Hemodynamic effects of inhaled nitric oxide using pulse delivery and continuous delivery systems in pulmonary hypertension

OBJECTIVE: Inhaled nitric oxide (NO) has been used for pulmonary vasodilation therapy in patients with pulmonary hypertension. Inhaled NO for awake and ambulatory patients, however, is unusual because it requires intubation or a tightly fitting facemask, and a large-scale delivery system for the safe management of toxic nitrogen oxides. We undertook this study to investigate the possibility of using inhaled NO therapy for awake and ambulatory patients with pulmonary hypertension. METHODS: Patients with pulmonary hypertension underwent cardiac catheterization and hemodynamic variables were measured at the baseline, after inhaled NO using our pulse delivery system, which involved a nasal cannula and a pulse device, and after inhaled NO using a continuous delivery system. PATIENTS OR MATERIALS: We studied seventeen patients with precapillary pulmonary hypertension (4 men and 13 women; age, 41+/-3, ranging from 19 to 61). RESULTS: Cardiac output was increased significantly by each system. Pulmonary vascular resistance was decreased significantly by each system. There was no significant change in mean pulmonary artery pressure, mean systemic artery pressure, or systemic vascular resistance. The concentrations of NO and nitrogen dioxide (NO2) in the expiratory gas using the pulse delivery system were 0.0 ppm as long as the pulse device was synchronized with the patient's respiratory cycle. CONCLUSION: Inhaled NO using our pulse delivery system changed the hemodynamic variables similarly to those when using the continuous delivery system. The concentrations of NO and NO2 in the expiratory gas using the pulse delivery system were within safe limits.     

Comparison of inhaled nitric oxide versus oxygen on hemodynamics in patients with mitral stenosis and severe pulmonary hypertension after mitral valve surgery

Pulmonary hypertension represents an important cause of morbidity and mortality in patients with mitral stenosis who undergo cardiac surgery, especially in the postoperative period. The aim of this study was to test the hypothesis that inhaled nitric oxide (iNO) would improve the hemodynamic effects and short-term clinical outcomes of patients with mitral stenosis and severe pulmonary hypertension who undergo cardiac surgery in a randomized, controlled study. Twenty-nine patients (4 men, 25 women; mean age 46 ± 2 years) were randomly allocated to receive iNO (n = 14) or oxygen (n = 15) for 48 hours immediately after surgery. Hemodynamic data, the use of vasoactive drugs, duration of stay, and short-term complications were assessed. No differences in baseline characteristics were observed between the groups. After 24 and 48 hours, patients receiving iNO had a significantly greater increase in cardiac index compared to patients receiving oxygen (p <0.0001). Pulmonary vascular resistance was also more significantly reduced in patients receiving iNO versus oxygen (-117 dyne/s/cm(5), 95% confidence interval -34 to -200, vs 40 dyne/s/cm(5), 95% confidence interval -34 to 100, p = 0.005) at 48 hours. Patients in the iNO group used fewer systemic vasoactive drugs (mean 2.1 ± 0.14 vs 2.6 ± 0.16, p = 0.046) and had a shorter intensive care unit stay (median 2 days, interquartile range 0.25, vs median 3 days, interquartile range 7, p = 0.02). In conclusion, iNO immediately after surgery in patients with mitral stenosis and severe pulmonary hypertension improves hemodynamics and may have short-term clinical benefits.     

