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Biomedical subjects

M Packer

Publications and source records attributed to M Packer.

At least 109 records · Page 6Linked to original sources
PubMed1985

Hemodynamic changes mimicking a vasodilator drug response in the absence of drug therapy after right heart catheterization in patients with chronic heart failure.

We suspected that patients with severe chronic heart failure may show hemodynamic changes after cardiac catheterization in the absence of drug therapy that could complicate assessment of the hemodynamic effects of new vasodilator and inotropic agents. To evaluate this phenomenon prospectively, hemodynamic variables were measured in 21 patients with heart failure 30 min and 2, 6, 24, and (in 12 patients) 48 hr after right heart catheterization, during which time therapy was not altered. During the first 2 hr we noted a significant increase in cardiac index and decreases in left ventricular filling pressure, mean arterial pressure, mean right atrial pressure, and systemic vascular resistance (p less than .01); a further decline in left ventricular filling pressure was noted over the next 24 hr, after which all hemodynamic variables remained stable. The magnitude of these hemodynamic changes resembled the effects of many established vasodilator drugs and was further enhanced after meals. These data indicate that hemodynamic improvement may be observed without any therapeutic intervention during the course of invasive studies in patients with severe chronic heart failure; such changes may lead investigators to attribute efficacy to ineffective drug therapy. To minimize the occurrence of such responses, we recommend that intravascular catheters be inserted the day before drug evaluation and that hemodynamic measurements be made with patients in a postprandial state.

Adult↗
PubMed1985

Long-term oral administration of amrinone for congestive heart failure: lack of efficacy in a multicenter controlled trial.

A number of uncontrolled studies have indicated that oral administration of amrinone, a phosphodiesterase inhibitor with potent positive inotropic effects in experimental preparations, may be beneficial in patients with chronic congestive heart failure. The present multicenter trial was designed to prospectively evaluate clinical response and change in exercise tolerance during 12 weeks of amrinone therapy in a double-blind, placebo-controlled protocol. Ninety-nine patients with NYHA functional class 3 or 4 congestive heart failure on digitalis and diuretics, of whom 31 were also receiving captopril, were enrolled. After baseline clinical assessment and determination of exercise tolerance, radionuclide left ventricular ejection fraction, and roentgenographic cardiothoracic ratio, patients were randomly assigned to receive amrinone or placebo, beginning at 1.5 mg/kg tid and increasing to a maximum dosage of 200 mg tid. After 12 weeks of therapy or at the last blinded evaluation in patients who did not complete this protocol, there were no significant differences from baseline values between treatment with amrinone or placebo with regard to symptoms, NYHA functional class, left ventricular ejection fraction, cardiothoracic ratio, frequency and severity of ventricular ectopy, or mortality. Exercise tolerance improved significantly from baseline by 37 +/- 10% (mean 163 sec) in patients on amrinone and 35 +/- 11% (mean 149 sec) in patients on placebo, but there was no significant difference between treatments. Adverse reactions were significantly more frequent and more severe on amrinone, occurring in 83% of patients and necessitating withdrawal in 34%.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1985

Vasodilator therapy for primary pulmonary hypertension. Limitations and hazards.

Vasodilator drugs were initially administered to patients with primary pulmonary hypertension based on the unproven hypothesis that pulmonary vasoconstriction played an important role in the pathogenesis of the disease. There were early reports of hemodynamic and clinical improvement after treatment with various vasodilating agents, but subsequent experience did not confirm these uncontrolled observations, and emphasized the limitations and hazards of this approach. Vasodilator therapy generally fails to reduce pulmonary vascular resistance selectively during long-term administration and frequently leads to systemic hypotension, exacerbation of the pulmonary hypertensive state, worsening of right ventricular failure, and systemic arterial desaturation. Beneficial hemodynamic responses are seen in only 15% to 25% of patients. Vasodilator therapy should not be considered an established treatment of patients with primary pulmonary hypertension.

Adrenergic alpha-Antagonists↗
PubMed1985

Does pulmonary vasoconstriction play an important role in patients with primary pulmonary hypertension? A skeptic's view of vasodilator therapy.

