The additive pulmonary vasodilatory effects of inhaled prostacyclin and inhaled milrinone in postcardiac surgical patients with pulmonary hypertension.

UNLABELLED: Selective pulmonary vasodilation is an advantageous therapeutic strategy for cardiac surgical patients with increased pulmonary vascular resistance (PVR) and right ventricular failure. We hypothesized that milrinone, an adenosine-3',5'-cyclic monophosphate (cAMP)-selective phosphodiesterase enzyme (PDE) inhibitor may, when nebulized and inhaled, cause selective pulmonary vasodilation and potentiate the vasodilation by inhaled prostacyclin (iPGI(2)). Consequently, we investigated the hemodynamic effects of inhaled milrinone or the combination iPGI(2) + inhaled milrinone in cardiac surgical patients with postoperative mean pulmonary arterial pressure (MPAP) >25 mm Hg and PVR >200 dynes. s(-1). cm(-5). During mechanical ventilation and using a conventional nebulizing system, 9 patients inhaled incremental concentrations of milrinone (0.25, 0.5 and 1 mg/mL) in subsequent 10-min periods (Study Part 1). In the same manner, 11 patients received iPGI(2) (10 microg/mL) followed by the combination of iPGI(2) (10 microg/mL) and inhaled milrinone (1 mg/mL) (Study Part 2). Inhaled milrinone reduced PVR with a maximal effect (-20%, P < 0.001) at the largest concentration. As compared with iPGI(2) alone, iPGI(2) + inhaled milrinone caused a further and prolonged reduction of PVR (-8%, P < 0.05) and increased stroke volume (+5%, P < 0.05). Systemic vascular resistance or mean arterial pressure was not affected by inhalation of either drug(s). The authors conclude that inhalation of the cAMP-selective PDE-inhibitor milrinone selectively dilates the pulmonary vasculature without systemic effects in cardiac surgical patients with pulmonary hypertension. Furthermore, inhaled milrinone appears to potentiate and prolong the pulmonary selective vasodilatory effect of iPGI(2). Inhaled milrinone alone or combined with iPGI(2) may be an important therapeutic option in the treatment of patients with pulmonary hypertension and right ventricular failure. IMPLICATIONS: Pulmonary hypertension may cause or aggravate right heart failure. IV vasodilators reduce systemic blood pressure and might thereby further impair coronary perfusion and right heart performance. In the present study of cardiac surgical patients with pulmonary hypertension, selective pulmonary vasodilation without systemic effects was induced by nebulized, inhaled vasodilators.

Inhaled prostacyclin and platelet function after cardiac surgery and cardiopulmonary bypass.

OBJECTIVE: To study the effects of 6 h inhalation of aerosolized prostacyclin (PGI2) on platelet function. DESIGN: In a prospective, double-blind, randomized study, 28 patients scheduled for elective cardiac surgery requiring cardiopulmonary bypass (CPB), received either 0.9% sodium chloride (n = 8), PGI2 5 microg x ml(-1) (n = 10) or PGI2 10 microg x ml(-1) (n = 10) as an aerosol for 6 h postoperatively. SETTING: Cardiothoracic intensive care unit at a university hospital. INTERVENTIONS: All patients were studied immediately after surgery during mechanical ventilation and sedation. The PGI2 solutions or saline were administered with a jet nebulizer. MEASUREMENTS AND RESULTS: Bleeding time and chest tube drainage were measured. Blood samples for platelet aggregation, thrombelastography (TEG) and analysis of coagulation parameters and the stable prostacyclin metabolite 6-keto-PGF1alpha were obtained immediately before inhalation and after 2, 4 and 6 h of inhalation. After 6 h of PGI2 inhalation, regardless of administered dose, there was a lower rate of platelet aggregation and a lower maximal increase in light transmission in response to adenosine diphosphate (ADP) than in the control group. The TEG variable reaction time (R) was prolonged after 4 and 6 h of inhalation in the PGI2 group receiving 10 microg x ml(-1). There were no differences between groups with respect to bleeding time and chest tube drainage or any of the other variables examined. CONCLUSION: Inhalation of PGI2 for 6 h in patients after cardiac surgery is associated with impaired platelet aggregation detected by in vitro techniques, with no in vivo signs of platelet dysfunction.

Coronary and systemic hemodynamic effects of clevidipine, an ultra-short-acting calcium antagonist, for treatment of hypertension after coronary artery surgery.

