Monitoring of Levosimendan Administration in Patients with Pulmonary Hypertension Undergoing Cardiac Surgery and Effect of Two Different Dosing Schemes on Hemodynamic and Echocardiographic Parameters.

INTRODUCTION: The perioperative management of patients with pulmonary hypertension (PH) undergoing cardiac surgery represents one of the most challenging clinical scenarios. This fact mainly depends on the relationship existing between PH and right ventricular failure (RVF). Levosimendan (LS) is an inodilator that might be an effective agent in the treatment of PH and RVF. The aim of this study was to examine the impact of the duration of cardiopulmonary bypass (CPB) on the therapeutic drug monitoring of LS and to evaluate the effect of preemptive administration of LS on perioperative hemodynamic and echocardiographic parameters in cardiac surgical patients with preexisting PH. MATERIALS AND METHODS: In this study, LS was administered in adult patients undergoing cardiac surgery before CPB in order to prevent exacerbation of preexisting PH and subsequent right ventricular dysfunction. Thirty cardiac surgical patients with preoperatively confirmed PH were randomized to receive either 6 µg/kg or 12 µg/kg of LS after the induction of anesthesia. The plasma concentration of LS was measured after CPB. In this study, a low sample volume was used combined with a simple sample preparation protocol. The plasma sample was extracted by protein precipitation and evaporated; then, the analyte was reconstituted and detected using specific and sensitive bioanalytical liquid chromatography with mass spectrometry (LC-MS/MS) methodology. The clinical, hemodynamic, and echocardiographic parameters were registered and evaluated before and after the administration of the drug. RESULTS: A fast bioanalytical LC-MS/MS methodology (a run time of 5.5 min) was developed for the simultaneous determination of LS and OR-1896, its main metabolite in human plasma. The LC-MS/MS method was linear over a range of 0.1-50 ng/mL for LS and 1-50 ng/mL for its metabolite OR-1896. Measured plasma concentrations of LS were inversely related to the duration of CPB. LS administration before CPB during cardiac surgery was effective in reducing pulmonary artery pressure and improving hemodynamic parameters after CPB, with a more pronounced and durable effect of the drug at the dose of 12 µg/kg. Additionally, administration of LS at a dose of 12 µg/kg in cardiac surgical patients with PH before CPB improved right ventricular function. CONCLUSION: LS administration decreases pulmonary artery pressure and may improve right ventricular function in patients with PH undergoing cardiac surgery.

A retrospective comparison of inhaled milrinone and iloprost in post-bypass pulmonary hypertension.

During cardiac operations, weaning from cardiopulmonary bypass (CPB) may prove challenging as a result of superimposed acute right ventricular dysfunction in the setting of elevated pulmonary vascular resistance (PVR). The aim of this study was to retrospectively evaluate the effect of inhaled milrinone versus inhaled iloprost in patients with persistent pulmonary hypertension following discontinuation of CPB. Eighteen patients with elevated PVR post-bypass were administered inhaled milrinone at a cumulative dose of 50 µg kg-1. These patients were retrospectively matched with 18 patients who were administered 20 µg of inhaled iloprost. Both drugs were administered through a disposable aerosol-generating jet nebulizer device and inhaled for a 15-min period. Hemodynamic measurements were performed before and after cessation of the inhalation period. Both inhaled milrinone and inhaled iloprost induced significant reductions in mean pulmonary artery pressure and PVR and significant increases in cardiac index in patients with post-CPB pulmonary hypertension. The favorable effect of both agents on the pulmonary vasculature was confirmed by echocardiographic measurements. Both agents were devoid of systemic side effects, since mean arterial pressure and systemic vascular resistance were not affected. A decrease in intrapulmonary shunt by inhalation of both agents was also demonstrated. Pulmonary vasodilatation attributed to iloprost seems to be of greater magnitude and of longer duration as compared to that of inhaled milrinone. Both substances proved to be selective pulmonary vasodilators. The greater magnitude and of longer duration vasodilatation attributed to iloprost may be due to its longer duration of action.

Atrial and brain natriuretic peptide changes in an experimental model of intra-abdominal hypertension.

