第六届世界肺高血压会议:聚焦肺高血压定义与诊断分类更新

第六届世界肺高血压会议对肺高血压(pulmonary hypertension, PH)的定义和诊断分类进行了修订和更新。PH的血流动力学定义维持不变, 将毛细血管前性PH定义更新为:肺动脉平均压＞20 mm Hg、肺动脉楔压 < 15 mm Hg且肺血管阻力> 3 WU。诊断分类更新包括:增加急性肺血管扩张试验阳性肺动脉高压(pulmonary arterial hypertension, PAH)亚类, 将甲基苯丙胺(冰毒)和达沙替尼致PAH作用由可能升级为肯定, 将肺静脉闭塞病/肺毛细血管瘤病由特殊的1'更新为PAH的一个亚类, 将脾切除术后和甲状腺疾病从PH诊断分类中移除等。本次PH定义和诊断分类更新将为临床实践提供重要指导意义。     

Pulmonary Hypertension: Evaluation and Management

Pulmonary hypertension (PH) is a hemodynamic state characterized by elevation in the mean pulmonary arterial pressure and pulmonary vascular resistance leading to right ventricular failure and premature death. PH can be the result of a variety of diseases of different etiologies. Pulmonary arterial hypertension (PAH) should be distinctly differentiated from pulmonary venous hypertension (PVH) as a result of left heart disease. PAH is commonly caused by or associated with an underlying pulmonary, cardiac, or systemic disease (APAH). In the absence of an identifiable etiology or associated underlying disease, PAH is referred to as idiopathic (IPAH). IPAH, formerly known as primary pulmonary hypertension (PPH), is a rare disease most commonly seen in women of childbearing age. Presenting symptoms and signs are nonspecific and include dyspnea on exertion, fatigue, and a loud pulmonary component of the second heart sound. Transthoracic Doppler echocardiography is an excellent noninvasive test to detect the presence of pulmonary hypertension, although every patient should receive a right heart catheterization to confirm the diagnosis. A detailed work up, including laboratory tests and imaging studies, is also indicated to rule out known causes of pulmonary hypertension. Several targeted treatment options have become available in recent years and include parenteral and inhaled prostanoids, oral endothelin receptor antagonists, and oral phosphodiesterase type-5 inhibitors. As a result of their complex care, patients should be referred to centers with expertise in pulmonary hypertension.     

Canine biventricular performance during acute progressive pulmonary microembolization: Regional myocardial perfusion and fatty acid uptake

The cardiac output during acute pulmonary artery hypertension (PAH) may be compromised by right ventricular (RV) outflow obstruction, myocardial ischemia, or adverse ventricular interactions. To study the relative contributions of these mechanisms to impaired biventricular function during PAH, we injected 75 to 105-μm glass beads into the pulmonary vasculature of 11 dogs and correlated the hemodynamic alterations with changes in biventricular function. Biventricular ejection fractions and interventricular septal motion were evaluated by gated blood pool angiocardiograms. Regional myocardial blood flow (n = 8 dogs) was measured with microspheres, and regional myocardial fatty acid metabolism during PAH (n = 8 dogs) was assessed by measuring the regional myocardial extraction of the radioiodinated fatty acid analog, 15-(p-iodophenyl)-3-methylpentadecanoic acid (3m-PIP/PDA). Following microembolization, the mean pulmonary artery pressure increased from 14 ± 1 to 48 ± 2 mm Hg (P < .001) and cardiac output decreased from 3.5 ± 0.3 to 2.6 ± 0.3 1 /min (P < .05). Right ventricular volume increased and RV ejection fraction decreased progressively. Abnormal septal motion during PAH occurred in 5 of 11 dogs and was associated with decreased LV diastolic compliance. Right ventricular myocardial blood flow remained increased during PAH while the regional extraction of 3m-PIP/PDA was uniform throughout the heart. These findings suggest that during moderate PAH the canine cardiac output is limited by RV outflow obstruction and decreased LV diastolic compliance rather than by ischemia.     

