Inhaled nitric oxide for pulmonary hypertension after heart transplantation.

BACKGROUND: Recipient pulmonary hypertension due to chronic congestive heart failure is a major cause of right ventricular (RV) dysfunction after heart transplantation. We hypothesized that inhaled nitric oxide (NO), in the postoperative period, would a) selectively reduce pulmonary vascular resistance and improve RV hemodynamics and b) reduce the incidence of RV dysfunction compared with a matched historical group. METHODS: Sixteen consecutive adult heart transplant recipients with lowest mean pulmonary artery (PA) pressures >25 mmHg were prospectively enrolled. Inhaled NO at 20 parts per million (ppm) was initiated before termination of cardiopulmonary bypass (CPB). At 6 and 12 hours after CPB, NO was stopped for 15 minutes and systemic and pulmonary hemodynamics were measured. RV dysfunction was defined as central venous pressure >15 mmHg and consistent echocardiographic findings. The incidence of RV dysfunction and 30-day survival in this group was compared with a historical cohort of 16 patients matched for pulmonary hypertension. RESULTS: Discontinuation of NO for 15 minutes at 6 hours after transplantation resulted in a significant rise in mean PA pressure, pulmonary vascular resistance (PVR), and RV stroke work index. Systemic hemodynamics were not affected by NO therapy. One patient in the NO-treated group, compared with 6 patients in the historical cohort group, developed RV dysfunction (P< .05). The 30-day survival in the NO-treated group and the historical cohort group were 100% and 81%, respectively (P> .05). CONCLUSION: In heart transplant recipients with pulmonary hypertension, inhaled NO in the postoperative period selectively reduces PVR and enhances RV stroke work. Furthermore, NO reduces the incidence of RV dysfunction in this group of patients when compared with a historical cohort matched for pulmonary hypertension. Inhaled NO is a useful adjunct to the postoperative treatment protocol of heart transplant patients with pulmonary hypertension.     

Inhaled nitric oxide reduces pulmonary artery pressures in portopulmonary hypertension.

Pulmonary artery hypertension in association with liver failure (portopulmonary hypertension [PPHTN]) is a significant barrier to liver transplantation because patients with this condition have a very high mortality when transplantation is undertaken. Inhaled nitric oxide (NO), a potent pulmonary vasodilator, reduces pulmonary artery pressure (PAP) in some patients with primary pulmonary hypertension, but its effect in patients with PPHTN is controversial. We investigated the hemodynamic effects of inhaled NO in 6 patients with PPHTN. Five of 6 patients responded to NO inhalation with decreases in PAP and pulmonary vascular resistance of greater than 10%; these decreases were statistically significant at NO concentrations of 10 and 30 ppm. Cardiac output did not significantly change. We conclude that inhalation of NO reduces PAPs in some patients with PPHTN.     

Inhaled nitric oxide in patients with normal and increased pulmonary vascular resistance after cardiac surgery

We studied the haemodynamic effects of inhaled nitric oxide40 p.p.m. in two groups of patients after cardiac surgery (mitralvalve surgery or coronary artery bypass grafting). Nitric oxidecaused a significant reduction in pulmonary vascular resistanceafter mitral valve surgery in patients who had pre-existingpulmonary hypertension, but no change in haemodynamic statein the coronary artery bypass group of patients, who had normalpulmonary arterial pressures.     

Urapidil reduces elevated pulmonary vascular resistance in patients before heart transplantation.