BACKGROUND: Intra-abdominal hypertension (IAH) can have a profound impact on the cardiovascular system. We hypothesized that natriuretic peptides (Nt-pro-ANP and Nt-pro-BNP) are produced in response to the cardiovascular changes observed in an experimental model of IAH. MATERIALS AND METHODS: Eleven female pigs were enrolled in this study. Four experimental phases were created: a baseline phase for instrumentation (T1); two subsequent phases (T2 and T3), in which helium pneumoperitoneum was established at 20 and 35 mm Hg, respectively; and the final phase (T4), in which abdominal desufflation took place. Hemodynamic parameters and concentrations of Nt-pro-ANP and Nt-pro-BNP were measured. RESULTS: Central venous pressure and pulmonary capillary wedge pressure increased significantly during the elevation of intra-abdominal pressure (IAP) and returned to baseline after abdominal desufflation. Right and left transmural pressures remained unaffected by the elevation of IAP. Cardiac output decreased in phases T2 and T3 and was restored to baseline levels after abdominal desufflation. Systemic and pulmonary vascular resistances increased significantly with IAH and decreased after abdominal desufflation. Nt-pro-ANP did not change significantly in comparison to baseline. Nt-pro-BNP increased significantly in comparison to baseline at T3 and T4. Peak Nt-pro-BNP levels at T3 (peak IAP) correlated positively with indices of afterload at this time point, that is, systemic vascular resistance and pulmonary vascular resistance (r(2) = 0.38, P = 0.042 and r(2) = 0.55, P = 0.009, respectively). A strong negative correlation between Nt-pro-BNP and cardiac output at T3 was also demonstrated (r(2) = 0.58, P = 0.006). CONCLUSIONS: IAH resulted in cardiovascular compromise. The unchanged Nt-pro-ANP concentrations might reflect unaltered atrial stretch with IAH, despite the elevation of right atrial filling pressure. The significant increase of Nt-pro-BNP in response to high levels of IAP may reflect left ventricular strain and dysfunction due to the severe IAH and provide an alternative marker in the monitoring of IAH.

Hemodynamic effects of combination therapy with inhaled nitric oxide and iloprost in patients with pulmonary hypertension and right ventricular dysfunction after high-risk cardiac surgery.

OBJECTIVE: The purpose of this study was to evaluate the hemodynamic effects of inhaled nitric oxide (NO) plus aerosolized iloprost in patients with pulmonary hypertension/right ventricular dysfunction after cardiac surgery. DESIGN: A retrospective study. SETTING: A single center. PARTICIPANTS: Eight consecutive patients with valve disease and postextracorporeal circulation (ECC) pulmonary hypertension/right ventricular dysfunction. INTERVENTION: The continuous inhalation of nitric oxide (10 ppm) and iloprost, 10 µg, in repeated doses. MEASUREMENTS AND MAIN RESULTS: The hemodynamic profile was obtained before inhalation, during the administration of inhaled NO alone (prior and after iloprost), and after the first 2 doses of iloprost. Tricuspid annular velocity and tricuspid annular plane systolic excursion were estimated at baseline and before and after adding iloprost. At the end of the protocol, there were significant decreases in pulmonary vascular resistance (p < 0.001), the mean pulmonary arterial pressure (p < 0.001), and the mean pulmonary artery pressure/mean arterial pressure ratio (p = 0.006). Both tricuspid annular velocity (p < 0.001) and tricuspid annular plane systolic excursion (p < 0.001) increased. The cardiac index (p < 0.001) and venous blood oxygen saturation (p = 0.001) increased throughout the evaluation period. Each iloprost dose was associated with further decreases in pulmonary vascular resistances/pressure. By comparing data at the beginning of inhaled NO with those after the second dose of iloprost, the authors noticed decreases in pulmonary vascular resistances (p = 0.004) and the mean pulmonary artery pressure (p = 0.017) and rises in tricuspid annular velocity (p < 0.001) and tricuspid annular systolic plane systolic excursion (p < 0.001). CONCLUSIONS: Inhaled NO and iloprost significantly reduced pulmonary hypertension and contributed to the improvement in right ventricular function. Inhaled NO and iloprost have additive effects on pulmonary vasculature.

Inhaled nitric oxide plus iloprost in the setting of post-left assist device right heart dysfunction.

