Risk assessment in pulmonary arterial hypertension: Insights from the GRIPHON study.

BACKGROUND: Approaches to risk assessment in pulmonary arterial hypertension (PAH) include the noninvasive French risk assessment approach (number of low-risk criteria based on the European Society of Cardiology and European Respiratory Society guidelines) and Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) 2.0 risk calculator. The prognostic and predictive value of these methods for morbidity/mortality was evaluated in the predominantly prevalent population of GRIPHON, the largest randomized controlled trial in PAH. METHODS: GRIPHON randomized 1,156 patients with PAH to selexipag or placebo. Post-hoc analyses were performed on the primary composite end-point of morbidity/mortality by the number of low-risk criteria (World Health Organization functional class I-II; 6-minute walk distance >440 m; N-terminal pro-brain natriuretic peptide <300 ng/liter) and REVEAL 2.0 risk category. Hazard ratios and 95% confidence intervals were calculated using Cox proportional hazard models. RESULTS: Both the number of low-risk criteria and the REVEAL 2.0 risk category were prognostic for morbidity/mortality at baseline and any time-point during the study. Patients with 3 low-risk criteria at baseline had a 94% reduced risk of morbidity/mortality compared to patients with 0 low-risk criteria and were all categorized as low-risk by REVEAL 2.0. The treatment effect of selexipag on morbidity/mortality was consistent irrespective of the number of low-risk criteria or the REVEAL 2.0 risk category at any time-point during the study. Selexipag-treated patients were more likely to increase their number of low-risk criteria from baseline to week 26 than placebo-treated patients (odds ratio 1.69, p = 0.0002); similar results were observed for REVEAL 2.0 risk score. CONCLUSIONS: These results support the association between risk profile and long-term outcome and suggest that selexipag treatment may improve risk profile.

Totally Implantable IV Treprostinil Therapy in Pulmonary Hypertension Assessment of the Implantation Procedure.

BACKGROUND: Prostacyclins improve symptoms and survival in pulmonary arterial hypertension (PAH). In response to risks associated with external delivery systems, an implantable IV infusion system was developed. A multicenter, prospective, single-arm, clinical trial (DelIVery for PAH) was conducted to evaluate this system for treprostinil in PAH. This analysis describes the findings related to the implant procedure. METHODS: Patients (N = 64) with PAH (World Health Organization group 1) receiving stable IV treprostinil were enrolled. Patients were transitioned to a temporary peripheral IV infusion catheter prior to the procedure. System implantation was performed at 10 centers under general anesthesia or deep IV sedation by clinicians from various specialties. Central venous access was via the cephalic, subclavian, jugular, or axillary vein. Using an introducer and fluoroscopic guidance, the distal tip of the infusion catheter was placed at the superior caval-atrial junction. The catheter was tunneled from the venous access site to an abdominal subcutaneous pocket, where the pump was placed. RESULTS: Of the 64 patients enrolled, four exited prior to implantation. All 60 implant procedures were successful. At baseline, all patients were receiving treprostinil via an external pump at a mean dose of 71.4 ± 27.8 ng/kg/min (range: 22-142 ng/kg/min). The implant averaged 102 ± 32 min (range: 47-184 min). Clinically significant implant procedure-related complications included one pneumothorax, two infections, and one episode of atrial fibrillation. There were three postimplantation catheter dislocations in two patients. Common implant-related events that were not complications included implant site pain (83%) and bruising (17%). CONCLUSIONS: The procedure for inserting a fully implantable system for treprostinil was successfully performed, with few complications. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01321073; URL: www.clinicaltrials.gov.

Pilot assessment of the response of several pulmonary hemodynamic variables to sublingual sildenafil in candidates for heart transplantation.