Hemodynamic effects of sildenafil in patients with congestive heart failure and pulmonary hypertension: combined administration with inhaled nitric oxide

STUDY OBJECTIVES: In patients with pulmonary hypertension (PH) secondary to congestive heart failure, inhaled nitric oxide (NO) increases pulmonary vascular smooth-muscle intracellular cyclic guanosine monophosphate (cGMP) concentration, thereby decreasing pulmonary vascular resistance (PVR) and increasing cardiac index (CI). However, these beneficial effects of inhaled NO are limited in magnitude and duration, at least in part due to cGMP hydrolysis by the type 5 isoform of phosphodiesterase (PDE5). The goal of this study was to determine the acute pulmonary and systemic hemodynamic effects of the selective PDE5 inhibitor, sildenafil, administered alone or in combination with inhaled NO in patients with congestive heart failure and PH. DESIGN: Single center, case series, pharmacohemodynamic study. SETTING: Cardiac catheterization laboratory of a tertiary care academic teaching hospital. PATIENTS: We studied 11 patients with left ventricular systolic dysfunction due to coronary artery disease or idiopathic dilated cardiomyopathy who had PH. INTERVENTIONS: We administered oral sildenafil (50 mg), inhaled NO (80 ppm), and the combination of sildenafil and inhaled NO during right-heart and micromanometer left-heart catheterization. MEASUREMENTS AND RESULTS: Sildenafil administered alone decreased mean pulmonary artery pressure by 12 +/- 5%, PVR by 12 +/- 5%, systemic vascular resistance (SVR) by 13 +/- 6%, and pulmonary capillary wedge pressure by 12 +/- 7%, and increased CI by 14 +/- 5% (all p < 0.05) [+/- SEM]. The combination of inhaled NO and sildenafil decreased PVR by 50 +/- 4%, decreased SVR by 24 +/- 3%, and increased CI by 30 +/- 4% (all p < 0.01). These effects were greater than those observed with either agent alone (p < 0.05). In addition, sildenafil prolonged the pulmonary vasodilator effect of inhaled NO. Administration of sildenafil alone or in combination with inhaled NO did not change systemic arterial pressure or indexes of myocardial systolic or diastolic function. CONCLUSIONS: PDE5 inhibition with sildenafil improves cardiac output by balanced pulmonary and systemic vasodilation, and augments and prolongs the hemodynamic effects of inhaled NO in patients with chronic congestive heart failure and PH.     

One-year continuous inhaled nitric oxide for primary pulmonary hypertension

We describe a case of long-term administration of nitric oxide (NO) in a 32-year-old man who was admitted with exertional dyspnea and anasarca. A diagnosis of primary pulmonary hypertension was made. An acute vasodilator trial with inhaled NO showed a 5% reduction of the mean pulmonary artery pressure. Long-term NO inhalation therapy was initiated. Twenty days later, the dyspnea improved, the anasarca resolved, and the PaO(2) level increased. After 12 months of NO therapy, the patient remained stable and no signs of toxicity or tachyphylaxis were observed. To our knowledge, this is the first report of 1 year of continuously inhaled NO in an adult patient with primary pulmonary hypertension. These findings suggest that prolonged NO therapy might be an effective alternative, at a lower cost, to the continuous IV infusion of epoprostenol.     

Hemodynamic effects of inhaled nitric oxide and phosphodiesterase inhibitor (dipyridamole) on secondary pulmonary hypertension following heart valve surgery in adults

BACKGROUND: Inhaled nitric oxide (iNO) is proposed in the management of pulmonary hypertension (PH) in patients undergoing cardiac surgery. Secondary PH related to a long-standing heart valve disease however may be refractory to iNO. Aim of this prospective study was to determine whether the combination of iNO plus dipyridamole (DP), a cyclic guanosine monophosphate-specific phosphodiesterase inhibitor (PDE5), may enhance and/or prolong the response to iNO in adult patients with secondary valve-related PH undergoing cardiac surgery, and attenuate rebound events related to its discontinuation. METHODS: Responses in 27 patients, 11 male, mean age 72+/-11 years, with PH due to mitral and/or aortic valve disease, were studied in the Intensive Care Unit after cardiac surgery, during sedation and stable hemodynamic conditions. The effect of isolated iNO administration (40 ppm), iNO combined with DP (0.2 mg/kg i.v.), and DP alone (1 mg/kg/24 h) on pulmonary vascular resistance, mean pulmonary artery pressure, cardiac index, mixed venous O2Sat%, and mean arterial pressure were determined. RESULTS: All patients showed at least a 10% decrease in pulmonary vascular resistance vs. baseline after administration of iNO [responders]. Inhaled NO and the combination of iNO/DP produced a reduction of pulmonary vascular resistance and mean pulmonary artery pressure (p<0.05). Cardiac index improved with a significant difference between iNO and the association iNO/DP versus baseline (p<0.05). This significant hemodynamic improvement versus baseline was maintained during isolated DP administration (p<0.05), but not during isolated iNO discontinuation. Mixed venous oxygen saturation showed an overall improvement of 17% (p<0.05). CONCLUSIONS: Inhaled NO and DP infusion might represent a valuable association in the management of PH secondary to a heart valve disease in patients undergoing cardiac surgery. Their beneficial hemodynamic effects might be particularly valuable in the management of patients with associated right ventricular dysfunction.     