Pulmonary hypertension: a review of pathophysiology and anesthetic management

Pulmonary hypertension is a condition that can result in serious complications in patients undergoing any type of anesthesia during the perioperative period. By definition, pulmonary artery hypertension is caused by a persistent rise in mean pulmonary artery pressure ≥25 mm Hg with Pulmonary capillary wedge pressure ≤ 15 mm Hg or exercise mean pulmonary artery pressure ≥35 mm Hg and pulmonary vascular resistance ≥ 3 wood unit's. The severity of the complications depends on the severity of the underlying condition, other comorbidities, and type of procedure, anesthetic technique, and anesthetic drugs. In this article, we briefly review the pulmonary vascular physiology, pathophysiology of the disease, clinical assessment and diagnosis, treatment options, and the anesthetic management of these patients.     

Update on pulmonary arterial hypertension pharmacotherapy

Pulmonary artery hypertension (PAH) refers to several subgroups of disease in which the mean pulmonary artery pressure (mPAP) is elevated to more than 25 mm Hg, pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg, and an elevated pulmonary vascular resistance (PVR) > 3 Wood units as confirmed by right heart catheterization. The prevalence and geographic distribution of PAH vary depending on the type and etiology of the disease. Despite enormous efforts in the research and development of therapeutic agents in the last twenty years, the disease remains relatively incurable and the overall prognosis remains guarded. Median survival for an untreated patient is 2.8 years. In the last three decades, there have been dramatic advances in understanding the molecular mechanisms and signaling pathways involved in the disease, resulting in emerging new treatment strategies. In the following pages, we will review currently approved treatments for PAH, as well as a new generation of investigational drugs.     

Current recommendations on diagnosis and treatment of pulmonary arterial hypertension

Pulmonary hypertension is a rather frequent pathophysiological and hemodynamic condition detectable in many clinical situations including pulmonary and cardiac diseases. Pulmonary arterial hypertension (pAH) is a specific clinical group of severe and rare diseases with similar morphological, hemodynamic and therapeutic characteristics. PAH diagnosis is confirmed by catheterization of the right heart. Special pharmacotherapy has been developed of late for PAH-oriented treatment. PAH is a progressive disease and therefore demands continuous monitoring and escalation of pharmacotherapy if therapeutic targets fail to be achieved with monotherapy. Combined treatment of PAH seems to be optimal now.     

Managing pulmonary hypertension in heart transplantation: meeting the challenge

The most common measurements of pulmonary hypertension include systolic and mean pulmonary artery pressures, PVR, and transpulmonary gradient. Pulmonary artery pressures greater than 50 mm Hg, PVR greater than 6 Woods units, and transpulmonary gradient greater than 15 mm Hg that are unresponsive to optimal vasodilators are contraindications to orthotopic heart transplantation. Therapies used to reduce PVR in the cardiac catheterization laboratory include high-flow oxygen; sublingual nitroglycerin; and intravenous inotropic agents, vasodilators, and selective pulmonary vasodilators. Systemic hypotension may be an undesirable side effect of vasodilators. Inhaled agents such as nitric oxide and prostacyclin are specific to the pulmonary vasculature and reduce PVR without causing systemic hypotension. All pharmacological therapies used to optimize pulmonary hemodynamics before transplantation can be used during transplantation in patients who are at high risk for acute right ventricular failure and death after orthotopic heart transplantation because of elevated pulmonary hemodynamic values. Use of larger donor hearts for patients with elevated PVR and referral for heart-lung transplantation are potential treatment options. A heterotopic heart transplantation might also be attempted. However, because of the poor success with heterotopic transplantation, other options such as treatment with inhaled pulmonary vasodilators show much more promise and are associated with long-term survival after transplantation. Finally, nursing knowledge and implementation of transplantation protocols are essential for continued assessment and management of candidates for heart transplantation who are cared for in the intensive care or coronary care unit.     

