西地那非与前列腺素E1治疗猪肺动脉高压

目的 比较西地那非和前列腺素E1对幼猪肺动脉高压模型的影响。方法 体质量约5kg实验用健康幼猪24只，用经气管内吸入胎粪法诱发幼猪产生肺动脉高压，2h后建立急性缺氧性肺动脉高压模型。随机将幼猪分成4组：对照组，不给予任何药物治疗;西地那非组，静脉注射枸橼酸西地那非（2mg/kg）、前列腺素E1组，持续静脉滴注前列腺素E120ng/（kg·min）至实验结束;合用组同时给予西地那非组和前列腺素E1。结果 吸入胎粪2h后，记录动物的肺动脉压、肺血管阻力（pulmonary vascular resistance，PVR）和体循环血管阻力（systemic vascular resistance，SVR）。发现肺动脉压、PVR和PVR/SVR均随时间明显增加。施加药物干预以后，西地那非组与合用组的上述指标均明显迅速下降，并且心输出量和心脏指数明显提高;前列腺素E1组肺动脉压、PVR以及PVR/SVR下降程度不如西地那非组明显，心输出量、心脏指数无改善;对照组的肺动脉压、PVR以及PVR/SVR无下降。结论 西地那非降低肺动脉压和肺血管阻力，改善心功能，同时对体循环血流动力学无不良影响;在本实验用量，西地那非扩张肺血管和降低肺血管阻力的作用比前列腺素E1强;两者联合应用没有发生协同降低肺动脉压作用。     

Intravenous sildenafil as an effective treatment of pulmonary hypertensive crises during acute intestinal malabsorption

Oral sildenafil has been demonstrated to be an effective treatment for pulmonary hypertension, and is increasingly used in children. We report an infant with pulmonary hypertension, stable on regular treatment with oral sildenafil, who presented in acute respiratory failure after aspiration, requiring ventilation and intensive care. The course of the stay in intensive care was difficult, with recurrent pulmonary hypertensive crises despite use of oral sildenafil, use of 100% oxygen, high frequency oscillatory ventilation, and inhaled nitric oxide. In view of his instability, and the presumed inability to absorb the sildenafil orally due to gastrointestinal malabsorption, sildenafil was administered as a continuous intravenous infusion. With this therapy, it proved possible to wean from oxygen, nitric oxide, and ventilatory support. Intravenous sildenafil, therefore, might be an effective alternative for children with pulmonary hypertension during episodes of acute deterioration and malabsorption, preventing life-threatening pulmonary hypertensive crises. Its pharmacokinetics, efficacy, and safety, nonetheless, need to be validated in randomized controlled trials.     

Beneficial effect of sildenafil following surgery for mitral stenosis complicated by pre-capillary pulmonary hypertension: report of two cases

Pulmonary hypertension is a serious disorder, difficult to treat especially in the severe forms. The treatment consists mainly of calcium channel blockers, anti-coagulation, intravenous epoprostenol, inhaled nitric oxide and recent agents as bosentan and sildenafil. Sildenafil, a phosphodiesterase 5 specific inhibitor, has been largely evaluated in primary pulmonary hypertension, and in some cases of secondary pulmonary hypertension including parenchymal and thromboembolic diseases; it has not yet been evaluated in severe pulmonary hypertension with elevated pre-capillary resistance in operated mitral stenosis. We report the cases of two patients operated from mitral valve replacement for severe mitral stenosis with elevated pre-capillary resistance, where oral sildenafil, introduced empirically immediately after the surgical procedure at the dose of 50 mg/d, permitted a significant decrease in pulmonary pressures and resistances, allowing a rapid withdrawal of nitric oxide and reducing therefore hospitalization time in the intensive care unit. We think that this simple treatment, with or without association to nitric oxide, should be generalized to persistent pulmonary hypertension following cardiac surgery.     