OBJECTIVE: To determine the acute vasodilator effect of sublingual sildenafil in heart transplant candidates with severe pulmonary hypertension due to severe left ventricular dysfunction (LVD). BACKGROUND: Pulmonary hypertension confers an increased risk of early graft failure. PATIENTS AND METHODS: Seven patients, (mean age of 53+/-8) with severe LVD (mean EF: 19+/-1.7%, functional class III-IV) due to coronary artery disease, dilated cardiomyopathy and valvulopathy were evaluated for heart transplant. All patients presented a mean transpulmonary gradient >12 mmHg and pulmonary vascular resistances >2.5 W.U., despite full treatment for advanced heart failure. The following hemodynamic data were obtained at basal state and then 15, 30 and 45 min after administration of 100 mg of sublingual sildenafil: right atrial, mean pulmonary artery pressure (mPAP), mean pulmonary capillary wedge pressures, mean transpulmonary gradient (mTPG), blood pressure, cardiac output, pulmonary vascular resistances (PVR) and systemic vascular resistances. Sublingual sildenafil was given without changing the previous treatment of heart failure. RESULTS: After 30 min of sublingual sildenafil, mPAP decreased from 37 (28-61) to 30 (16-42) mmHg and PVR decreased from 5.2 (1.9-13.8) to 2.5 (1.4-3.9) W.U. after 45 min. Mean TPG decreased from 19 (16-33) to 12 (8-14) mmHg at 45 min. Mean pulmonary capillary wedge pressure, cardiac output, systemic vascular resistances and mean blood pressure were unchanged. Sublingual sildenafil was well tolerated, with only transient facial flushing in 4 patients and mild headache in 2. CONCLUSIONS: Based on this initial study, sublingual sildenafil may be a useful alternative drug to perform acute vasodilator test in heart transplant candidates with significant pulmonary hypertension due to severe LVD. Nevertheless, further studies are warranted to confirm our results.

The use of milrinone in pre-transplant assessment of patients with congestive heart failure and pulmonary hypertension.

BACKGROUND: Pulmonary hypertension in patients with congestive heart failure (CHF) is a risk factor for increased mortality after orthotopic cardiac transplantation. Reversibility of elevated pulmonary vascular resistance (PVR) by pharmacologic agents predicts improved outcomes. Milrinone, a phosphodiesterase inhibitor with vasodilating and positive inotropic properties, has been shown to lower PVR in one previous study. However, no study has documented outcomes after cardiac transplantation in patients in whom reversibility of pulmonary hypertension was demonstrated after administration of milrinone. METHODS: We retrospectively reviewed 19 patients with CHF and pulmonary hypertension defined as PVR > or = 3 Wood units, PVRI (pulmonary vascular resistance index) > or = 4 resistance units, or TPG (transpulmonary gradient = mean pulmonary artery pressure--mean capillary wedge pressure) > or = 12 mmHg being assessed for cardiac transplantation. A sub-group of 14 patients with severe pulmonary hypertension defined as PVR > or = 4, PVRI > or = 6 and TPG > or = 15 was also examined. Milrinone was administered as a bolus (50 ug/kg) and hemodynamic parameters were measured at 5, 10 and 15 minutes. Six patients received cardiac transplants. RESULTS: Administration of milrinone significantly lowered PVR, PVRI, mean pulmonary artery pressure (PAM)(all p = 0.002) and pulmonary capillary wedge pressure (PCWP)(p = 0.006). Cardiac output (CO) increased significantly (p = 0.001). TPG did not change (p = 0.33). In patients with severe pulmonary hypertension, the magnitude of these changes was greater. In addition, TPG was significantly lowered (p = 0.02). CONCLUSION: Milrinone lowered PVR by decreasing PAM and increasing CO significantly. In addition, PCWP was significantly lowered. These finding confirm both vasodilatory and inotropic effects of milrinone. Patients with severe pulmonary hypertension had more pronounced effects. There were no deaths in the group of patients proceeding to cardiac transplantation. Our study demonstrates the efficacy of milrinone in lowering PVR as well as suggesting safety in use in patients undergoing cardiac transplantation.

Evaluation of right ventricular function by assessment of cardiac efficiency: influence of induction of anaesthesia in coronary artery bypass grafting patients.