Potts分流术治疗顽固性肺动脉高压:历史与展望

肺动脉高压是继发于先天性心脏病、肺血管病变、肺栓塞或因特发性疾病导致的以肺动脉压力升高为特点的疾病.充分靶向药物降压治疗下仍进展的顽固性肺动脉高压需手术干预,传统的肺移植或心肺联合移植手术面临供体有限、配型困难、免疫排斥等诸多问题.在此背景下,以建立心外体肺分流、缓解致命性右心衰竭为目的的Potts分流术逐渐复兴,但其...     

Lessons from oncology to understand and treat pulmonary hypertension

Pulmonary artery hypertension (PAH) is now considered to be a proliferative disorder characterised by unexplained proliferation of pulmonary artery smooth muscle cells (PA-SMCs) and pulmonary artery endothelial cells (PA-ECs). An abnormal phenotype of PA-SMCs and PA-ECs has been described in PAH and some analogies now appear between pulmonary vascular cells from patients with PAH and cancer cells. Such analogies are discussed here with respect to essential hallmarks of cancer cells and with the hope that new treatments targeted at one or more of these cancer cell abnormalities may be appropriate for PAH.     

Pathophysiology of non-cardiogenic pulmonary hypertension

The pathophysiology of non cardiogenic pulmonary hypertension consists mainly of pulmonary vascular changes and alveolar hypoxia. Pulmonary vascular changes might have different etiologies. First the vessel itself with local thrombosis, embolic obstruction, vasoconstriction and endothelial cell dysfunction with intimal proliferation. Secondly parenchymal changes with secondary vascular affection could contribute to pulmonary hypertension. The mechanism of hypoxic pulmonary vasoconstriction is unknown, a direct interaction of oxygen with the smooth muscle cell is possible. The interaction of activated circulating cells - i.e. platelets or leukocytes - and - possibly predamaged - endothelial cells could be the initiating mechanism for several forms of pulmonary hypertension. This could be especially true for the so called primary forms or for dietary pulmonary hypertension e.g. after ingestion of toxic oil.     

Longitudinal distribution of pulmonary vascular resistance after endotoxin administration in sheep.

BACKGROUND AND METHODS: Pulmonary hypertension may increase pulmonary capillary pressure and exacerbate pulmonary edema in acute respiratory failure. The effects of pulmonary hypertension on pulmonary capillary pressure depend on the longitudinal distribution of pulmonary vascular resistance. Since pulmonary hypertension occurs during acute respiratory failure, we hypothesized that acute respiratory failure may produce time-dependent changes in the longitudinal distribution of pulmonary vascular resistance. Therefore, we measured pulmonary capillary pressure and the longitudinal distribution of pulmonary vascular resistance in an animal model of acute respiratory failure. Escherichia coli endotoxin (2.5 to 5.0 micrograms/kg) was administered over a 1-hr period in eight anesthetized sheep. Pulmonary and systemic hemodynamics, including pulmonary artery occlusion pressure (PAOP), pulmonary capillary pressure, and the longitudinal distribution of pulmonary vascular resistance, were measured over the next 5 hrs. Pulmonary capillary pressure was estimated by analysis of the pressure decay following pulmonary artery balloon inflation. RESULTS: Endotoxin administration resulted in sustained pulmonary hypertension for the subsequent 5 hrs of the study. Pulmonary capillary pressure was increased 7 mm Hg above baseline at 0.5 and 0.75 hrs during the infusion of endotoxin but returned to baseline values at 1.5 hrs. Despite sustained pulmonary hypertension, pulmonary capillary pressure remained at baseline values for the duration of the study. Similar to pulmonary capillary pressure, pulmonary venous (or postcapillary) resistance was increased approximately four-fold over baseline at 0.5 and 0.75 hrs after initiating endotoxin administration, but returned to baseline values by the end of endotoxin administration and remained at baseline values throughout the remainder of the study. In contrast, pulmonary arterial (or precapillary) resistance remained at values approximately three times baseline during the infusion and throughout the duration of the study. CONCLUSIONS: In this experimental model of acute respiratory failure, the effects of endotoxin on the longitudinal distribution of pulmonary vascular resistance are time-dependent. If these data from animals can be extrapolated to humans, we speculate that the importance of pulmonary venoconstriction in exacerbating pulmonary edema may vary over time in patients with acute respiratory failure.     