Pulmonary hemodynamic responses to brain natriuretic peptide and sildenafil in patients with pulmonary arterial hypertension

STUDY OBJECTIVES: Brain natriuretic peptide (BNP) blunts hypoxic pulmonary hypertension in animal models, but its acute hemodynamic effects in patients with pulmonary arterial hypertension (PAH) are not known. The aim of this study was to determine if human B-type natriuretic peptide is a safe and efficacious pulmonary vasodilator in patients with PAH and if the pulmonary hemodynamic effects are potentiated by phosphodiesterase inhibition. DESIGN: Open-label study. SETTING: Medical ICUs of three tertiary care hospitals in New England. PATIENTS: Thirteen consecutive adult patients undergoing right-heart catheterization and a pulmonary vasodilator trial for the initial evaluation of PAH. INTERVENTIONS: Patients were administered inhaled nitric oxide (iNO), i.v. epoprostenol, and a 3-h infusion of BNP alone and 1 h after an oral dose of the phosphodiesterase-5 inhibitor sildenafil. RESULTS: iNO and sildenafil alone decreased mean pulmonary artery pressure (mPAP) without a significant fall in pulmonary vascular resistance (PVR). Epoprostenol decreased both mPAP and PVR. BNP alone had no significant effect on pulmonary hemodynamics, but the combination of sildenafil plus BNP decreased mPAP and PVR for up to 6 h after stopping BNP. The decrease in mPAP with sildenafil plus BNP (+/- SE) was greater than after 1 h of sildenafil alone (44.6 +/- 3.8 to 40.6 +/- 3.9 mm Hg, p = 0.027). An acute vasodilator response, defined as a decrease in mPAP > 10 mm Hg and end mPAP < 40 mm Hg, was seen in 0 of 8 patients with iNO, 1 of 13 patients with epoprostenol, 0 of 13 patients with BNP, and 4 of 12 patients with sildenafil plus BNP. BNP decreased mean systemic arterial pressure (5.6 +/- 2.8 mm Hg) but had no effect on cardiac output or systemic vascular resistance. CONCLUSIONS: A 3-h BNP infusion does not significantly improve pulmonary hemodynamics in most patients with PAH but is well tolerated and augments the acute pulmonary vasodilator effect of sildenafil.     

应用体外膜肺氧合技术治疗胎粪吸入综合征一例及文献复习

目的探讨应用体外膜肺氧合技术（extracorporeal membrane oxygenation,ECMO）救治重症新生儿胎粪吸入综合征的治疗方法。方法报告1例应用ECMO救治重症新生儿胎粪吸入综合征的过程,并进行文献复习。结果患儿病情危重,经使用肺表面活性物质、高频振荡辅助通气及一氧化氮吸入等治疗后效果欠佳,后予ECMO治疗有效。最终治愈出院。结论对于危重症胎粪吸入综合征患儿可适当放宽ECMO治疗指征,及早予ECMO治疗。但需注意术中及术后感染、神经系统损害等相关并发症。     

Acute effects of sildenafil in patients with primary pulmonary hypertension receiving epoprostenol

Epoprostenol therapy has improved survival in primary pulmonary hypertension; however, only two thirds of patients are alive 3 years after starting treatment. Combined therapy with sildenafil, a phosphodiesterase 5 inhibitor, may provide additional benefit. The authors prospectively evaluated the acute hemodynamic and biochemical effects of sildenafil and inhaled nitric oxide, alone and in combination, in 8 patients with primary pulmonary hypertension receiving chronic epoprostenol. Average duration of epoprostenol therapy was 2.9 +/- 1.6 years (mean +/- SD) and mean dose was 25.7 +/- 10.8 ng/kg/min. A single 50 mg dose of sildenafil decreased mean pulmonary arterial pressure 10% (P<.05), increased cardiac output 8%, and decreased pulmonary vascular resistance 24% (P<.005). Although nitric oxide led to a similar decrease in mean pulmonary arterial pressure of 10% (P<.05), cardiac output was unchanged, resulting in a decrease in pulmonary vascular resistance of only 13%, which was not statistically different from baseline. These results suggest that sildenafil has greater acute hemodynamic effects than nitric oxide and that it can further reduce pulmonary vascular resistance in patients already demonstrating a benefit from chronic epoprostenol.     