BACKGROUND: Elevated pulmonary vascular resistance is a major limitation for heart transplantation. Urapidil is a centrally and peripherally acting anti-hypertensive drug, able to decrease elevated pulmonary vascular resistance in patients with either chronic obstructive pulmonary disease or heart failure. Urapidil is available as an oral or intravenous drug. In this study, we evaluated the possible beneficial effects of intravenous urapidil in patients with reversible, elevated pulmonary vascular resistance who were scheduled for heart transplantation. METHODS: After approval by the Ethics Committee and written consent, 22 consecutive patients with end-stage heart failure and history of pulmonary vascular resistance >3 Wood units were enrolled into an open, prospective study. Using a (right ventricular ejection fraction) REF-Swan-Ganz catheter, hemodynamics were determined during administration of nitric oxide, and before and after 3 repeated intravenous applications of 10 mg urapidil. The treatment goal was reduction of pulmonary vascular resistance by at least 30%. RESULTS: Twenty-two patients were included to obtain complete data for 14 patients. Eight patients were not treated with urapidil: 7 patients had normal pulmonary vascular resistance at baseline, and 1 patient experienced moderate pulmonary edema before the study began. Two patients did not reach the treatment goal. In patients who responded to urapidil, the following hemodynamic changes were observed: decreased pulmonary vascular resistance (-48%), decreased transpulmonary gradient (20.0 to 13.7 mm Hg), decreased mean pulmonary arterial pressure (40 to 31 mm Hg), decreased systemic vascular resistance (-27%), mean arterial pressure (80 to 72 mm Hg), and increased right heart ejection fraction (21% to 27%). Heart rate remained unchanged. CONCLUSIONS: Intravenous urapidil lowered elevated pulmonary vascular resistance in patients before heart transplantation. In comparison with other vasodilative drugs, the major benefit of urapidil is its oral formulation.     

Inhaled nitric oxide (NO) in the management of severe pulmonary hypertension following open heart surgery

The use of inhaled nitric oxide (NO) in a five-year-old boy following cardiac surgery for a complex lesion is reported. Pulmonary hypertension causing right ventricular failure and severe hypoxaemia was dramatically reversed by 40 ppm NO added to the inhaled gases. The patient eventually died from the results of left ventricular failure.     

Inhaled nitric oxide lowers pulmonary capillary pressure and changes longitudinal distribution of pulmonary vascular resistance in patients with acute lung injury

In acute lung injury (ALI), where pulmonary microvascular permeability is increased, transvascular fluid filtration depends mainly on the hydrostatic capillary pressure. In the presence of intrapulmonary vasoconstriction pulmonary capillary pressure (PCP) may increase thereby promoting transvascular fluid filtration and lung oedema formation. We studied the effect of 40 ppm inhaled nitric oxide (NO) on PCP and longitudinal distribution of pulmonary vascular resistance (PVR) in 18 patients with ALI.
PCP was estimated by visual analysis of the pressure decay profile following pulmonary artery balloon inflation. Contribution of venous pulmonary resistance to total PVR was calculated as the percentage of the pressure gradient in the pulmonary venous system to the total pressure gradient across the lung.
Inhalation of 40 ppm NO produced a prompt decrease in mean pulmonary artery pressure (PAP) from 34.1 6.8 to 29.65.7 (s.d.) mmHg; ( P < 0.0001). PCP declined from 24.86.2 to 21.65.2 mmHg; ( P < 0.0001) while pulmonary artery wedge pressure (PAWP) did not change. PVR decreased from 16673 to 12850 dyn sec cm^-5; ( P < 0.0001). Pulmonary venous resistance (PVRven) decreased to a greater extent (from 7641 to 5028 dyn. sec. cm^-5; ( P < 0.001) than pulmonary arterial resistance (PVRart) (from 9036 to 7929 dyn sec cm^-5; ( P < 0.01). The contribution of PVRven to PVR feU from 44.310.8 to 37.811.9%; ( P < 0.01). Cardiac output (CO) remained constant. The findings demonstrate that NO has a predominant vasodilating effect on pulmonary venous vasculature thereby lowering PCP in patients with ALI.     