BACKGROUND: Pulmonary hypertension and right ventricular (RV) dysfunction may complicate the implantation of a left ventricular assist device (LVAD). We examined whether inhaled vasodilators can sufficiently reduce RV afterload, avoiding the need for temporary RV mechanical support. METHODS: The study includes 7 patients with RV dysfunction after LVAD insertion. Treatment consisted of inotropes, inhaled nitric oxide (10 ppm), and iloprost (10 µg) in repeated doses. Full hemodynamic profile was obtained before inhalation, during administration of inhaled NO alone (before and after iloprost), as well as after the first two doses of inhaled iloprost. Tricuspid annular velocity was estimated at baseline and before and after adding iloprost. RESULTS: There was a statistically significant reduction in pulmonary vascular resistance (PVR), mean pulmonary artery pressure (MPAP), RV systolic pressure, and pulmonary capillary wedge pressure, and a considerable increase in LVAD flow, LV flow rate index, and tricuspid annular velocity at all points of evaluation versus baseline. By the end of the protocol, MPAP/mean systemic arterial pressure, and PVR/systemic vascular resistance ratios were reduced by 0.17±0.03 (95% confidence interval, 0.10 to 0.25, p=0.001) and 0.12±0.025 (95% confidence interval, 0.06 to 0.18; p=0.003), respectively. The tricuspid annular velocity increased by 2.3±0.18 cm/s (95% confidence interval, 1.83 to 2.73 cm/s; p<0.001). Pairwise comparisons before and after iloprost showed an important decrease in PVR (p=0.022), MPAP (p=0.001), pulmonary capillary wedge pressure (p=0.002), and RV systolic pressure (p<0.001), and a rise in tricuspid annular velocity (p=0.008). CONCLUSIONS: Inhaled vasodilators mainly affected the pulmonary vasculature. Combination treatment with inhaled NO and iloprost sufficiently decreased PVR and MPAP on the basis of an additive effect, improved RV function, and avoided the need for RV assist device.

Transcatheter aortic valve implantation: first Greek experience.

INTRODUCTION: Percutaneous aortic valve replacement represents an alternative to conventional open-heart surgery for selected high-risk patients without the need for sternotomy, aortotomy, or cardiopulmonary bypass. We present the first Greek series of transcatheter prosthetic aortic valve implantation procedures, performed in our centre. METHODS: All 12 patients (age 81 +/- 5 years) had severe, symptomatic, calcific aortic stenosis and were judged not to have a reasonable surgical option by a medical team including experienced cardiac surgeons. The patients' mean logistic EuroSCORE was 34 +/- 15% (min 11%, max 61%). Eight (8) of them underwent transfemoral (SAPIEN, Edwards 23 mm valve in 7 and 26 mm in 1 patient) and 4 transapical (26 mm in 2 and 23 mm in 2 patients) prosthetic aortic valve implantation, all in the cardiac catheterisation laboratory under general anaesthesia. RESULTS: The procedural, in-hospital and 2-month (mean follow up 50 days, min 17, max 122 days) mortality was 0%. The length of hospital stay was 8 +/- 2 days (min 5, max 12 days). The aortic valve area increased from 0.64 +/- 0.14 cm2 to 1.83 +/- 0.14 cm2 and the mean pressure gradient decreased from 57 +/- 23 mmHg to 10 +/- 3 mmHg post-implantation (p<0.001 for both). The patients' mean NYHA functional status improved from 2.8 +/- 0.7 to 1.3 +/- 0.5 at follow-up (p<0.001). CONCLUSIONS: Our initial experience with transcatheter prosthetic aortic valve implantation demonstrates that it can be performed safely and with excellent short and mid-term clinical outcomes.

Orthotopic heart transplantation: ten years' clinical experience.

INTRODUCTION: Heart transplantation is the "gold standard" in the treatment of patients with end-stage heart failure who satisfy strict selection criteria. METHODS: We reviewed ten years' clinical experience (1996-2006) from 53 orthotopic transplants in our centre. RESULTS: Low perioperative (3.7%) and long-term (7.5%) mortality rates yielded a 95% survival rate in the first year, 92% at five years, and 70% at ten years--significantly better than the corresponding rates worldwide. In addition, excellent functional recovery was achieved in all transplant recipients. CONCLUSIONS: The strict application of international criteria in the selection of both candidates and donors, together with uninterrupted, multidisciplinary follow up, have made it feasible to perform heart transplantation with excellent results, despite the curiously low number of potential recipients and the shortage of acceptable donor hearts.