Inhaled nitric oxide. A selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction

Background. The gas nitric oxide (NO) is an important endothelium-derived relaxing factor, inactivated by rapid combination with heme in hemoglobin. Methods and Results. Awake spontaneously breathing lambs inhaled 5-80 ppm NO with an acutely constricted pulmonary circulation due to either infusion of the stable thromboxane endoperoxide analogue U46619 or breathing a hypoxic gas mixture. Within 3 minutes after adding 40 ppm NO or more to inspired gas, pulmonary hypertension was reversed. Systemic vasodilation did not occur. Pulmonary hypertension resumed within 3-6 minutes of ceasing NO inhalation. During U46619 infusion pulmonary vasodilation was maintained up to 1 hour without tolerance. In the normal lamb, NO inhalation produced no hemodynamic changes. Breathing 80 ppm NO for 3 hours did not increase either methemoglobin or extravascular lung water levels nor modify lung histology compared with control lambs. Conclusions. Low dose inhaled NO (5-80 ppm) is a selective pulmonary vasodilator reversing both hypoxia- and thromboxane-induced pulmonary hypertension in the awake lamb [corrected].     

Inhaled nitric oxide improves oxygenation in piglets with meconium aspiration

We hypothesized that nitric oxide (NO) inhalation in a model of meconium aspiration in newborn piglets would decrease pulmonary vascular resistance. Seven neonatal piglets were obtained at less than 48 hr of age and instrumented under fentanyl anesthesia. Inhaled NO (40 parts per million) was administered during normoxia and again after hypoxia was induced by reducing FiO, to 0.13. During normoxia NO inhalation caused a fall in pulmonary artery pressure from a mean of 3.15 (SD 0.8) kPa to 2.84 (SD 0.7) kPa (P < 0.01). Hypoxia (mean arterial 0, saturation 35%) increased PA pressures to a mean of 5.4 (SD 1.6) kPa and NO administration during hypoxia decreased PA pressures to 3.6 (SD 1.2) kPa (P < 0.001). In order to determine the effects of NO in a model of meconium aspiration, 6 to 7 mUkg of 20% human meconium in normal saline was instilled into the trachea. This procedure induced hypoxemia (mean SaO, 43.4%, SD 19), respiratory acidosis, (mean PaCO, 12.1 kPa, SD 0.5; mean pH 7.04, SD 0.03), and pulmonary arterial hypertension (mean pulmonary artery pressure 6.0 kPa, SD 1.3) despite ventilation with 90% oxygen. Inhaled NO was then administered in concentrations of 5, 10, 20, 30, 40, 60, and 80 parts per million in random order according to a Latin square design. After meconium instillation, NO inhalation led to significant increases in mean arterial saturation of between 18 and 24 percentage points at all doses, and to statistically significant decreases in pulmonary arterial pressure (from 6.0 kPa, SD 1.3 to 5.1 kPa, SD 1.5, P < 0.01) and pulmonary vascular resistance index (from 0.033 kPa/mL/min/kg, SD 0.003 to 0.029 kPa/mL/min/kg, SD 0.003, P < 0.01). Systemic blood pressure, cardiac index and systemic vascular resistance index did not change. The ratio between pulmonary and systemic vascular resistances fell, therefore, from a mean of 0.54 (SD 0.18) to 0.46 (SD 0.14). The effects of NO inhalation after meconium aspiration were qualitatively different to the effects during aveolar hypoxia, in that there was a lesser fall in the PAP and PVR1 and a significant increase in SaO₂. These results suggest that inhaled NO may be beneficial in meconium aspiration syndrome in human neo-nates, improving oxygenation by decreasing extrapulmonary shunting and by improving ventilationiperfusion ratios. Pediatr Pulmonol. 1995; 20:27–33 . © 1995 Wiley-Liss, Inc.     