吸入伊洛前列素和一氧化氮治疗先天性心脏病术后肺动脉高压

目的 探讨吸入伊洛前列素对先天性心脏病(CHD)术后早期机械通气和持续吸入一氧化氮(NO)的基础上,仍合并肺动脉高压(PH)病儿的疗效及对预后的影响,并初步探讨其作用机制.方法 30例CHD根治手术后在机械通气和持续一氧化氮(NO)吸入的基础上仍合并PAH的病儿,随机分为试验(T)组和对照(C)组.在原治疗基础上,T组给予伊洛前列素100 ng·kg-1·min-1,吸入10 min,C组给予0.9%NaCl 4ml吸入.每4h一次,连续治疗48 h.超声和心电监测观察病儿的血流动力学和呼吸机条件的改变.对比首次吸药前后血浆环磷酸腺苷(cAMP)和环磷酸鸟苷(cGMP)浓度变化.结果 T组停止吸入伊洛前列素后20min,肺动脉收缩压(sPAP)和肺动脉收缩压/主动脉收缩压(sPAP/sBP)明显下降,分别为:(43.23±11.72)mm Hg(1 mm Hg=0.133 kPa)和0.48±0.13,均小于C组(53.13±13.60)mm Hg和0.60 ±0.15,P<0.05.停止吸药120 min,T组sPAP/sBP仍然小于C组(0.48±0.09对0.59±0.14,P<0.05).连续治疗24 h和48 h,T组sPAP和sPAP/sBP继续下降,均明显小于C组(P<0.01).停止首次吸药后20 min,T组cAMP(578.68±193.05)pg/dl较治疗前(406.64±179.18)pg/dl明显升高(P<0.01),也明显大于C组(392.26±94.46)pg/dl(P<0.01).C组2例因肺高压危象(PHC)死亡,T组无死亡.结论 CHD双心室矫正术后早期机械通气和持续吸入NO仍合并PH病儿,吸入伊洛前列素后可明显降低sPAP和sPAP/sBP.伊洛前列素可能减少肺高压危象(PHC)导致的死亡.其扩血管作用可能与血浆cAMP浓度升高有关.     

PGE1与NO对先天性心脏病术后肺动脉高压疗效的对比研究

目的比较静脉应用前列腺素E1(PGE1)和吸入外源性一氧化氮(NO)对先天性心脏病(先心病)术后中重度肺动脉高压的治疗效果.方法对12例术后存在中重度肺动脉高压的先心病病人,进行前瞻性、交叉、随机试验研究.分别应用PGE1(30ngkg-1min-1)、NO(30ppm)、PGE1+NO,检测用药前后心率(HR)、平均动脉压(mSAP)、平均肺动脉压(mPAP)、中心静脉压(CVP)、肺毛细血管嵌压 (PCWP)、心排指数(CI)、肺血管阻力(PVR)和体血管阻力(SVR)等血液动力学参数.同时检测吸入NO前后二氧化氮(NO2)和高铁血红蛋白(MetHb)的浓度.结果 PGE1和NO在降低mPAP和PVR方面均有非常显著的疗效(P＜0.01),但联合应用(PGE1+NO)并未显示出较单纯应用更明显的效果.对mPAP和PVR降低的幅度比较,PGE1和NO之间差异无显著性(P＞0.05).NO对肺血管有更强的选择性,但PGE1在提高CI方面明显优于NO(P＜0.05).吸入NO后,NO2和MetHb的浓度明显高于吸入前(P＜0.01),但仍在正常范围内.结论 PGE1和NO对先心病合并的中重度肺动脉高压均有显著的治疗作用,二者的作用效果相近.考虑到NO的潜在毒性和PGE1在提高心功能方面的良好效果,在临床上首选合适剂量的PGE1更合理可行.     

Inhaled nitric oxide in the preoperative evaluation of pulmonary hypertension in heart transplant candidates

OBJECTIVE: The goal of this study was to evaluate the efficacy of 100% oxygen and inhaled nitric oxide (iNO) in decreasing pulmonary vascular resistance (PVR) and transpulmonary gradient (TPG) in dilated cardiomyopathy patients being evaluated for orthotopic heart transplantation (OHT); who, despite maximal intravenous (IV) dilator therapy, had persistent moderate-to-severe pulmonary hypertension. DESIGN: A prospective nonrandomized clinical study. SETTING: University hospital, major transplant center. PARTICIPANTS: Twenty-one adult patients undergoing OHT evaluation. Interventions: One hundred percent oxygen and iNO at 20 and 40 ppm were sequentially administered to the patients once they were optimized with IV vasodilators and inotropes. MEASUREMENTS AND MAIN RESULTS: Although no significant change was noted with oxygen, iNO 20 ppm reduced the mean pulmonary artery pressure (44.1 +/- 1.7 to 38.6 +/- 1.8 mmHg, p < 0.05), PVR index (823 +/- 47 to 621 +/- 55 dyne/s/m(2)/cm(5), p < 0.05), TPG (22.4 +/- 1.4 to 17.0 +/- 1.5 mmHg, p < 0.05), and right ventricular stroke work index (14.7 +/- 1.2 to 11.1 +/- 1.2 g . m/m(2)/beat, p < 0.05). In 13 of 21 patients, PVR decreased by greater than 25% after iNO therapy. Nine of these patients had PVR and TPG decrease to levels considered acceptable for OHT listing. CONCLUSIONS: iNO can further improve right ventricular hemodynamics even after presumed optimization with IV vasodilators and serves as a test of PVR reversibility during the preoperative assessment of OHT candidates.     