BACKGROUND: The aim was to evaluate the use of clevidipine, a new vascular selective, ultra-short-acting calcium antagonist for blood pressure control after coronary artery bypass grafting (CABG). METHODS: The effects of clevidipine on central hemodynamics, myocardial blood flow and metabolism were studied at two different phases after CABG. In phase 1 (n=13), the hypertensive phase, the effects of clevidipine were compared to those of sodium nitroprusside (SNP) when used to control postoperative hypertension. In phase 2 (n=9), the normotensive phase, a clevidipine dose-response relationship was established. RESULTS: At a target mean arterial pressure (MAP) of 75 mmHg, systemic vascular resistance (SVR) and heart rate (HR) were lower, preload, stroke volume (SV) and pulmonary vascular resistance (PVR) were higher, while there were no differences in myocardial lactate metabolism or oxygen extraction with clevidipine compared to SNP. In the normotensive phase, clevidipine induced a dose-dependent decrease in MAP (-19%), SVR (-27%) and PVR (-15%), accompanied by an increase in SV (10%), but no reflex increase in HR or changes in cardiac preload. Clevidipine caused a direct coronary vasodilation, as indicated by a decrease in myocardial oxygen extraction from 54% to 45%. Myocardial lactate metabolism was unaffected by clevidipine. The blood clearance of clevidipine was 0.05 l x min(-1) x kg(-1), the volume of distribution at steady state was 0.08 l x kg(-1) and the initial and terminal half-lives were <1 min and 4 min, respectively. CONCLUSIONS: Clevidipine rapidly reduced MAP and induced a systemic, pulmonary and coronary vasodilation with no effect on venous capacitance vessels or HR. Clevidipine caused no adverse effects on myocardial lactate metabolism. Clevidipine thus appears suitable to control blood pressure after CABG.

Comparison of inhaled nitric oxide and inhaled aerosolized prostacyclin in the evaluation of heart transplant candidates with elevated pulmonary vascular resistance.

STUDY OBJECTIVE: Elevated pulmonary vascular resistance is a risk factor in heart transplantation and reversibility of high pulmonary vascular resistance is evaluated preoperatively in potential recipients using i.v. vasodilators or inhaled nitric oxide. Prostacyclin is a potent vasodilator, which when inhaled, has selective pulmonary vasodilatory properties. The aim of this study was to compare the central hemodynamic effects of inhaled prostacyclin with those of inhaled nitric oxide in heart transplant candidates. DESIGN: A pharmacodynamic comparative study. SETTING: Cardiothoracic ICU or laboratory for diagnostic heart catheterization at a university hospital. PATIENTS: Ten heart transplant candidates with elevated pulmonary vascular resistance (>200 dynes x s x cm(-5) and/or a transpulmonary pressure gradient > 10 mm Hg) were included in the study. INTERVENTIONS: Nitric oxide (40 ppm) and aerosolized prostacyclin (10 microg/mL) were administered by inhalation in two subsequent 10-min periods. Hemodynamic measurements preceded and followed inhalation of each agent. MEASUREMENTS AND RESULTS: Both inhaled nitric oxide and inhaled prostacyclin reduced mean pulmonary artery pressure (-7% vs -7%), pulmonary vascular resistance (-43% vs -49%), and the transpulmonary gradient (-44% vs -38%). With inhaled prostacyclin, an 11% increase in cardiac output was observed. Other hemodynamic variables, including the systemic BP, remained unaffected by each of the agents. CONCLUSIONS: Inhaled prostacyclin induces a selective pulmonary vasodilation that is comparable to the effect of inhaled nitric oxide. Major advantages with inhaled prostacyclin are its lack of toxic reactions and easy administration as compared with the potentially toxic nitric oxide requiring more complicated delivery systems.

Inhaled prostacyclin for treatment of pulmonary hypertension after cardiac surgery or heart transplantation: a pharmacodynamic study.