Considering the heart as a physical pump cardiac efficiency is calculated from the ratio of cardiac work performed to the maximum level of energy of the heart. The aim of the study was to compare cardiac efficiency with cardiac output and right ventricular ejection fraction. Nine patients scheduled for coronary artery bypass grafting were investigated. A femoral arterial and a right ventricular ejection fraction pulmonary artery catheter were placed in the awake state. Anaesthesia was induced with eltanolone and fentanyl. Cardiac output, pulmonary artery and central venous pressures, and right ventricular ejection fraction were measured in the awake state (baseline), 2 min after induction of anaesthesia and 1 and 5 min after intubation. Cardiac efficiency was calculated by dividing the stroke work by the maximum energy of the heart as calculated from the pressure volume diagram. An analysis of variance was carried out for cardiac efficiency, cardiac output and right ventricular ejection fraction. Cardiac efficiency was significantly (p < 0.05) reduced 1 min after intubation from 28 +/- 11 to 14 +/- 5%. In contrast the right ventricular ejection fraction (from 48 +/- 10 to 35 +/- 13%) and cardiac output (from 6.5 +/- 1.5 to 5.3 +/- 1.2 L/min) did not change significantly during the induction of anaesthesia. Cardiac efficiency was found to be a more sensitive parameter to describe changes in the right ventricular function than the ejection fraction and cardiac output during induction of anaesthesia with eltanolone and fentanyl which was used as a model to vary cardiac performance and afterload.

The effects of loading changes on intraoperative Doppler assessment of mitral regurgitation.

Anesthetic agents may significantly alter the patient's blood pressure, and thus affect the intraoperative assessment of mitral regurgitation. This study examined the impact of an increase in afterload on a variety of parameters thought to reflect the severity of mitral regurgitation, and related them to changes in hemodynamic parameters. Twenty-four patients with mitral regurgitation undergoing cardiac surgery were studied. Following the induction of anesthesia, color-flow mapping of the entire left atrium was performed, and pulmonary vein flow was then measured. Phenylephrine was administered to increase the patients' blood pressures to their preoperative values, and the assessment was repeated. Regurgitant jet area increased 56% (482 +/- 405 v 750 +/- 440 mm2 P < 0.001), and there were significant reductions in systolic pulmonary venous velocity (0.33 +/- 0.17 v 0.18 +/- .31 m/s P < .01) with increases in diastolic flow (0.43 +/- 12 v 0.58 +/- 0.18 m/s P < .001). These changes in pulmonary venous flow were not related to the changes in the driving force across the incompetent mitral valve. Also, an additional six patients developed systolic flow reversal after phenylephrine administration. Intraoperative hemodynamic variations can significantly alter the apparent severity of mitral regurgitation, and this factor must be considered during decision making.

Effect of prostaglandin E1 on myocardial contractility in dogs anesthetized with halothane: load-independent and noninvasive assessment using transesophageal echocardiography.

The presence of an inotropic action of prostaglandin E1 (PGE1) in vivo is controversial, and there are conflicting results obtained by various indices of myocardial contractility. In this study, a direct effect of PGE1 on contractility was investigated in dogs by use of a load-independent contractile index: left ventricular end-systolic wall stress (LVESWS) versus the velocity of circumferential fiber shortening with rate-corrected (Vcfc) relationship using transesophageal echocardiography (TEE). Hemodynamics, arterial blood gas, and TEE data were obtained before PGE1 infusion (control), and with a 10%, 20%, and 30% decrease in mean arterial pressure (MAP) following intravenous PGE1 administration. PGE1 infusion rates were 0.19 +/- 0.03 at 10%, 0.82 +/- 0.17 at 20%, and 2.32 +/- 0.36 micrograms/kg/min at a 30% decrease in MAP. Pulmonary capillary wedge pressure, systemic vascular resistance index, and left ventricular stroke work index significantly decreased, and heart rate, cardiac index, and stroke volume index were not significantly altered. Analysis of the TEE data showed LVESWS (index of afterload) significantly decreased from 92.0 +/- 11.2 g/cm2 to 72.7 +/- 7.8 at 10%, 59.3 +/- 7.8 at 20%, and 44.6 +/- 6.2 at a 30% decrease in MAP, and Vcfc significantly increased from 0.595 +/- 0.065 circ/sec of control value to 0.670 +/- 0.056 at 10%, 0.824 +/- 0.049 at 20%, and 0.939 +/- 0.070 at a 30% decrease in MAP. In the LVESWS versus Vcfc relationship, no significant difference could be detected between the control state and the 10%, 20%, and 30% decrease in MAP, and no inotropic effect was found.(ABSTRACT TRUNCATED AT 250 WORDS)

Dextran administration avoids hemodynamic changes following paracentesis in cirrhotic patients. A safe and inexpensive option.