Long-term inhaled nitric oxide plus dipyridamole for pulmonary arterial hypertension

Inhaled nitric oxide (iNO) has been shown to be a potent and selective vasodilator in pulmonary arterial hypertension (PAH). However, the clinical experience in prolonged treatment is limited. We assess the safety and effectiveness of long-term administration of iNO in severe PAH. Two female patients were admitted to our hospital because of severe dyspnea (World Health Organization functional class IV) and hypoxemia. They were diagnosed with PAH (primary and secondary to congenital heart disease) and treated with iNO for 2 years. The delivery system consisted of an NO tank of 800 ppm, a modified gas-pulsing device, and nasal cannulas. On iNO treatment the patients showed remarkable improvement of symptoms, oxygenation and 6-min walk distance. After 16 months the patients began to experience a progressive rebound of symptoms. A phosphodiesterase type 5 inhibitor (dipyridamole) was added to iNO. This intervention proved useful in improving clinical deterioration and hemodynamics. This is the first study reporting 2-year iNO therapy in 2 patients with primary and secondary pulmonary hypertension. The combination of dipyridamole with iNO augments the pulmonary vasodilatation and may be useful in managing PAH.     

Hemodynamic effects of inhaled nitric oxide in right ventricular myocardial infarction and cardiogenic shock

OBJECTIVES: We sought to determine whether or not inhaled nitric oxide (NO) could improve hemodynamic function in patients with right ventricular myocardial infarction (RVMI) and cardiogenic shock (CS). BACKGROUND: Inhaled NO is a selective pulmonary vasodilator that can decrease right ventricular afterload. METHODS: Thirteen patients (7 males and 6 females, age 65 +/- 3 years) presenting with electrocardiographic, echocardiographic, and hemodynamic evidence of acute inferior myocardial infarction associated with RVMI and CS were studied. After administration of supplemental oxygen (inspired oxygen fraction [F(i)O(2)] = 1.0), hemodynamic measurements were recorded before, during inhalation of NO (80 ppm at F(i)O(2) = 0.90) for 10 min, and 10 min after NO inhalation was discontinued (F(i)O(2) = 1.0). RESULTS: Breathing NO decreased the mean right atrial pressure by 12 +/- 3%, mean pulmonary arterial pressure by 13 +/- 2%, and pulmonary vascular resistance by 36 +/- 8% (all p < 0.05). Nitric oxide inhalation increased the cardiac index by 24 +/- 11% and the stroke volume index by 23 +/- 12% (p < 0.05). The NO administration did not change systemic arterial or pulmonary capillary wedge pressures. Contrast echocardiography identified three patients with a patent foramen ovale and right-to-left shunt flow while breathing at F(i)O(2) = 1.0. Breathing NO decreased shunt flow by 56 +/- 5% (p < 0.05) and was associated with markedly improved systemic oxygen saturation. CONCLUSIONS: Nitric oxide inhalation results in acute hemodynamic improvement when administered to patients with RVMI and CS.     