Effects of prostaglandin E1 and hydralazine on the longitudinal distribution of pulmonary vascular resistance during vasoconstrictor pulmonary hypertension in sheep.

Pulmonary capillary pressure (Ppc) is dependent upon left atrial pressure, pulmonary venous resistance, and cardiac output. The effects of pulmonary vasodilators on Ppc will therefore depend upon any alterations in the longitudinal distribution of pulmonary vascular resistance (precapillary [arterial] and postcapillary [venous] components). We therefore studied the effects of two pulmonary vasodilators (prostaglandin E1 and hydralazine) on Ppc and the longitudinal distribution of pulmonary vascular resistance. Pulmonary hypertension was produced in sheep by the continuous administration of the thromboxane A2-mimetic U46619. Ppc was measured by analysis of pulmonary artery occlusion pressure decay curves. U46619 increased Ppc by 9 mmHg and increased both the arterial and venous components of pulmonary vascular resistance. Subsequent administration of prostaglandin E1 decreased Ppc by 5 mmHg and decreased both the arterial and venous components of pulmonary vascular resistance (by 50 and 69% respectively). Hydralazine produced smaller decreases in the arterial and venous components of pulmonary vascular resistance (by 35 and 49% respectively) and did not significantly reduce Ppc. We conclude that prostaglandin E1 but not hydralazine is effective in decreasing Ppc in this experimental model of pulmonary hypertension.     

Inhaled nitric oxide decreases pulmonary soluble guanylate cyclase protein levels in 1-month-old lambs

BACKGROUND: Inhaled nitric oxide produces potent pulmonary vasodilation by activating soluble guanylate cyclase and increasing smooth muscle cell concentrations of cyclic guanosine monophosphate. However, responses are often nonsustained, and clinically significant increases in pulmonary vascular resistance have been noted on its acute withdrawal. In vitro and in vivo data suggest that inhaled nitric oxide decreases endogenous nitric oxide synthase activity. The effects of inhaled nitric oxide on the downstream mediators of the nitric oxide/cyclic guanosine monophosphate cascade, soluble guanylate cyclase and phosphodiesterase 5, have not been investigated. We sought to determine the effects of inhaled nitric oxide on endogenous cyclic guanosine monophosphate levels, soluble guanylate cyclase, and phosphodiesterase 5 protein levels in the intact lamb. METHODS: Eleven 1-month-old lambs were mechanically ventilated. In 7 lambs, inhaled nitric oxide (40 ppm) was administered for 24 hours and then acutely withdrawn. Intermittent lung biopsy samples were obtained for cyclic guanosine monophosphate concentrations and soluble guanylate cyclase and phosphodiesterase 5 protein levels (Western blot analysis). RESULTS: Initiation of nitric oxide decreased left pulmonary vascular resistance by 26.2%, and withdrawal rapidly increased pulmonary vascular resistance by 77.8% (P <.05). Tissue cyclic guanosine monophosphate concentrations initially increased during nitric oxide therapy but were not maintained during the 24-hour exposure. In addition, cyclic guanosine monophosphate concentrations rapidly decreased after nitric oxide withdrawal (P <.05). The alpha soluble guanylate cyclase (-45.7%) and beta soluble guanylate cyclase (-48.4%) protein levels decreased during nitric oxide therapy (P <.05), whereas phosphodiesterase 5 proteins levels were unchanged. CONCLUSIONS: These data suggest a role for decreased soluble guanylate cyclase and its resulting decrease in cyclic guanosine monophosphate concentrations in the nonsustained response to nitric oxide and the rebound pulmonary hypertension noted on its acute withdrawal. Phosphodiesterase 5 inhibitors may be a useful adjunct therapy during inhaled nitric oxide to preserve cyclic guanosine monophosphate levels and thereby preserve nitric oxide responsiveness and prevent rebound pulmonary hypertension.     