Despite isolated reports of dramatic hemodynamic and clinical improvement over the past 30 years, most patients with primary pulmonary hypertension fail to benefit from treatment with vasodilator drugs and many develop serious adverse reactions. The failure of this approach strongly suggests that pulmonary vasoconstriction does not play an important role in the pathogenesis of this disorder.

Humans↗
PubMed1984

Failure of low doses of amrinone to produce sustained hemodynamic improvement in patients with severe chronic congestive heart failure.

Although amrinone produces acute hemodynamic improvement in patients with severe chronic congestive heart failure (CHF), it has not produced clinical benefits in long-term controlled trials. To determined if the administration of subtherapeutic doses of amrinone may account for its lack of efficacy in these studies, the dose requirements of the drug were investigated in 30 patients with severe CHF. Doses of 100 mg of oral amrinone produced moderate increases in cardiac index (0.35 liters/min/m2) and decreases in pulmonary capillary wedge pressure (6.8 mm Hg) and systemic vascular resistance (16%) (all p less than 0.01); these effects, however, were short-lived (less than 2.5 hours). Doses of 200 mg of oral amrinone produced marked increases in cardiac index (0.56 liters/min/m2) and substantial decreases in left ventricular filling pressure (9.9 mm Hg) and systemic vascular resistance (30%) (all p less than 0.01), and these effects persisted for longer than 4 hours. Only 4 patients showed hemodynamic responses with 100 mg of the drug that were sufficiently marked and long-lasting to merit chronic therapy, whereas 28 patients had such a response with the 200-mg dose. When 200 mg of amrinone was administered orally every 8 hours, sustained hemodynamic benefits were seen for 48 hours. However, 16 of 22 patients who received 600 mg of the drug daily for more than 1 week had intolerable adverse reactions that required drug withdrawal. In conclusion, hemodynamically effective doses of amrinone (600 mg/day) cannot be tolerated for long periods by most patients with severe chronic CHF.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1984

Efficacy of captopril in low-renin congestive heart failure: importance of sustained reactive hyperreninemia in distinguishing responders from nonresponders.

To determine the efficacy of converting-enzyme inhibition in patients with low-renin congestive heart failure (CHF), the long-term hemodynamic and clinical responses to captopril were evaluated in 26 consecutive patients with severe, chronic CHF whose pretreatment plasma renin activity (PRA) was less than 2 ng/ml/hour. After 2 to 8 weeks of continuous treatment with captopril, 14 patients (54%) showed long-term hemodynamic benefits, of whom 13 (50%) improved clinically by at least 1 New York Heart Association functional class. To distinguish responders from nonresponders, patients were grouped based on the presence or absence of sustained reactive hyperreninemia (PRA during chronic therapy greater than 4 ng/ml/hour). After 2 to 8 weeks of therapy with captopril, 14 patients had sustained reactive hyperreninemia. Their cardiac index increased by 0.33 liters/min/m2 (p less than 0.01), left ventricular filling pressure decreased by 12.6 mm Hg (p less than 0.001), mean right atrial pressure decreased by 4.9 mm Hg (p less than 0.001) and systemic vascular resistance decreased by 529 dyne s cm-5 (p less than 0.001). Twelve of these 14 patients improved clinically. Twelve other patients had no reactive increase in PRA, and these patients showed no significant improvement in any hemodynamic variable after 2 to 8 weeks of treatment with captopril; only 1 of the 12 patients improved clinically (p less than 0.001 between groups). The 2 groups were otherwise similar with regard to pretreatment demographic, hemodynamic and hormonal variables.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1984

Conceptual dilemmas in the classification of vasodilator drugs for severe chronic heart failure. Advocacy of a pragmatic approach to the selection of a therapeutic agent.

