us and others following administration of both intravenous'r! and oral" phentolamine supports the concept of a direct effect and distinguishes phentolamine from vasodilators such as nitrates," hydralazine'" and prazosin!' which do not consistently increase heart rate when given to patients with severe heart failure. The clinical usefulness of oral phentolamine for long-term management of patients with refractory heart failure has not been determined. Although acute circulatory effects are of interest, a close correlation between early hemodynamic changes following oral vasodilator administration and persisting symptomatic and functional improvement during chronic therapy has yet to be established.P-" The possibility that tachyphylaxis to phentolamine might rapidly develop, as has been described with use of prazosin.P is a consideration which requires further investigation. In the present study, we utilized the same phentolamine dose for each patient. Although peak changes in hemodynamics were comparable to those CHEST, 76: 5, NOVEMBER, 1979

achieved with other orally active vasodilators used in the treatment of patients with heart failure, the duration of action may be less than achieved with hydralazine or prazosin. Additional studies will be necessary to define the range of patient-to-patient variability with regard to dose response and to see if further hemodynamic benefit might be achieved with increased dose or frequency of administration or by using the slow release form. Finally, the longterm effects of oral phentolamine with regard to potential adverse reactions must be assessed. It is apparent that well-controlled studies of both efficacy and safety will be needed to define the role of oral phentolamine and a variety of other orally active vasodilators currently being considered for extended use in patients with refractory heart failure. REFERENCES

1 Majid PA, Sharma B, Taylor SH: Phentolamine for vasodilator treatment of severe heart failure. Lancet 2:719723,1971 2 Kelly DT, Delgado CE, Taylor DR, et al: Use of phentolamine in acute myocardial infarction associated with hypertension and left ventricular failure. Circulation 47: 729-734, 1973 3 Henning RJ, Shubin H, Weil MH: Afterload reduction with phentolamine in patients with acute pulmonary edema. Am Heart J 63:568-573, 1977 4 Stern M, Gohlke H, Loeb HS, et al: Hemodynamic effects of intravenous phentolamine in low output cardiac failure-dose response relationships. Circulation 58: 157163, 1978 5 Sharpe N, Long B: Efficacy of oral slow-release phentolamine in severe chronic heart failure (abstr). Circulation 58: (Supp II) 11-247, 1978 6 Miller RR, Vismara LA, Williams DO, et al: Pharmacological mechanisms for left ventricular unloading in clinical congestive heart failure. Circ Res 39:127-133, 1976 7 Gould L, Reddy CVR: Phentolamine. Am Heart J 92: 397-402, 1976 8 Gould L, Reddy CVR, Gomprecht RF: Oral phentolamine in angina pectoris. jap Hrt J 14:393-397, 1973 9 Kovick RB, Tillisch JH, Berens SC, et al: Vasodilator therapy for chronic left ventricular failure. Circulation 53:322-328, 1976 10 Franciosa JA, Pierpont G, Cohn IN: Hemodynamic improvement with hydralazine in left heart failure. Ann Intern Med 86:388-393, 1977 11 Awan NA, Miller RR, DeMaria AN, et al: Efficacy of ambulatory systemic vasodilator therapy with oral prazosin in chronic refractory heart failure. Circulation 56: 346-354, 1977 12 Jacobs WR, Henrick A, Loeb HE, et al: Non-invasive assessment of daily hydralazine therapy in patients with advanced cardiac failure. (abstr) Circulation 56 (supp III) :111-255, 1977 13 Franciosa JA, Pierpont GL, Cohn IN: Acute postural and exercise hemodynamic effects of vasodilators in heart failure. (abstr) Circulation 56 (suppl III) :III-175, 1977 14 Packer M, Meller J, Gorlin R, et al: Hemodynamic and clinical tachyphylaxis to prazosin-mediated afterload reduction in severe chronic congestive heart failure. Circulation 59:531-539, 1979

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