Comparison of hyperventilation and inhaled nitric oxide for pulmonary hypertension after repair of congenital heart disease

BACKGROUND: Pulmonary hypertension is associated with congenital heart lesions with increased pulmonary blood flow. Acute increases in pulmonary vascular resistance (PVR) occur in the postoperative period after repair of these defects. These increases in PVR can be ablated by inducing an alkalosis with hyperventilation (HV) or bicarbonate therapy. Studies have shown that these patients also respond to inhaled nitric oxide (iNO), but uncertainty exists over the relative merits and undesirable effects of HV and iNO. HYPOTHESIS: Alkalosis and iNO are equally effective in reducing PVR and pulmonary artery pressure (PAP) in children with pulmonary hypertension after open heart surgery. SETTING: Critical care unit of a tertiary care pediatric hospital. DESIGN: Prospective, randomized, crossover design. PATIENTS: Twelve children with a mean PAP > 25 mm Hg at normal pH after biventricular repair of congenital heart disease. INTERVENTIONS: Patients were assigned to receive iNO or HV (pH > 7.5) in random order, and the effect on hemodynamics was measured. Each treatment was administered for 30 mins with a 30-min washout period between treatments. Finally, both treatments were administered together to look for a possible additive effect. MEASUREMENTS AND MAIN RESULTS: Cardiac output and derived hemodynamic parameters using the dye dilution technique. Hyperventilation, achieved by an increase in ventilator rate without a change in mean airway pressure, decreased Pa(CO2) from a mean (SD) of 43.7+/-5.3 to 32.3+/-5.4 mm Hg and increased pH from 7.40+/-0.04 to 7.50+/-0.03. This significantly altered both pulmonary and systemic hemodynamics with a reduction in PAP, PVR, central venous pressure, and cardiac output and an increase in systemic vascular resistance. In comparison, iNO selectively reduced PAP and PVR only. The reduction in PVR was comparable between treatments, although addition of iNO to HV resulted in a small additional reduction in PVR. An additional decrease in PAP was seen when HV was added to iNO, attributable to a reduction in cardiac output rather than a further decrease in PVR. CONCLUSIONS: Inhaled NO and HV are both effective at lowering PAP and PVR in children with pulmonary hypertension after repair of congenital heart disease. The selective action of iNO on the pulmonary circulation offers advantages over HV because a decrease in cardiac output and an increase in SVR are undesirable in the postoperative period.     

Failure of postnatal adaptation of the pulmonary circulation after chronic intrauterine pulmonary hypertension in fetal lambs.

To determine the effects of chronic intrauterine pulmonary hypertension on the perinatal pulmonary circulation, we induced chronic elevations of pulmonary artery pressure in 24 late-gestation fetal lambs by maintaining partial compression of the ductus arteriosus with an inflatable vascular occluder. Pulmonary artery pressure was increased from 44 +/- 1 to 62 +/- 3 mmHg for 3-14 d. Although left pulmonary artery blood flow initially increased during acute partial ductus compression, the increase in flow was not sustained during chronic ductus compression despite persistent elevations of pulmonary artery pressure (P less than 0.01). Chronic hypertension decreased the slope of the pressure-flow relationship from 3.4 +/- 0.3 (initial) to 0.9 +/- 0.1 ml/min per mmHg, and blunted the fetal pulmonary vascular response to small increases in PO2 (P less than 0.0001). Pulmonary hypertension for greater than 8 d increased the wall thickness of small pulmonary arteries (P less than 0.001). Compared with controls, hypertensive animals had higher pulmonary artery pressure, lower pulmonary blood flow, and predominant right-to-left ductus shunting after cesarean-section delivery (P less than 0.0001). We conclude that chronic pulmonary hypertension in utero, in the absence of hypoxemia or sustained increases in blood flow, causes abnormal fetal pulmonary vasoreactivity, structural remodeling, and the failure to achieve the normal decline in pulmonary resistance at birth.     