OBJECTIVE: To study the effects of incremental concentrations of inhaled aerosolized prostacyclin (PGI2) on pulmonary and systemic hemodynamics after cardiac surgery or heart transplantation. DESIGN: Pharmacodynamic dose-response study. SETTING: Cardiothoracic intensive care unit (ICU) at a university hospital. PARTICIPANTS: Nine patients with pulmonary hypertension after cardiac surgery or heart transplantation and an elevated pulmonary vascular resistance (PVR) (> 20 dynes.sec.cm-5) treated in the ICU with inotropic support were studied. INTERVENTIONS: Inhaled prostacyclin was administered at concentrations of 2.5, 5.0, and 10.0 micrograms/mL using conventional systems for nebulization. MEASUREMENTS AND MAIN RESULTS: Pulmonary and systemic hemodynamics as well as right ventricular (RV) function variables (n = 3) were measured before, during, and 10 and 20 minutes after inhalation of PGI2. Inhaled PGI2 induced a dose-dependent decrease in PVR and the transpulmonary gradient (which decreased by -29% and -26%, respectively) at an inhaled concentration of 10 micrograms/mL. Inhaled PGI2 caused no changes in systemic vascular resistance. Central venous pressure decreased during PGI2 inhalation with no change in stroke volume, indicating an improvement in RV performance, which was particularly obvious in one patient with RV failure after heart transplantation. Twenty minutes after discontinuation of inhaled PGI2, hemodynamic variables returned to baseline. CONCLUSIONS: Inhaled PGI2 induces a dose-dependent selective pulmonary vasodilation and may improve RV performance after cardiac surgery complicated by pulmonary hypertension and RV failure.

Effects of prostacyclin on myocardial hemodynamics and metabolism after coronary artery bypass grafting.

OBJECTIVE: To study the effects of incremental infusion rates of prostacyclin on myocardial blood flow and metabolism and central hemodynamics shortly after coronary artery bypass grafting. DESIGN: A pharmacodynamic dose-response study. SETTING: A multi-institutional university hospital. PARTICIPANTS: Twelve patients with two- or three-vessel coronary artery disease and with an ejection fraction greater than 0.5 were studied in the operating room after sternal closure and elective coronary artery bypass grafting. INTERVENTIONS: Prostacyclin was administered at infusion rates of 2.5, 5, 10, and 20 ng/kg/min. Systemic and pulmonary hemodynamics and global (coronary sinus) as well as regional (great cardiac vein) myocardial blood flow and metabolic variables were measured. MEASUREMENTS AND MAIN RESULTS: Infusion rates of 10 and 20 ng/kg/min decreased mean arterial blood pressure (13% and 21%, respectively), systemic vascular resistance (31% and 42%), and pulmonary vascular resistance (11% and 33%), increased cardiac output (28% and 37%), heart rate (9% and 13%), and stroke volume (15% and 20%), but had no effect on central filling pressures. Prostacyclin caused no changes in great cardiac vein flow or coronary sinus flow. Furthermore, prostacyclin caused no changes in regional myocardial oxygen extraction, indicating that prostacyclin did not induce direct coronary vasodilation. There were no electrocardiographic or obvious metabolic signs of myocardial ischemia during prostacyclin infusion. CONCLUSION: Prostacyclin may be a useful afterload-reducing compound after coronary artery bypass grafting because it has no direct coronary vasodilatory effect, which minimizes the risk of myocardial ischemia.

A comparison of prostacyclin and sodium nitroprusside for the treatment of heart failure after cardiac surgery.

OBJECTIVE: To study the effects of the two vasodilators, prostacyclin and sodium nitroprusside, on central hemodynamics in heart failure after cardiac surgery. DESIGN: Randomized cross-over study. SETTING: Multi-institutional university hospital. PARTICIPANTS: Ten patients. INCLUSION CRITERIA: cardiac index less than 2.5 L/min/m2; pulmonary capillary wedge pressure greater than 15 mmHg, systemic vascular resistance index greater than 2,500 dynes.s.cm-5/m2, and treatment with inotropic support. Five patients were treated with intra-aortic balloon counterpulsation. INTERVENTIONS: After control measurements, mean arterial pressure was decreased by 10% to 20% with each vasodilator in each patient. MEASUREMENTS AND RESULTS: Sodium nitroprusside induced decreases in mean pulmonary arterial pressure (-21%), pulmonary capillary wedge pressure (-29%), central venous pressure (-17%), and systemic vascular resistance (-25%), and increases in cardiac output (+7%) and stroke volume (+6%) compared with control. Prostacyclin decreased mean pulmonary arterial pressure (-14%), pulmonary capillary wedge pressure (-19%), central venous pressure (-7%), and systemic (-40%) and pulmonary (-25%) vascular resistances, whereas cardiac output (+25%) and stroke volume (+22%) increased compared with control. Prostacyclin, compared with sodium nitroprusside, induced a more pronounced increase in cardiac output and stroke volume, associated with less pronounced decreases in cardiac filling pressures and more profound decreases in systemic and pulmonary vascular resistances. CONCLUSION: Prostacyclin appears to be a useful agent, superior to sodium nitroprusside, in the treatment of postoperative heart failure in patients with normal or mildly elevated cardiac filling pressures, where vasodilator treatment is indicated.