Two distinct systems of classifying vasodilator drugs have been developed over the past decade in an attempt to guide the choice of a therapeutic agent for the patient with severe heart failure, but the merits and utility of these systems have not been critically evaluated. Vasodilator drugs may be categorized according to their peripheral site of action: an agent may exert its effects preferentially on systemic arteries, systemic veins, or on both circulations. However, changes in the peripheral circulation cannot be directly translated into an improvement in central hemodynamic variables; furthermore, immediate hemodynamic responses may not be predictive of long-term clinical efficacy. Hence, there is no evidence that characterization of patients into hemodynamic subsets determined by the findings of right heart catheterization improves the clinical outcome of vasodilator therapy in chronic heart failure. An alternative classification system groups vasodilator drugs according to their mechanism of action: an agent may possess direct vasodilating effects or may exert its actions via selective neurohumoral inhibition. However, attempts to identify patients who might be most responsive to neurohumoral antagonism by measuring plasma renin activity or circulating levels of catecholamines before treatment have not been successful in predicting the clinical responses to therapy. Because neither system of drug classification provides the clinician with useful therapeutic guidelines, patients with severe heart failure appear to be best managed using a pragmatic approach in which specific drugs that produce predictable therapeutic benefits with a low frequency of side effects are utilized preferentially. Among presently available vasodilator agents, only captopril and oral isosorbide dinitrate have been shown to produce consistent hemodynamic and clinical improvement with an acceptable degree of adverse reactions.

Captopril↗
PubMed1984

Nitroglycerin therapy in the management of pulmonary hypertensive disorders.

Vasodilator therapy has not been effective in patients with pulmonary hypertension because most of the drugs that have been utilized in treating this disorder do not exert selective effects on the pulmonary circulation. Nonselective agents may cause predominant systemic vasodilation and lead to severe hypotension; they may elicit reflex activation of the sympathetic nervous system and further elevate pulmonary artery pressures; or they may exert depressant effects on right ventricular function and aggravate right-sided heart failure. Nitroglycerin has theoretic appeal as a vasodilator drug in patients with pulmonary hypertension because it exerts a direct effect on the pulmonary circulation in doses that do not affect systemic resistance vessels or the myocardium and do not activate neurohumoral reflexes. Furthermore, the drug uniquely reduces pulmonary artery pressures in addition to pulmonary vascular resistance due to its ability to dilate venous capacitance vessels. Preliminary studies with sublingual and intravenous nitroglycerin in patients with pulmonary hypertension have shown that the drug produces marked hemodynamic improvement and that clinical benefits follow long-term therapy with transcutaneous or oral nitrates. However, treatment may provoke hypotensive events in some patients and systemic hypoxemia in others; still others may fail to benefit because the pulmonary vasculature is unresponsive to any vasodilator stimulus. Further work is needed to define the benefits and risks of nitroglycerin therapy in patients with pulmonary hypertension.

Humans↗
PubMed1984

Prostaglandins in severe congestive heart failure. Relation to activation of the renin--angiotensin system and hyponatremia.

To determine whether prostaglandins are involved in circulatory homeostasis in congestive heart failure, we measured plasma levels of the metabolites of vasodilator prostaglandins I2 and E2 in 15 patients with severe chronic heart failure. Mean circulating levels of both metabolites were 3 to 10 times higher than those in normal subjects. Plasma levels of both metabolites correlated directly with plasma renin activity and plasma angiotensin II concentrations (r = 0.64 and 0.84, respectively). Individual serum sodium concentrations were inversely correlated with levels of prostaglandin E2 metabolites (r = -0.92, P less than 0.001) and plasma renin activity (r = -0.69, P less than 0.02). Of 23 patients with severe heart failure challenged with indomethacin (an inhibitor of prostaglandin synthesis), the 9 with hyponatremia had significant decreases in the cardiac index (1.99 +/- 0.12 to 1.72 +/- 0.13 liters per minute per square meter of body-surface area, P less than 0.001) and significant increases in the pulmonary capillary wedge pressure (17.4 +/- 2.0 to 24.0 +/- 1.9 mm Hg, P less than 0.001) and systemic vascular resistance (1882 +/- 239 to 2488 +/- 315 dyn x sec x cm-5, P less than 0.001), whereas the 14 patients with a normal serum sodium concentration had no significant hemodynamic changes. We conclude that both vasoconstrictor (renin-angiotensin) and vasodilator (prostaglandin) mechanisms are operative in patients with heart failure complicated by hyponatremia and that these mechanisms interact to modulate circulatory homeostasis.