Paracentesis associated with albumin administration has been shown to be a safe and useful procedure in the treatment of patients with cirrhosis and ascites. Given the high cost of albumin, 20 patients with cirrhosis and ascites were treated in an open study, with daily paracentesis using dextran 70, an inexpensive volume expander, instead of albumin. In the first 10 patients, hemodynamic evaluation was performed in basal conditions, after each paracentesis (5 liter), and after dextran infusion. Twelve hours after each paracentesis without expansion, a significant drop in pulmonary capillary wedge pressure from 9.5 +/- 1.0 to 7.1 +/- 1.7 (P less than 0.01) and a reduction in cardiac output from 6.6 +/- 1.0 to 5.0 +/- 1.9 (NS) were observed. Moreover, the hematocrit rose significantly from 36.8 +/- 5.6 to 39.2 +/- 4.8 (P less than 0.01). These parameters returned to baseline values after the administration of 84 +/- 14 ml of dextran 70 for each 1000 ml of ascites removed. The other 10 patients received dextran 70 simultaneously with the paracentesis without hemodynamic control. No significant changes in renal and hepatic functions were observed at the end of the study. The mean volume of ascites removed was 12.3 +/- 4.6 liter. Two patients developed hyponatremia that required no treatment. No patient developed renal failure. One patient died because of gastrointestinal bleeding.(ABSTRACT TRUNCATED AT 250 WORDS)

Dynamic arm exercise during cardiac catheterization in the assessment of stenotic valvular disease.

Assessment of hemodynamic responses during some form of exertion or stress during cardiac catheterization is useful among patients suspected of having valvular stenosis who demonstrate normal or borderline valve gradients at rest. Leg raising exercise and drug administration are commonly used for this purpose, but each has inherent limitations. To evaluate the usefulness of dynamic arm raising exercise as a means of altering hemodynamics during cardiac catheterization, 23 such patients were studied. Measurements obtained during arm raising exercise were compared with those at rest. Heart rate rose by 34 +/- 4 beats/min (p less than 0.001), while cardiac output increased by 1.4 +/- 0.2 l/min (p less than 0.001). Stroke volume decreased slightly, although left ventricular filling pressures and pulmonary capillary wedge pressures rose in nearly all subjects. The change in valvular gradients was variable. These data were compared with those obtained in 11 similar patients receiving either dopamine or isoproterenol as an intervention. The changes in heart rate and cardiac output from the resting state were similar between the groups, with fewer side effects occurring during arm exercise. Dynamic arm exercise is a safe and effective maneuver which can be performed during cardiac catheterization in patients undergoing diagnostic evaluation of stenotic valvular disease.

Assessment of the inotropic and vasodilator effects of amrinone versus isoproterenol.

The hemodynamic effects of graded-dose infusions of amrinone (maximal dose 30 micrograms/kg/min) (10 patients) and isoproterenol (maximum dose 4 micrograms/min) (11 patients) were assessed in patients with a range of left ventricular (LV) function. LV ejection fraction ranged from 0.13 to 0.77 (mean +/- standard deviation 0.47 +/- 0.23) among the patients who received amrinone and from 0.24 to 0.77 (mean 0.52 +/- 0.18) among those who received isoproterenol. Peak-dose amrinone produced a reduction in LV filling pressure (from 15 +/- 10 to 10 +/- 7 mm Hg, p less than 0.001), but no significant change in heart rate, cardiac output, mean aortic pressure, total systemic vascular resistance (TSVR) or LV dP/dt max. In contrast, peak-dose isoproterenol produced a similar reduction in LV filling pressure (from 17 +/- 12 to 13 +/- 13 mm Hg, p less than 0.05), but also caused increases in heart rate, cardiac output and LV dP/dt max and decreases in mean aortic pressure and TSVR (p less than 0.001). The absolute change in cardiac output and stroke volume correlated closely with the change in TSVR in response to amrinone (r = -0.90, p less than 0.001 and r = -0.84, p = 0.002, respectively), but not in response to isoproterenol. Although isoproterenol produced a marked increase in cardiac output and LV dP/dt max (not explained by heart rate changes alone) in all patients, amrinone produced an increase in cardiac output only in those with markedly elevated LV filling pressures (who had a reduction in TSVR), and an increase in LV dP/dt in a minority.