Vasodilator therapy after heart transplantation: effects of inhaled nitric oxide and intravenous prostacyclin, prostaglandin E1, and sodium nitroprusside.

BACKGROUND: Vasodilator therapy is frequently needed to treat pulmonary hypertension after heart transplantation. In the present study, the effects of intravenous sodium nitroprusside, prostacyclin, prostaglandin E1, and inhaled nitric oxide (5, 10, and 20 parts per million) on central hemodynamics, right ventricular function, and pulmonary selectivity were evaluated shortly after heart transplantation. METHODS: Hemodynamic measurements were made after surgery in the intensive care unit. The intravenous vasodilators were compared at equipotent infusion rates. Effects of inhaled nitric oxide were measured after 10 minutes inhalation at each dose level. RESULTS: Cardiac output, stroke volume, right ventricular end-diastolic volume, and central filling pressures were highest with prostacyclin (16 +/- 2 ng/kg/min) compared with both prostaglandin E1 (202 +/- 27 ng/kg/min) and sodium nitroprusside (1.0 +/- 0.2 microgram/kg/min). Systemic and pulmonary vascular resistance were lowest with prostacyclin. None of the intravenous vasodilators induced a selective pulmonary vasodilation. In contrast, nitric oxide inhalation induced a selective decrease in pulmonary vascular resistance, with no change in systemic vascular resistance. Cardiac output increased with nitric oxide, whereas mean pulmonary arterial pressure, transpulmonary pressure gradient, and central venous pressure decreased, with the most pronounced effect at an inhaled concentration of 20 parts per million. CONCLUSIONS: Prostacyclin is the best choice for intravenous vasodilator therapy after heart transplantation. However, inhaled nitric oxide is the only selective pulmonary vasodilator, which should be used in cases of pulmonary hypertension and severe right ventricular failure associated with systemic hypotension.

Inhaled nitric oxide in the evaluation of heart transplant candidates with elevated pulmonary vascular resistance.

The reversibility of elevated pulmonary vascular resistance in heart transplant candidates is currently evaluated with intravenous vasodilators. The aim of this study was to evaluate the effects of increased concentrations of inhaled nitric oxide (20, 40, and 80 ppm) on central hemodynamics and right ventricular function in heart transplant candidates with elevated pulmonary vascular resistance (> 2.5 Wood units). Comparison was made with intravenous vasodilators, sodium nitroprusside, and prostacyclin in doses that lowered the mean arterial pressure by about 15%. Inhalation of nitric oxide did not change systemic or pulmonary arterial pressure, cardiac output, right ventricular function, or systemic vascular resistance. Pulmonary capillary wedge pressure increased and transpulmonary pressure gradient and pulmonary vascular resistance decreased (-34% +/- 4% and -36% +/- 4%, respectively; p < 0.01) during 20 ppm nitric oxide, with no further effects at higher doses. Prostacyclin and sodium nitroprusside decreased pulmonary vascular resistance (-50% +/- 6% and -33% +/- 5%; p < 0.01). Prostacyclin reduced to some extent (p = 0.08) transpulmonary pressure gradient, which was not seen during sodium nitroprusside infusion. Systemic vascular resistance decreased during both sodium nitroprusside (-37% +/- 5%) and prostacyclin (-44% +/- 4%) infusion. The pulmonary vascular resistance/systemic vascular resistance ratio, used as an index of pulmonary selectivity, was decreased by nitric oxide (p < 0.01) but not by the intravenous vasodilators. Metabolic data indicate that inhaled nitric oxide is metabolized in the same way as that formed endogenously. In conclusion, inhaled nitric oxide is a selective pulmonary vasodilator that can be used safely in the hemodynamic evaluation of heart transplant candidates with elevated pulmonary vascular resistance.

Metabolism and excretion of nitric oxide in humans. An experimental and clinical study.