Adult↗
PubMed1984

Adverse hemodynamic and clinical effects of calcium channel blockade in pulmonary hypertension secondary to obliterative pulmonary vascular disease.

The hemodynamic and clinical responses to calcium channel blockade with verapamil and nifedipine were compared with those of hydralazine in 12 patients with pulmonary hypertension secondary to obliterative pulmonary vascular disease. All three drugs produced a marked and similar decrease in pulmonary vascular resistance; however, this was accompanied by a significant increase in cardiac index with hydralazine (+0.71 liter/min per m2, p less than 0.01), no change in cardiac index with nifedipine and a significant decrease in cardiac index with verapamil (-0.25 liter/min per m2, p less than 0.05). Mean pulmonary artery pressure decreased markedly with both calcium channel blocking drugs (-16.0 mm Hg with verapamil and -14.5 mm Hg with nifedipine, both p less than 0.01), but this was associated with a concomitant increase in mean right atrial pressure (+6.2 mm Hg with verapamil and +4.4 mm Hg with nifedipine, both p less than 0.01); neither variable changed after hydralazine. Hence, right ventricular performance (as reflected by right ventricular stroke work index) deteriorated during treatment with both calcium channel blocking drugs, despite the decrease in resistance to right ventricular ejection; in contrast, right ventricular stroke work index increased after hydralazine. The unfavorable hemodynamic effects of calcium channel blockade were accompanied by severe adverse clinical events, including profound hypotension and cardiogenic shock during acute drug administration and the exacerbation of right heart failure during long-term treatment. These deleterious responses to verapamil and nifedipine are likely the result of a direct depressant effect exerted by these drugs on right ventricular function independent of their pulmonary vasodilatory actions.

Adult↗
PubMed1984

Relation between exercise-induced changes in ejection fraction and systolic loading conditions at rest in aortic regurgitation.

To examine the role of systolic wall stress at rest in determining left ventricular performance during exercise in aortic regurgitation (AR), systolic wall stress (measured by M-mode echocardiography) was related to changes in left ventricular function during maximal exercise (evaluated by radionuclide ventriculography) in 30 patients with chronic aortic regurgitation. Of these 30 patients, 7 had a normal exercise response, defined as an absolute increase in ejection fraction of 5% or greater (Group I) and 23 had abnormal exercise response, defined as no change (less than 5% change) or a decline (less than or equal to 5%) in ejection fraction (Group II). Patients in Group I had a significantly lower radius/wall thickness ratio (2.5 +/- 0.2 versus 3.1 +/- 0.1, p less than 0.01) and lower peak systolic wall stress (123 +/- 11 versus 211 +/- 12 X 10(3) dynes/cm2, p less than 0.01) than patients in Group II. An increase in ejection fraction during exercise was seen in 6 of the 9 patients with normal systolic wall stress at rest (less than 150 X 10(3) dynes/cm2), but in only 1 of 21 patients with elevated systolic wall stress (p less than 0.001). Peak systolic wall stress at rest varied linearly, and inversely with changes in left ventricular ejection fraction during exercise (r = 0.60, p less than 0.001). Groups I and II did not differ in ejection fraction at rest, clinical symptoms or maximal work load achieved.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1984

Relation between serum sodium concentration and the hemodynamic and clinical responses to converting enzyme inhibition with captopril in severe heart failure.