Hemodynamic effects of inhaled aerosolized iloprost and inhaled nitric oxide in heart transplant candidates with elevated pulmonary vascular resistance.

OBJECTIVE: An elevated pulmonary vascular resistance (PVR) is described as a predictor of postoperative right heart failure and increased mortality in patients undergoing orthotopic heart transplantation. The use of intravenous vasodilators is limited by their systemic effects. We evaluated the pulmonary and systemic hemodynamic effects of inhaled nitric oxide (NO) and inhaled aerosolized iloprost (IP) in heart transplant candidates with elevated PVR. METHODS: Fourteen male heart transplant candidates due to dilative or ischemic cardiomyopathia with elevated PVR (> or = 180 dyn s cm(-5)) were included in the study. Increasing concentrations of NO (5, 10 and 30 ppm) and 50 microg aerosolized IP were administered by inhalation. Hemodynamic measurements preceded and followed administration of each agent. RESULTS: Inhalation of IP, 10, and 30 ppm NO reduced PVR and mean pulmonary artery pressure (MPAP), but did not affect blood pressure or systemic vascular resistance. Comparing the effectiveness of 10 ppm NO and IP, we found a significant higher reduction of MPAP in patients treated with IP. An increase of cardiac index and stroke index could only be shown with IP-inhalation. CONCLUSIONS: Inhaled iloprost induces pulmonary vasodilation which is significantly greater than the effects of 10 and 30 ppm NO. The results of our study show, that inhaled iloprost induces a reliable hemodynamic response in the evaluation of heart transplant candidates. Further advantages of iloprost inhalation are the lack of adverse reactions and toxic side effects and an easier administration. Due to this facts we recommend iloprost as a routine screening drug for vascular reactivity in HTx-candidates. Based on our results it would be of great interest to investigate the role of iloprost in management of postoperative right heart insufficiency following cardiac transplantation.     

Inhaled nitric oxide improves survival rates during hypoxia in a sickle cell (SAD) mouse model

BACKGROUND: The hallmark of sickle cell disease (SCD) is erythrocyte sickling during deoxygenation of the abnormal hemoglobin S (HbS). When HbS is deoxygenated, it aggregates into polymers, resulting in distortion of the erythrocyte structure, producing microvascular thrombosis and ischemia. The transgenic SAD mouse produces three types of human hemoglobin: S, Antilles, and D-Punjab (HbSAD) and provides an animal model for SCD. We studied the effects of nitric oxide (NO) breathing at various doses and time regimens in the presence of severe hypoxia (6% oxygen) using the SAD mouse model. METHODS: Age- and sex-matched control and SAD mice were exposed to 6% oxygen breathing in an environmental chamber and assessed for survival up to 1 h. Animals received different inhaled NO concentrations before and/or during hypoxia. Blood was obtained to evaluate the oxyhemoglobin dissociation curve and measure methemoglobinemia. RESULTS: Pretreatment by breathing NO at 20 ppm by volume in air for 30 min, and continuing to breathe 20 ppm NO during hypoxia resulted in improvement in survival rates in the SAD mouse (75%, n = 8) as compared with control SAD mice (11%, n = 9; P < 0.001). Pretreatment alone or breathing lower doses of NO were not protective. Changes in HbSAD oxygen affinity were not detected with NO breathing, and methemoglobin levels were low in all surviving mice. CONCLUSIONS: Breathing NO produced a rapid, protective effect to severe hypoxic stress in SAD mice. There appears to be a required loading period between NO breathing and its beneficial effect during hypoxic stress, possibly because of the total amount of NO delivered to SAD hemoglobin, blood cell components, and endothelium. NO breathing may be beneficial as a therapeutic intervention in SCD.     

Bridging to heart transplantation: prostaglandin E1 versus prostacyclin versus dobutamine.