Despite the increasing insight in the clinical importance of nitric oxide (NO), formerly known as endothelium-derived relaxing factor (EDRF), there is limited information about the metabolism and elimination of this mediator in humans. We studied the degradation of NO in healthy subjects inhaling 25 ppm for 60 minutes and in patients with severe heart failure inhaling 20, 40, and 80 ppm in consecutive 10-minute periods. In other healthy subjects, the renal clearance of NO metabolite was measured. The metabolism ex vivo was evaluated by direct incubation of nitrite, the NO oxidation product, in blood from healthy humans. During inhalation of NO, the plasma levels of nitrate increased progressively, both in the healthy subjects (from 26 to 38 mumol/L, P < .001) and in the patients (from 72 to 90 mumol/L, P < .001). Methemoglobin (MetHb) also increased in the healthy subjects (from 7 to 13 mumol/L, P < .001) as well as in the patients (from 19 to 42 mumol/L, P < .01). No change in nitrosohemoglobin (HbNO) was detected, either in the healthy subjects or in the patients. In arterialized blood (O2 saturation, 94% to 99%), incubated nitrite was semiquantitatively converted to nitrate and MetHb. In venous blood (O2 saturation, 36% to 85%) moderate amounts of HbNO were also formed. Plasma and urinary clearance of nitrate in healthy subjects averaged 20 mL/min. We conclude that uptake into the red blood cells with subsequent conversion to nitrate and MetHb is a major metabolic pathway for endogenously formed NO. Nitrate may then enter the plasma to be eliminated via the kidneys.(ABSTRACT TRUNCATED AT 250 WORDS)

Central hemodynamics and right ventricular function after coronary artery bypass surgery. A comparison of prostacyclin, sodium nitroprusside, and nitroglycerin for treatment of postcardiac surgical hypertension.

The aim of this study was to compare the effects of prostacyclin on central hemodynamics and right ventricular function to the more widely used vasodilators sodium nitroprusside (SNP) and nitroglycerin (NTG), and to investigate whether prostacyclin is more selective to the pulmonary vascular bed compared to SNP and NTG after coronary artery bypass surgery. Twelve patients with two-vessel or three-vessel coronary artery disease and an ejection fraction > 0.5 were included. Hemodynamic measurements were made postoperatively in the intensive care unit using a pulmonary artery fast-response ejection fraction/volumetric thermodilution catheter. The aim was to control and maintain mean arterial blood pressure around 75 to 80 mmHg with each drug. After a 10-minute infusion of each drug at a stable infusion rate, central hemodynamic variables as well as right ventricular end-diastolic volume (RVEDV), end-systolic volume (RVESV) and ejection fraction (RVEF) were measured or derived in triplicate. The average infusion rates of SNP, NTG, and prostacyclin were 2.3 +/- 0.8 micrograms/kg/min, 12.6 +/- 6.0 micrograms/kg/min and 20.0 +/- 0.5 ng/kg/min, respectively. Cardiac output, stroke volume, RVEDV, and central filling pressures were highest for prostacyclin compared to both NTG and SNP. Systemic vascular resistance (SVR) was lowest for prostacyclin but the effects on pulmonary vascular resistance (PVR) were comparable to that of SNP. The PVR/SVR ratio was significantly lower with both SNP and NTG when compared to prostacyclin. RVEF did not differ among the three drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Pulmonary vasodilation after heart transplantation. A comparison among prostacyclin, sodium nitroprusside, and nitroglycerin on right ventricular function and pulmonary selectivity.

The aim of this study was to compare the effects of prostacyclin on central hemodynamics and right ventricular function to the more widely used vasodilators, sodium nitroprusside and nitroglycerin, and to investigate whether prostacyclin is more selective to the pulmonary vascular bed compared to sodium nitroprusside and nitroglycerin in patients after heart transplantation. Hemodynamic measurements were made after the operation in the intensive care unit with a pulmonary artery fast-response ejection fraction/volumetric thermodilution catheter. The aim was to maintain mean arterial pressure around 70 mm Hg with each drug. After a 10-minute infusion of each drug at a stable infusion rate, central hemodynamic variables and right ventricular end-diastolic volume, end-systolic volume, and ejection fraction were measured or derived in triplicate. The average infusion rates of sodium nitroprusside, nitroglycerin, and prostacyclin were 3.3 +/- 1.7 micrograms/kg/min, 6.6 +/- 1.8 micrograms/kg/min, and 12.4 +/- 1.7 ng/kg/min, respectively. Cardiac output, stroke volume, right ventricular end-diastolic volume, and central filling pressures were highest for prostacyclin compared to both nitroglycerin and sodium nitroprusside. Pulmonary vascular resistance was lower for prostacyclin compared to nitroglycerin but was comparable to that of sodium nitroprusside. Systemic vascular resistance was lowest for prostacyclin compared to both sodium nitroprusside and nitroglycerin. The pulmonary vascular resistance/systemic vascular resistance ratio used as an index of pulmonary selectivity did not differ between the vasodilators. The right ventricular ejection fraction did not differ among the three drugs.(ABSTRACT TRUNCATED AT 250 WORDS)