Inhaled iloprost controls pulmonary hypertension after cardiopulmonary bypass.

PURPOSE: Severe pulmonary hypertension (PH) is a major cause of right ventricular (RV) dysfunction. Various iv vasodilator modalities have been used with limited results because of lack of pulmonary selectivity. The aim of the present controlled study was to evaluate the efficacy of inhaled iloprost, a synthetic prostacyclin analogue, in patients with elevated pulmonary vascular resistance (PVR) immediately after separation from cardiopulmonary bypass (CPB). METHODS: Twelve patients with persistent PH after discontinuation of CPB were included in the study. In all patients standard hemodynamic monitoring was used. Inhaled iloprost was administered via nebulized aerosol at a cumulative dose of 0.2 micro g*kg(-1) for a total duration of 20 min. Complete sets of hemodynamic measurements were performed before inhalation (baseline), during and after cessation of the inhalation period. Echocardiographic monitoring of RV function was also used. RESULTS: Inhaled iloprost induced a reduction in the transpulmonary gradient at the end of the inhalation period in comparison to baseline (9.33 +/- 3.83 mmHg vs 17.09 +/- 6.41 mmHg, P < 0.05). The mean pulmonary artery pressure to systemic artery pressure ratio decreased over this period (0.28 +/- 0.08 vs 0.45 +/- 0.17, P < 0.05). A statistically significant decrease of the PVR to systemic vascular resistance ratio was also observed (0.15 +/- 0.05 vs 0.21 +/- 0.05, P < 0.05). Improved indices of RV function were observed in echocardiographic monitoring. CONCLUSION: Inhaled iloprost appears to be a selective pulmonary vasodilator and may be effective in the initial treatment of PH and the improvement of RV performance in the perioperative setting.

Cardiac surgery in patients with heparin-induced thrombocytopenia using preoperatively determined dosages of iloprost.

BACKGROUND: Patients with preoperatively diagnosed type II heparin-induced thrombocytopenia (HIT) scheduled for cardiopulmonary bypass (CPB) present a challenge in their intraoperative anticoagulation management because re-exposure to heparin may result in profound thrombocytopenia, intravascular thromboses, bleeding, and even death. Iloprost, a prostacyclin analogue that reversibly inhibits platelet aggregation, has been suggested as a management approach in such cases. The purpose of this study was to assess and confirm the efficacy of a perioperative intravenous iloprost infusion in preventing thromboembolic complications in patients with type II HIT undergoing cardiac surgery and requiring the use of heparin and CPB. METHODS: During a one-and-a-half-year period, 22 patients with type II HIT presented at the Cardiac Surgery Service of the Onassis Cardiac Center in Athens. In these patients, platelet aggregation test results were found strongly positive at heparin serum concentrations corresponding to those achieved during CPB. Iloprost was used in a preoperatively, in vitro-determined, patient-specific concentration that was assessed and modified perioperatively depending on its in vivo effect on platelet aggregation as opposed to the conventional constant rate. RESULTS: In the 22 patients, the preoperatively determined concentration of iloprost seemed to correlate well with the in vivo interruption of platelet aggregation, as tested by a perioperative heparin-induced platelet aggregation (HIPA) assay, and in only 3 cases (14%) was the rate of iloprost infusion increased. The patients' platelet counts, which were evaluated peri- and postoperatively, were preserved with no statistically significant fluctuations. Postoperative bleeding was within normal limits and no thrombotic episodes or other complications were reported. CONCLUSION: Although a number of alternative anticoagulation methods, such as the use of another anticoagulant (danaparoid sodium and recombinant hirudin) or the preoperative use of a defibrinogenating agent (ancorod), have been suggested for patients with type II HIT requiring anticoagulation during CPB, the use of heparin associated with a potent platelet inhibitor such as the prostacyclin analog iloprost is, as this study confirmed, the only to-date safe and effective choice.