Pulmonary thromboembolism superimposed on a congenital ventricular septal defect in a 50-year-old man inhaled nitric oxide and sildenafil to the rescue

We report the combined use of inhaled nitric oxide (iNO) and sildenafil to selectively lower pulmonary vascular resistance (PVR) and reverse right-to-left shunt flow across a congenital ventricular septal defect (VSD) in a 50-year-old man. The patient developed right-to-left shunt flow with profound hypoxia because of an acute pulmonary embolism superimposed on underlying pulmonary hypertension. The dramatic improvement in oxygenation and PVR with sildenafil plus iNO has been sustained with sildenafil monotherapy. To our knowledge, use of this combination therapy in patients with decompensated pulmonary arterial hypertension (PAH) and a predisposition to right-to-left shunting has not been previously reported.     

Inhaled Rho kinase inhibitors are potent and selective vasodilators in rat pulmonary hypertension

We have found in chronically hypoxic rats that acute intravenous administration of the Rho kinase inhibitor Y-27632 nearly normalizes the pulmonary hypertension (PH) but has no pulmonary vascular selectivity. In this study, we tested if oral or inhaled Y-27632 would be an effective and selective pulmonary vasodilator in hypoxic PH. Although acute oral Y-27632 caused a marked and sustained decrease in mean pulmonary arterial pressure (MPAP), it also decreased mean systemic arterial pressure (MSAP). In contrast, 5 minutes of inhaled Y-27632 decreased MPAP without reducing MSAP. The hypotensive effect of inhaled Y-27632 on hypoxic PH was greater than that of inhaled nitric oxide, and the effect lasted for at least 5 hours. Inhaled fasudil, another Rho kinase inhibitor, caused selective MPAP reductions in monocrotaline-induced PH and in spontaneous PH in fawn-hooded rats, as well as in chronically hypoxic rats. These results suggested that inhaled Y-27632 was more effective than inhaled nitric oxide as a selective pulmonary vasodilator in hypoxic PH, and that Rho kinase-mediated vasoconstriction was also involved in the other models of PH. Inhaled Rho kinase inhibitors might be useful for acute vasodilator testing in patients with PH, and future work should evaluate their efficacy in the long-term treatment of PH.     

Acute effects of the combination of sildenafil and inhaled treprostinil on haemodynamics and gas exchange in pulmonary hypertension

BACKGROUND: Inhaled treprostinil was recently developed for the treatment of pulmonary arterial hypertension (PAH). We investigated the safety and acute haemodynamic effects of the combination oral sildenafil and inhaled treprostinil in an open label study in patients with precapillary pulmonary hypertension. METHODS AND PATIENTS: Inhaled nitric oxide (20ppm; n=50), sildenafil (50mg; n=50) and inhaled treprostinil (15mug; n=25 or 30mug; n=25) were applied in subsequent order during right heart catheter investigation to consecutive patients with pulmonary arterial hypertension (PAH; n=28), non-operable chronic thromboembolic pulmonary hypertension (CTEPH; n=17) and pulmonary fibrosis associated pulmonary hypertension (n=5). RESULTS: Inhaled nitric oxide reduced pulmonary vascular resistance (PVR) to 87.3+/-5.1% of baseline values, reduced mean pulmonary arterial pressure (PAP) to 89.7+/-3.5% and increased cardiac output (CO) to 102.4+/-2.9%. Sildenafil reduced PVR to 80.1+/-5.0%, mPAP to 86.5+/-2.9% and increased CO to 103.8+/-3.2%. Treprostinil, inhaled 1h after sildenafil, reduced PVR to 66.3+/-3.8%, mPAP to 77.8+/-3.3%, and increased CO to 107.1+/-3.3% (mean+/-95% confidence interval). Subgroup analysis showed similar acute haemodynamic effects in PAH and CTEPH patients. Ventilation/perfusion distribution measurement in six patients with pre-existing gas exchange limitations was not changed by sildenafil and treprostinil. Relevant side effects were not observed. CONCLUSION: The combination of sildenafil and inhaled treprostinil was well tolerated and induced additive, pulmonary selective vasodilatation in pulmonary hypertension patients. This could be of relevance also for long-term treatment of PAH and CTEPH patients.     

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.     