Recent progress in the treatment of pulmonary arterial hypertension: expectation for rho-kinase inhibitors

Pulmonary arterial hypertension (PAH) is a disease with poor prognosis characterized by progressive elevation of pulmonary arterial pressure and vascular resistance due to pulmonary artery hyperconstriction and remodeling. However, the precise mechanism of PAH still remains to be elucidated. Although anticoagulant agents, vasodilators (e.g., prostaglandins, sildenafil, and bosentan), and lung transplantation are currently used for the treatment of PAH, more effective treatment needs to be developed. Rho-kinase causes vascular smooth muscle hyperconstriction and vascular remodeling through inhibition of myosin phosphatase and activation of its downstream effectors. In a series of experimental and clinical studies, we have demonstrated that Rho-kinase-mediated pathway plays an important role in various cellular functions, not only in vascular smooth muscle hyperconstriction but also in actin cytoskeleton organization, cell adhesion and motility, cytokinesis, and gene expression, all of which may be involved in the pathogenesis of arteriosclerosis. We also have recently demonstrated that Rho-kinase is activated in animal models of PAH with different etiologies (monocrotaline and chronic hypoxia) associated with enhanced pulmonary vasoconstricting and proliferating responses, impaired endothelial vasodilator functions, and pulmonary remodeling. Indeed, we were able to demonstrate that intravenous fasudil, a selective Rho-kinase inhibitor, exerts acute pulmonary vasodilator effects in patients with severe PAH who were refractory to conventional therapies. Taken together, our findings indicate that Rho-kinase is a novel and important therapeutic target of PAH in humans and that Rho-kinase inhibitors are a promising new class of drugs for the fatal disorder.     

Use of sildenafil to facilitate weaning from inhaled nitric oxide in children with pulmonary hypertension following surgery for congenital heart disease

Pulmonary hypertension frequently complicates the postoperative management of patients after congenital cardiac surgery. Inhaled nitric oxide is an effective treatment option, but rebound pulmonary hypertension can occur upon its withdrawal. Sildenafil may facilitate its withdrawal by restoring cyclic guanosine monophosphate availability via phosphodiesterase-5 inhibition. The purpose of this study was to evaluate the use of sildenafil in facilitating weaning from inhaled nitric oxide after congenital cardiac surgery in patients who had previously failed weaning, and to compare the effects of sildenafil on pulmonary and systemic hemodynamics. Children who received sildenafil after cardiovascular surgery during a 23-month period at Riley Hospital for Children were identified. Medical records were retrospectively reviewed to determine sildenafil and nitric oxide dosing, pulmonary and systemic blood pressures, and adverse effects. Oral sildenafil was administered to 7 children who had failed attempts at inhaled nitric oxide weaning. Inhaled nitric oxide was weaned from 29.8+/-5.9 ppm prior to sildenafil initiation to 12.2+/-3.4 ppm (mean +/- SE; P= .024) in the 24 hours after sildenafil. Mean pulmonary artery and systemic arterial pressure were unchanged from baseline when measured 1 hour after sildenafil dosing (mean pulmonary artery pressure, 29+/-1 to 27+/-0.7 mm Hg, P= .066; mean systemic arterial pressure, 56+/-1.2 to 54+/-1.2 mm Hg, P= .202). Sildenafil may facilitate withdrawal of inhaled nitric oxide and prevent rebound pulmonary hypertension in patients previously failing inhaled nitric oxide weaning attempts.     