The relation between pretreatment serum sodium concentration and the early and late effects of captopril was examined in 77 consecutive patients with severe chronic heart failure, in whom cardiac catheterization was performed during initiation of treatment and after 2 to 8 weeks. Two groups of patients were defined: 37 patients had hyponatremia (serum sodium less than 135 mEq/liter, group A) and 40 patients had a normal serum sodium concentration (greater than or equal to 135 mEq/liter, group B). With first doses of captopril, patients in group A showed more marked hemodynamic responses than did patients in group B (p less than 0.02). The changes in mean arterial pressure and left ventricular filling pressure seen with first doses of the drug varied linearly and inversely with the pretreatment serum sodium concentration (r = -0.58 and r = -0.53, respectively); this was likely related to the finding that, before administration of captopril, the serum sodium concentration varied linearly and inversely with the logarithm of the plasma renin activity (r = -0.78). However, the pretreatment serum sodium concentration did not predict the long-term hemodynamic or clinical responses to converting enzyme inhibition. Symptomatic hypotension occurred early in the course of therapy (within 24 hours of initiating captopril therapy) in 9 (12%) of the 77 patients; 8 of these 9 had severe hyponatremia (serum sodium less than 130 mEq/liter) and comprised 53% of the 15 patients in our study with such low serum sodium concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1984

Detrimental effects of verapamil in patients with primary pulmonary hypertension.

Calcium channel blockade provides a logical approach to the treatment of pulmonary hypertension because these drugs exert direct vasodilator effects in the highly constricted pulmonary circulation. To determine the effectiveness of verapamil in the treatment of primary pulmonary hypertension the haemodynamic effects of the drug were evaluated in seven patients with this disorder; 10 mg was given intravenously to six patients and 120 mg orally to one patient. Verapamil produced a 20% decline in pulmonary vascular resistance and a 27% decrease in mean pulmonary arterial pressure without significant changes in systemic vascular resistance. One patient who received verapamil 480 mg orally daily for three months showed sustained haemodynamic and clinical improvement. Concomitant with its beneficial effects on the pulmonary circulation, however, verapamil produced a pronounced decrease in right ventricular stroke work index (42%) and increase in right ventricular filling pressure (50%), indicating a direct depressant effect of the drug on right ventricular function. In one patient these cardiodepressant effects were sufficiently pronounced to produce severe hypotension and cardiac arrest. In conclusion, although verapamil appears to exert preferential vasodilator effects on the pulmonary circulation, its negative inotropic effects may be particularly detrimental to patients with primary pulmonary hypertension who have pre-existing right ventricular dysfunction; hence, treatment with verapamil is not recommended in such cases.

Adult↗
PubMed1984

Hemodynamic and clinical limitations of long-term inotropic therapy with amrinone in patients with severe chronic heart failure.

To determine the hemodynamic and clinical effects of long-term positive inotropic stimulation on the myocardium, we treated 31 patients with severe chronic heart failure with oral amrinone (600 mg daily) and performed invasive hemodynamic studies during short- and long-term treatment with the drug. Stroke volume and stroke work indexes increased markedly during the first 48 hr of therapy (p less than .01) but returned to pretreatment values after 2 to 10 weeks; upon drug withdrawal, both variables deteriorated rapidly to values significantly lower than those observed before treatment with amrinone (p less than .01), despite similar values for left ventricular filling pressure, mean arterial pressure, and systemic vascular resistance. This pattern of response indicated that progression of the underlying heart disease had occurred during treatment with amrinone and contributed importantly to its failure to produce long-term benefits. Progression of left ventricular dysfunction was associated with a progressive increase in heart rate and plasma renin activity and a decline in serum sodium concentration. Clinically, amrinone therapy was complicated by sustained symptomatic ventricular tachycardia in four patients, worsening myocardial ischemia in four patients, and worsening congestive heart failure in eight patients, all of whom had been stable before entry into the study; only three of the 31 patients improved clinically. Ten patients died during the first 2 weeks of treatment, and 16 (52%) were dead within 3 months, a mortality rate twice as great as that seen during comparable trials with vasodilating drugs. Although noncardiac adverse effects were frequent, they were not the primary reason for drug failure. In conclusion, long-term therapy with amrinone may accelerate progression of left ventricular dysfunction, exacerbate myocardial ischemia, and provoke life-threatening ventricular tachyarrhythmias, thereby shortening survival in patients with severe chronic heart failure. Prolonged administration of inotropic drugs may achieve short-term gains at the expense of long-term detrimental effects on the myocardium.

Adult↗
PubMed1984

Correction of dilutional hyponatremia in severe chronic heart failure by converting-enzyme inhibition.