BACKGROUND: Prostaglandin E1 (PGE1) and prostacyclin have potent pulmonary and systemic vasodilating properties. This prospective, randomized trial compared PGE1 vs prostacyclin vs. low-dose dobutamine in patients with low-output heart failure awaiting heart transplantation (HTx) who were refractory to oral treatment. METHODS: Patients in advanced heart failure in New York Heart Association (NYHA) Class IV, with a cardiac index < or = 2.5 L/minute/m2 and a pulmonary capillary wedge pressure > or = 20 mmHg, who were listed for HTx were studied. In an inpatient study phase of 12 hours duration, therapy was aimed to increase cardiac output by 20% or more, when compared to baseline values, and to achieve a reduction of pulmonary vascular resistance below 550 dyn.s/cm-5m-2. During a long-term outpatient phase, the drugs were continuously infused to bridge these patients to HTx using three combined negative endpoints (worsening heart failure, serious adverse events, death) for analysis. RESULTS: Sixty-eight patients were enrolled, 30 patients on PGE1, 8 patients on prostacyclin, and 30 patients on dobutamine. During the inpatient study phase, maximum doses were 22 +/- 1.8 ng/kg/minute for PGE1, 7 +/- 1 ng/kg/minute for prostacyclin and 5 +/- 0.4 micrograms/kg/minute for dobutamine. During the inpatient study phase 21 patients failed, 4/30 (13%) patients on PGE1, 4/8 patients on prostacyclin (50%), and 13/30 (43%) on dobutamine (p < 0.05). Long-term continuous intravenous drug infusion in outpatients was begun in 26 patients on PGE1, in 4 patients on prostacyclin, and in 17 patients on dobutamine. Infusion therapy lasted for 88 +/- 14 days in the PGE1 group with 31 +/- 22 days in the prostacyclin group, and 30 +/- 8 days in the dobutamine group (NS). During the outpatient phase 23 patients reached a negative endpoint with 16 patients developing worsening heart failure, 5 severe adverse events and 2 deaths. Seven out of 26 (27%) failed on PGE1, 4/4 (100%) failed on prostacyclin, and 12/17 (71%) failed on dobutamine (p < 0.05, log rank test). Because prostacyclin treatment was ineffective in the first 8 patients, this trial arm was stopped prematurely. CONCLUSIONS: The findings from this prospective open pilot trial suggest that continuous PGE1 infusions at individualized dosages can be useful in certain patients as a pharmacologic bridging procedure with reduced risk to develop worsening heart failure before HTx compared to prostacyclin and dobutamine. Further comparative studies are warranted to investigate the effects of PGE1 among other bridging agents.     

Pulmonary vascular resistance in neonatal swine: response to right pulmonary artery occlusion, isoproterenol, and prostaglandin E1

The pulmonary physiological response of adults to unilateral pulmonary artery (PA) occlusion has been well-characterized as resulting in a decrease in the pulmonary vascular resistance (PVR), in order to maintain the same PA pressure and accommodate the entire cardiac output (CO). We evaluated the response of the neonate to unilateral PA occlusion and how this response is altered by infusions of Isoproterenol (Isuprel) and prostaglandin E1 (PGE1) in the neonatal swine model. Twenty farm piglets (five at 1 day, three at 5 days, seven at 14 days, and five at 60 days as controls) underwent left lateral thoracotomy and measurement of PA and left atrial (LA) pressures, CO, and PVR with the right PA open and occluded. To determine if neonatal PVR could be influenced by a vasodilator (indicating the vascular capacity is not fixed) or by an inotrope (indicating the lung is not maximally recruited) this experiment was then repeated with infusions of PGE1 (a vasodilator) at doses of 0.1, 0.5, and 1.0 micrograms/kg/min and subsequently with Isuprel (an inotrope and vasodilator) at doses of 0.1, 0.5, 1.0 micrograms/kg/min. Control measurements taken without unilateral PA occlusion showed that PVR is high at 1 day of age but progressively decreases to a level 89% lower by 60 days of age. The vascular capacity of the neonatal lung is fixed and responds to unilateral PA occlusion with a dramatic increase in PVR. This response cannot be altered by either a vasodilator (PGE1) or an inotrope (Isuprel) thereby limiting the utility of these drugs in treating neonatal pulmonary hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)