The haemodynamic effects of amrinone in patients with mitral stenosis and pulmonary hypertension

The aim of this study was to investigate the haemodynamic effects of amrinone in patients with pulmonary hypertension and impaired right ventricular function. Twelve patients with mitral stenosis (NYHA classification III and IV) took part in the study. The haemodynamic measurements were performed in the steady state under anaesthesia prior to surgery. The patients received a bolus injection of 1.5 mg kg-1 amrinone; haemodynamic measurements were taken at 3, 5, 10, 15, 20 and 30 min. Amrinone increased cardiac index by approximately 30%, heart rate rose from on average 76 to 82 beats per minute. Whereas pulmonary capillary pressure did not change significantly, mean pulmonary artery pressure fell clearly from 33 to 28 mmHg. A decrease in the elevated pulmonary vascular resistance of about 40% was calculated. The higher the initial value for resistance in the pulmonary circulatory system, the more marked was the reduction (r = 0.96). The study shows that amrinone induces a vasodilation in the pulmonary circulatory system. A reduction in ventricular afterload is of great significance particularly for the therapy of right heart insufficiency. Amrinone therefore appears to be a suitable substance with its observed vasodilating and its well known positive inotropic effects for the treatment of right heart failure in cases of pulmonary hypertension.     

Residual pulmonary vasoreactivity to inhaled nitric oxide in patients with severe obstructive pulmonary hypertension and Eisenmenger syndrome

OBJECTIVE—To determine whether inhaled NO (iNO) can reduce pulmonary vascular resistance in adults with congenital heart disease and obstructive pulmonary hypertension or Eisenmenger syndrome.
DESIGN—23 patients received graded doses of iNO. Pulmonary and systemic haemodynamic variables and circulating cyclic guanosine monophosphate (cGMP) concentrations were measured at baseline and after 20 and 80 ppm iNO. Patients were considered responders when total pulmonary resistance was reduced by at least 20%, and rebound was defined as a greater than 10% increase in total pulmonary resistance upon withdrawal from iNO.
RESULTS—In response to 20 ppm iNO, total pulmonary resistance decreased in four patients (18%, 95% confidence interval (CI), 2% to 34%), while in response to 80 ppm iNO it decreased in six patients (29%, 95% CI 10% to 38%). Systemic blood pressure did not change. Withdrawal resulted in rebound in three patients (16%, 95% CI 0% to 32%) after cessation of 20 ppm iNO, and in six patients (35%, 95% CI 12% to 58%) after cessation of 80 ppm iNO. Patients with predominant right to left shunting did not respond. In all patients cGMP increased from (mean (SD)) 28 (13) µmol/l at baseline to 55 (30) and 78 (44) µmol/l after 20 and 80 ppm iNO (p < 0.05 v baseline).
CONCLUSIONS—NO inhalation is safe and is associated with a dose dependent increase in circulating cGMP concentrations. Pulmonary vasodilatation in response to iNO was observed in 29% of patients and was influenced by baseline pulmonary haemodynamics. Responsiveness to acute iNO may identify patients with advanced obstructive pulmonary hypertension and Eisenmenger syndrome who could benefit from sustained vasodilator treatment.


Keywords: nitric oxide; pulmonary hypertension; Eisenmenger syndrome     

Role of closed mitral commissurotomy in mitral stenosis with severe pulmonary hypertension