Hypoxia-induced pulmonary hypertension: different impact of iloprost, sildenafil, and nitric oxide

OBJECTIVES: Chronic alveolar hypoxia induces pulmonary hypertension, evident from elevated pulmonary artery pressure (PAP), pulmonary vascular resistance, right ventricular hypertrophy (RVH), and increased muscularization of the pulmonary vasculature. Additionally, the vasoconstrictor response to acute hypoxia (HPV) may be reduced in the remodeled vasculature. However, no direct comparison of different treatments on the various parameters characterizing pulmonary hypertension has been performed yet. Against this background, we compared the effects of inhaled NO, infused iloprost, a stable prostacyclin analogue, and oral sildenafil, a phosphodiesterase 5 inhibitor, on hypoxia-induced pulmonary hypertension. METHODS: Exposure of rabbits to chronic hypoxia (FiO(2)=0.10) for 42 days. Treatment with infused iloprost, oral sildenafil, and inhaled nitric oxide. RESULTS: We quantified PAP, pulmonary vascular resistance, RVH, vascular remodeling, vasoreactivity, and the strength of HPV. Chronic hypoxia resulted in an increase in (a) the right ventricle/(left ventricle+septum) ratio from 0.26+/-0.01 to 0.44+/-0.01, (b) PAP, and (c) the degree of muscularization from 14.0+/-4.0% to 43.5+/-5.3%. Treatment with iloprost and sildenafil, but not with NO, prevented the increase in muscularization. In contrast, RVH was strongly inhibited by sildenafil, whereas NO had some minor, and iloprost had no effect. Only iloprost reduced PAP compared to NO and sildenafil. The downregulation of HPV was abrogated only by NO. CONCLUSION: We demonstrated (a) that the parameters characterizing hypoxia-induced pulmonary hypertension are not functionally linked, (b) that the downregulation of HPV under chronic hypoxia can be prevented by inhaled NO but not by sildenafil and iloprost, and (c) that iloprost is particularly effective in preventing vascular remodeling and sildenafil in preventing RVH.     

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.     

Meconium aspiration induces a concentration-dependent pulmonary hypertensive response in newborn piglets

To investigate the effects of aspirating different meconium concentrations on the pulmonary circulation in 10- to 12-day-old piglets, 30 catheterized animals were studied. The piglets received an intratracheal bolus of 3 ml/kg of a mixture of human meconium in saline with concentrations of 20 mg/ml (light, n = 7), 40 mg/ml (moderate, n = 6), or 65 mg/ml (thick, n = 10) meconium in saline. Control piglets (n = 7) received 3 ml/kg of intratracheal saline. Pulmonary and systemic pressures were measured and vascular resistances calculated at baseline and serially for 4 hours after instillation. Four of the piglets died early and were excluded from the study. In addition, 23 samples of human meconium-stained amniotic fluid were collected at delivery for determination of their meconium concentration. After an initial rise in pulmonary artery pressure and vascular resistance after meconium and saline instillation, pulmonary artery pressure and resistance increased progressively and concentration-dependently in the meconium groups, but returned to baseline in the control group. The saline and meconium-induced initial increases, and the subsequent meconium-stimulated progressive rise in vascular resistance occurred mainly in the postarterial segment. There were no significant changes in systemic hemodynamics. Mean airway pressure increased and oxygenation deteriorated after meconium instillation. The impairment of oxygenation depended on the meconium concentration in the instilled bolus and persisted throughout the study after moderate and thick meconium instillation. Similarly, the intrapulmonary shunt fraction increased initially and remained elevated in the moderate and thick meconium groups. Meconium concentrations in the human amniotic fluid samples were in the same range as concentrations used in the present experimental study. These results indicate that aspirated meconium at concentrations found in light to moderate meconium-stained human amniotic fluid has significant effects on pulmonary hemodynamic and oxygenation in newborn piglets. Pediatr. Pulmonol. 1998; 25:107–113. © 1998 Wiley-Liss, Inc.     