To determine the effects of vasodilator and inotropic therapy on hyponatremia in patients with severe heart failure, we measured serum sodium concentration before and after treatment with captopril (70 patients), hydralazine (42 patients), prazosin (22 patients), and amrinone (19 patients), while diuretic dosages were kept constant. Serum sodium concentration increased only in hyponatremic patients treated with captopril (131.2 +/- 0.5 to 135.9 +/- 0. 5 SE ; p less than 0.001), but not during therapy with the other agents and not in patients with normal serum sodium concentration before treatment. Serum sodium began to rise 48 hours after the initiation of captopril therapy and reached its peak after 14 to 16 days. Correction of hyponatremia was related to functional interference with the renin-angiotensin system, but not to changes in renal function, serum potassium concentration, body weight, or the magnitude of hemodynamic or clinical improvement. These findings support experimental evidence that the renin-angiotensin system is important in the pathogenesis of hyponatremia in patients with severe heart failure treated with diuretics.

Adult↗
PubMed1983

New perspectives on therapeutic application of nitrates as vasodilator agents for severe chronic heart failure.

Although nitrates produce marked decreases in ventricular filling pressures in patients with severe heart failure, their therapeutic value has long been believed to be limited because they were thought to exert minimal arterial dilating effects. Recently, however, new conceptual approaches to vasodilator drugs have been developed that have challenged this traditional view. These new perspectives indicate that nitrates exert dilator actions on both the arterial and venous circulations, and reduce both preload and afterload; such balanced circulatory responses are particularly evident when large doses of these drugs are used. Cardiac output increases markedly with nitrates in patients with a greatly increased systemic vascular resistance before treatment or with significant mitral regurgitation. The major reason for the limited increases in cardiac output noted in previous studies is the inclusion of patients with heart failure whose pretreatment values for cardiac output were within normal limits; in these persons nitrates markedly activate neurohumoral vasoconstrictor mechanisms that counteract the arterial dilating actions of these drugs. Long-term nitrate therapy attenuates exercise-induced increases in pulmonary venous pressures, which permit patients to undergo repeated submaximal exercise with fewer symptoms; this improves physical conditioning and exercise capacity, even in the absence of drug-related changes in cardiac output. The long-term hemodynamic and clinical benefits of nitrates in heart failure have been confirmed by two independent randomized double-blind placebo-controlled clinical trials.

Cardiac Output↗
PubMed1983

Quantitative differences in the hemodynamic effects of captopril and nitroprusside in severe chronic heart failure.

The hemodynamic effects of oral captopril and intravenous nitroprusside were compared in 15 patients with severe chronic congestive heart failure. At doses of both drugs titrated so as to produce similar decreases in systemic vascular resistance in each patient, nitroprusside produced substantially greater increases in cardiac index (+0.67 versus +0.31 liters/min/m2, p less than 0.01) but smaller decreases in mean arterial pressure (-18.4 versus -11.0 mm Hg, p less than 0.01) than did captopril. This finding was due to a significant decrease in heart rate with captopril (-7 beats/min, p less than 0.01) which was not seen with nitroprusside, since changes in stroke volume index with both drugs were similar. Nitroprusside produced a decrease in pulmonary arteriolar resistance quantitatively similar to the decrease in systemic vascular resistance, but the decrease in pulmonary arteriolar resistance with captopril was not significant. Despite similar decreases in systemic resistance, captopril produced a greater decrease in left ventricular filling pressure (-10.2 versus -6.9 mm Hg, p less than 0.01) but a smaller decrease in mean right atrial pressure (-3.1 versus -5.3 mm Hg, p less than 0.01) than did nitroprusside. Thus, captopril has actions independent of its systemic vasodilator effects which account for the quantitative differences observed in its hemodynamic responses compared with those of nitroprusside in patients with severe chronic heart failure. These differences support experimental evidence that angiotensin, in addition to its direct systemic arterial vasoconstrictor actions, exerts positive chronotropic effects and alters ventricular compliance but has minimal direct effects on the limb venous circulation and on the pulmonary vasculature.

Adult↗