Primary pulmonary hypertension: an overview of epidemiology and pathogenesis

Pulmonary arterial hypertension (PAH) refers to a group of diseases characterized by high pulmonary artery pressure of unknown mechanism. Primary pulmonary hypertension (PPH) is the idiopathic subset of PAH that affects a mostly young population and is more common in females than in males. A familial form of PPH accounts for about 6% of cases, and its autosomal dominant gene was recently identified. Pulmonary arterial hypertension is histologically characterized by endothelial and smooth muscle cell proliferation, medial hypertrophy, and thrombosis in situ. The pathogenesis of PAH remains unclear. Elevated pulmonary vascular resistance seems to result from an imbalance between locally produced vasodilators and vasoconstrictors, in addition to vascular wall remodeling. Nitric oxide, a locally produced selective pulmonary vasodilator, appears to play a central role in the pathobiology of PAH.     

Pulmonary hypertension in acute respiratory failure

In order to examine the prognostic value of pulmonary arterial hypertension (PAH) in patients with moderate and severe acute respiratory failure (ARF), 225 patients with ARF who had been treated with mechanical ventilation and admitted to our ICU during a 3-yr period (January, 1983 to January, 1986) were prospectively studied. All 70 (31%) patients with moderate and severe ARF also had some form of hemodynamic or pulmonary instability, and were monitored with a pulmonary artery catheter. Of these 70 patients, 38 (54%) had PAH (mean BP 29 +/- 6 mm Hg); their mortality was 79% (30/38). The rest of the patients (n = 32) did not have PAH (mean BP was 15 +/- 3 mm Hg) and their mortality was 44% (14/32) (p less than .01). Thirty patients met all the criteria for adult respiratory distress syndrome (ARDS), and their mortality was 70% (21/30); all of them were included among the 38 PAH patients. ARDS patients who died had a significantly higher pulmonary vascular resistance and a significantly lower cardiac index than patients who survived (p less than .001). We conclude that PAH (present in all our ARDS patients) is a good predictor of mortality in ARF of diverse causes.     

Recognition and management of pulmonary hypertension

Pulmonary hypertension is a common manifestation of many diverse diseases. In most cases, the cause of elevated pulmonary arterial pressure is apparent on the basis of history, physical examination, chest x-ray, and ancillary noninvasive tests such as blood gases, pulmonary function tests, or echocardiography. Occasionally, more invasive tests such as cardiac catheterization and pulmonary angiography may be necessary. In those patients in whom no cause can be found, the pulmonary hypertension is labeled as primary or idiopathic. Effective therapy exists for alleviating pulmonary hypertension in most cases of secondary pulmonary hypertension. The prognosis of patients with primary pulmonary hypertension is dismal, although encouraging reports are beginning to appear regarding the use of vasodilators.     

8例肺动脉高压患者靶向治疗的临床研究

目的探讨肺动脉高压患者药物靶向治疗的效果与耐受性。方法回顾分析2008年1月2009年8月期间8例肺动脉高压患者分别接受波生坦及西地那非治疗的临床资料,评估其临床表现、WHO肺动脉高压功能分级、6min步行距离及肺动脉收缩压在基线及治疗3个月后的变化。结果治疗后3个月,患者均能耐受药物治疗,无严重不良反应发生。WHO肺动脉高压功能分级在治疗前平均（3.1±0.4）,治疗后为（2.3±0.9）,明显得到改善（P〈0.05）。肺动脉收缩压在治疗前平均（69.5±11.2）mmHg（1mmHg=0.133kPa）,治疗后为（48.3±12.4）mmHg,明显降低（P〈0.05）。6min步行距离在治疗前平均（324±48）m,治疗后为（400±43）m,明显延长（P〈0.05）。结论肺动脉高压患者药物靶向治疗的疗效显著,且耐受良好。