Acute and chronic effects of sildenafil in patients with pulmonary arterial hypertension

Sildenafil and inhaled nitric oxide (iNO) relax smooth muscle by inhibiting the degradation and stimulating the production of cyclic guanosine monophosphate, respectively. We compared the acute pulmonary vasodilator effects of sildenafil, iNO, and epoprostenol and asked whether the combination of iNO with sildenafil had additive pulmonary vasodilator effects. We assessed the effects of extended use of sildenafil in a small cohort of patients. Twenty patients with pulmonary arterial hypertension underwent an acute vasodilator trial with sildenafil (all patients), iNO and iNO plus sildenafil (11), and epoprostenol (19). We also provided sildenafil to patients who were ineligible for, or had clinical deterioration on epoprostenol, treprostinil, or bosentan. Mean+/-se pulmonary artery pressure dropped by 13+/-3%, 19+/-4%, 14+/-3%, and 26+/-4% with epoprostenol, iNO, sildenafil, and iNO+sildenafil, respectively. Cardiac index increased with epoprostenol and sildenafil. A correlation was found between the effects of iNO and epoprostenol. Nine out of ten patients who were started on long-term sildenafil treatment alone or in combination with other vasodilators had symptomatic improvement. Three died of right heart failure. In conclusion, sildenafil is a potent acute pulmonary vasodilator, an effect that is potentiated by combination with iNO. Long-term therapy of pulmonary hypertension with sildenafil alone or in combination with other agents appears to be safe and well tolerated.     

枸橼酸西地那非治疗心脏手术后肺动脉高压的临床研究

目的研究枸橼酸西地那非对心脏手术后重度肺动脉高压的影响。方法自2002年9月至2005年1月共使用枸橼酸西地那非治疗心脏手术后重度肺动脉高压共27例,其中10例小儿,17例成人。男17例,女10例,年龄1～63岁(平均37岁),体重6～67kg(平均40kg)。所有病例均在术前行超声心动图检查确诊为重度肺动脉高压。27例患者中14例先天性心脏病,其中9例为室间隔缺损;1例为右室双出口;1例为房间隔缺损;1例为完全性肺静脉异位引流;1例为动脉导管未闭;1例为三房心。上述先心病患者均行心内畸形矫治术。另外13例为风湿性心脏病,其中11例重度二尖瓣狭窄,2例重度二尖瓣关闭不全,13例患者均合并有三尖瓣关闭不全,均行二尖瓣人工瓣膜置换术、三尖瓣整形术;其中2例合并有主动脉瓣病变同期行主动脉瓣人工瓣膜置换术,1例因合并有冠心病同期行冠状动脉旁路移植术。所有病例术后均予持续镇静和镇痛,保持适度的过度通气,维持轻度呼碱状态,同时积极地纠正各种水、电解质紊乱及代谢性酸中毒。给予多巴胺3～10μg.kg-1.min-1,米力农0.5μg.kg-1.min-1强心治疗,NO吸入(10～70)×10-6及前列腺素E1(PGE1)10～40ng.kg-1.min-1维持肺血管扩张,降低肺动脉压力。经上述处理后,27例患者术后72小时内尚反复出现肺动脉压升高,血氧饱和度、血氧分压下降,肺氧合功能下降,其中7例患者出现肺动脉高压危象。给予高浓度吸氧,增加NO吸入浓度及PGE1用量,肺动脉压仍无明显下降,肺氧合功能无进一步改善,即给予枸橼酸西地那非(辉瑞制药公司,商品名万艾可),1～2mg/kg,每8小时一次。观察患者肺动脉压、动脉血压、血氧饱和度、动脉氧分压、动脉二氧化碳分压、吸氧浓度、NO吸入浓度的变化。结果服用枸橼酸西地那非1小时以后,25例患者血氧饱和度、血氧分压渐上升,肺动脉压开始下降,体循环血压稳定或稍增高。1～2天后,吸氧浓度下降,渐降低或停用NO吸入,以及减量使用PGE1,肺动脉压基本稳定,无进一步上升,肺氧合功能改善,并顺利停用呼吸机。使用枸橼酸西地那非期间无一例患者再次出现肺动脉高压危象,血流动力学平稳。25例患者顺利出院,2例患者因术后低心排综合征而出现多器官功能衰竭死亡。结论枸橼酸西地那非是一种新型的、高选择性降低心脏手术后严重肺动脉高压的药物。     

Acute effects of nebulised epoprostenol in pulmonary hypertension due to systemic sclerosis.