BACKGROUND AND AIMS OF THE STUDY: Closed mitral commissurotomy (CMC) is a well-established method for treatment of rheumatic mitral stenosis, but outcome in patients with severe pulmonary arterial hypertension (PAH) has not been clearly documented. METHODS: Between April 1996 and October 1999, among 61 patients who underwent CMC, 27 had severe PAH (systolic pressure > 100 mmHg). Of these patients, 11 were in NYHA class III, and 16 were in class IV. Preoperatively, the mean pulmonary artery (PA) pressure was 107.85 +/- 5.74 mmHg (range: 100-118 mmHg), mitral valve area (MVA) 0.704 +/- 0.106 cm2 (range: 0.5-0.91 cm2), and transmitral gradient 11.93 +/- 1.54 mmHg (range: 10-15 mmHg). The echocardiographic mitral valve score was 6.37 +/- 1.11 (range: 6-10). RESULTS: There was no operative mortality or incidence of significant (> or = 2+) post-CMC mitral regurgitation or cerebrovascular accident. The MVA increased to 2.385 +/- 0.248 cm2 (range: 1.9-2.8 cm2), the transmitral gradient fell to 2.44 +/- 0.51 mmHg (range: 2-3 mmHg), and postoperative PA systolic pressure fell to 33.33 +/- 8.20 mmHg (range: 30-60 mmHg). During a mean follow up of 26.9 months (range: 11-51 months), 23 patients were in NYHA class I and four were in class II. There were no significant differences in parameters between sexes, but mean male age was five years less than mean female age. CONCLUSION: In the subset of patients with severe PAH, surgical CMC is a safe and effective procedure that results in greater MVA and a more significant and sustained fall in PA pressure compared with reported series of percutaneous balloon mitral valvuloplasty.     

Hemodynamic response to sildenafil, nitric oxide, and iloprost in primary pulmonary hypertension

STUDY OBJECTIVES: Different vasodilators and different routes of application are used for the treatment of primary pulmonary hypertension (PPH). Recently, sildenafil, a phosphodiesterase-V inhibitor, has been shown to have beneficial hemodynamic effects in PPH. However, the hemodynamic effects of sildenafil have not been characterized and compared to other vasodilators such as inhaled nitric oxide (iNO) or iloprost in PPH in the same group of patients. STUDY DESIGN: We investigated prospectively 10 consecutive patients with PPH using iNO, iloprost aerosol, and oral sildenafil to test acute hemodynamic response during right-heart catheterization. RESULTS: iNO, iloprost aerosol, and sildenafil caused a significant fall of mean pulmonary artery pressure and pulmonary vascular resistance (PVR) [p < 0.05]. Correspondingly, cardiac output and mixed venous saturation increased slightly in all groups. Systemic arterial pressure and vascular resistance were mainly unaltered. Using a PVR reduction of > or =20% to define a significant response, 7 of 10 patients were responders to iloprost aerosol, whereas 4 of 10 patients responded to iNO and oral sildenafil. Improvement of oxygenation as indicated by an increase of arterial oxygen tension was observed with iloprost aerosol (p < 0.01). CONCLUSION: All of the three substances, iNO, iloprost aerosol, and oral sildenafil, significantly improved pulmonary hemodynamics in patients with PPH. The most prominent hemodynamic effects and improvement of oxygenation were observed with iloprost aerosol.     

吸入一氧化氮在肺动脉栓塞术后肺动脉高压的临床应用

目的:评价吸入一氧化氮(nitric oxide,NO)对肺动脉栓塞外科手术治疗后肺动脉高压(pulmonary arterial hypertension,PH)患者的治疗作用。方法:回顾性分析安贞医院2005年1月1日至2011年8月1日,62例接受外科手术治疗的肺动脉栓塞患者临床资料,15例患者在肺动脉栓塞外科手术治疗后仍存在PH时,吸入NO浓度为(10～30)×10-6,记录NO吸入时间、吸入时呼吸功能指标和血流动力学参数。结果:术后平均吸入NO时间(46.3±6.4)h,动脉血氧饱和度(SaO2)、动脉血氧分压(PaO2)、动脉血氧分压与吸入氧浓度比值(PaO2/FiO2)较吸入前改善,平均肺动脉压(mPAP)较吸入前下降(P<0.05)。结论:对于肺动脉栓塞术后PH患者吸入NO,可以改善氧合并降低肺动脉压力。