Pulmonary hypertension often has a lethal outcome in systemic sclerosis and the treatment is challenging. Epoprostenol is a potent pulmonary vasodilator and its efficacy has been demonstrated when delivered by the intravenous and aerosolized routes. We report the haemodynamic and functional benefits of epoprostenol administered by inhalation to a spontaneously breathing patient with partially reversible pulmonary hypertension due to systemic sclerosis. Aerosolized epoprostenol, equivalent to the maximum tolerated intravenous dose (31.2 micrograms), produced a 58% fall in pulmonary vascular resistance, increased the cardiac output by 42% and improved functional performance by one MET (3.5 ml kg-1 min-1 of oxygen uptake) without any significant side-effects. Selective distribution of epoprostenol by the inhaled route may offer a new strategy for treatment of pulmonary hypertension.     

Effect of inhaled nitric oxide on raised pulmonary vascular resistance in children with congenital heart disease.

OBJECTIVE--To study the short-term effects of inhaled nitric oxide in infants and young children with congenital heart disease. SETTING--A supraregional referral centre for children with congenital heart disease. PATIENTS AND METHODS--22 infants and children aged 3-32 months (median age 5 months) with congenital heart disease undergoing preoperative cardiac catheterisation. All but one infant had intracardiac shunt lesions and 13 had increased pulmonary vascular resistance. During catheterisation the patients inhaled nitric oxide in a concentration of 40 parts per million in room air. Pulmonary and systemic haemodynamic variables were evaluated by means of measured oxygen consumption and the Fick principle before and after 10 minutes' exposure to nitric oxide. RESULTS--Inhaled nitric oxide did not affect the systemic circulation. There was a significant reduction in the pulmonary vascular resistance, but only in the 13 infants with pulmonary hypertension, in whom pulmonary vascular resistance was reduced by 34% from 8.6 (4.6) mm Hg.min.m2.l-1 (mean (SD)) to 5.7 (3.5) mm Hg.min.m2.l-1. The pulmonary circulation in infants with normal pulmonary vascular resistance was not affected. No statistically significant increase in methaemoglobin was seen, though there were large individual differences. No other side effects were seen. CONCLUSION--The present study shows that in infants with congenital heart disease inhaled nitric oxide reduced pathologically increased pulmonary vascular resistance without affecting systemic circulation and without important side effects with brief exposure.     

Inhaled iloprost is a potent acute pulmonary vasodilator in HIV-related severe pulmonary hypertension.

As antiretroviral therapy has improved life expectancy in human immunodeficiency virus (HIV) infection, the life-limiting complication of HIV-related pulmonary hypertension has come into focus. Inhalation of the stable prostacyclin analogue iloprost is an effective treatment for various forms of precapillary pulmonary hypertension. The main objective of the present study was to evaluate the safety and efficacy of inhaled iloprost in HIV-related pulmonary hypertension. In eight patients with severe pulmonary hypertension related to HIV infection, right heart and femoral artery catheterisation were performed. The acute effect of oxygen, inhaled nitric oxide and aerosolised iloprost was investigated. Four patients underwent long-term treatment with inhaled iloprost. The rank order of pulmonary vasodilatory potency was iloprost>NO>O2, with a maximum reduction (mean +/- SEM) in pulmonary vascular resistance of 30.6 +/- 3.1% (p < 0.001), 5.9 +/- 3.9% and -0.6 +/- 3.9%, respectively. Concomitantly, inhaled iloprost significantly increased the cardiac index and central venous oxygen saturation. Chronic treatment with inhaled iloprost tended to improve the 6 min walking distance and decreased pulmonary vascular resistance in all patients (although not significantly). No serious adverse events and no major interactions with the ongoing antiretroviral therapy were noted. In conclusion, inhaled iloprost is a potent pulmonary vasodilator in human immune deficiency virus-related pulmonary hypertension. Future studies are warranted to confirm the encouraging long-term beneficial results observed in the present limited number of patients.