Current Therapies for Pulmonary Arterial Hypertension
Shanon Takaoka, John L. Faul and Ramona Doyle The online version of this article can be found at: can be found at:
Seminars in Cardiothoracic and Vascular Anesthesia
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Seminars in Cardiothoracic
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Current Therapies for Pulmonary
Arterial Hypertension
Shanon Takaoka, MD, John L. Faul, MD, and Ramona Doyle, MD Pulmonary arterial hypertension (PAH) is a progressive dis- atrial septostomy, pulmonary thromboendarterectomy, and ease of the pulmonary vasculature, characterized by relent- transplantation, are briefly reviewed, and the rationale, indi- less deterioration and death. Patients with PAH are known cations, and selection criteria for each are discussed.
to be at increased risk for anesthetic complications and Although available medical and surgical therapies for PAH surgical morbidity and mortality. However, outcomes in have improved patient outcomes, acute decompensated patients have improved with the recent development of new right heart failure (RHF) remains a common and challeng- drug therapies. The 3 major drug classes for treatment of ing complication of PAH. The authors review this topic and PAH are prostanoids, endothelin-receptor antagonists, and provide an outline of the general pathophysiology of RHF phosphodiesterase-5 inhibitors. In this review, the authors provide an overview of each drug class, its mechanism ofaction, indications, and current supportive literature.
Surgical and interventional treatments of PAH, including exertion.4,5 It is a disease characterized by progressiveincreases in pulmonary vascular resistance (PVR) due Pulmonary arterial hypertension (PAH) is a severely disabling disease of the pulmonary vas-culature that, until recently, carried a very poor to pathologic changes in the pulmonary vasculature prognosis. In the absence of aggressive treatment, the characterized by medial hypertrophy, intimal prolifera- course of the disease is characterized by a relentless tion, and in advanced stages by plexiform lesions and and progressive functional and symptomatic decline in necrotizing arteritis.6 The various diseases and condi- the majority of patients, ultimately culminating in tions associated with PAH are delineated in a recently right heart failure (RHF) and death. Patients with pul- revised system of clinical classification (Table 1). In the monary hypertension are at increased risk for compli- new classification system idiopathic pulmonary arte- cations and death while undergoing anesthesia and rial hypertension (IPAH) replaces the entity once surgical procedures.1–3 However, recent advances in known as “primary pulmonary hypertension,” or PPH.
the understanding of the pathophysiology of PAH have This revised classification system illustrates the dis- led to the emergence of new medical and surgical ther- tinction between true PAH and other processes that apeutic modalities, which have in turn resulted in a can result in pulmonary hypertension (eg, elevation of significant improvement in the outcomes of patients pulmonary artery pressures secondary to left ventricu- lar failure, thromboembolic disease, or hypoxemic PAH is defined as a mean pulmonary artery pres- sure greater than 25 mm Hg at rest or 30 mm Hg with The screening test of choice for the diagnosis of PAH is transthoracic echocardiography, which provides From the Division of Pulmonary/Critical Care Medicine (ST, a preliminary estimation of pulmonary artery pressures JLF, RD), and the Vera M. Wall Center for Pulmonary Vascular and identification of concomitant left-heart, valvular, Disease (JLF, RD), Stanford University Medical Center, or congenital heart disease. However, cardiac catheter- ization is the gold standard for the diagnosis of PAH, Address correspondence to: Ramona Doyle, MD, Division of requires precise measurement of hemodynamics (pul- Pulmonary/Critical Care Medicine, and the Vera M. Wall Center monary artery pressures, pulmonary capillary wedge for Pulmonary Vascular Disease, Stanford University MedicalCenter, Stanford, CA 94305; e-mail: [email protected].
pressure, PVR, cardiac output), and is strongly advised Seminars in Cardiothoracic and Vascular Anesthesia / Vol. 11, No. 2, June 2007 Revised Nomenclature and Classification of Pulmonary Hypertension IPAH (idiopathic pulmonary arterial hypertension)FPAH (familial pulmonary arterial hypertension)Collagen vascular diseaseCongenital systemic to pulmonary shuntsPortal hypertensionHIV infectionDrugs and toxinsOther (glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, splenectomy, myeloproliferative disorders) Associated with significant venous or capillary involvementPulmonary veno-occlusive diseasePulmonary capillary hemangiomatosis Left-sided atrial or ventricular heart diseaseLeft-sided valvular heart disease Pulmonary hypertension associated with hypoxemia Chronic obstructive pulmonary diseaseInterstitial lung diseaseSleep disordered breathingAlveolar hypoventilation disordersChronic exposure to high altitude Pulmonary hypertension due to chronic thrombotic and/or embolic disease Thromboembolic obstruction of proximal pulmonary arteriesThromboembolic obstruction of distal pulmonary arteriesPulmonary embolism (tumor, parasites, foreign material) Sarcoidosis, histiocytosis X, lymphangiomatosis, compression of pulmonary vessels (adenopathy, tumor, in all patients with elevated right ventricular pressures on screening echocardiogram in whom PAH is clini- cally suspected.7 Further characterization of the etiol- No symptoms with ordinary physical activity ogy of elevated pulmonary artery pressures should be Symptoms with ordinary activity; slight limitation sought with a detailed history, including exposures to toxins or stimulants, a history of prior thromboembolic Symptoms with less than ordinary activity; marked disease, or any history suggestive of congenital heart disease (childhood murmur, blue baby syndrome).
Symptoms with any activity or even at rest Laboratory tests should include serologies for collagenvascular disease, thyroid function tests,8 liver functiontests, and HIV and hepatitis serologies. Imaging stud-ies should include chest imaging (radiography and strategy. In patients with forms of pulmonary hyper- computed tomography) and ventilation–perfusion lung tension other than IPAH, it may be beneficial to scans. All patients should undergo pulmonary function address the underlying cause (e.g., positive pressure testing with arterial blood gas analysis, an assessment ventilation for sleep apnea, optimization of heart of exercise capacity using the 6-minute walk test and failure therapy in left heart failure).9 For patients assignment to a New York Heart Association (NYHA) with PAH, there is a growing array of medical and functional class (Table 2). Polysomnography should be surgical treatment modalities available for chronic performed in patients with a clinical history suggestive therapy which are discussed in this review. Acute management of decompensated RHF, the most Identifying the etiology of pulmonary hyperten- common complication of PAH and a highly contro- sion is important as this determines the treatment Current Therapies for Pulmonary Arterial Hypertension / Takaoka et al Medical Treatment Options
of PAH. Endogenous prostacyclin is a vasodilatingprostaglandin produced by vascular endothelial cells, Calcium Channel Blockers
and it exerts potent vasodilatory effects on both the pulmonary and systemic vascular beds. Prostacyclin Although many different processes can result in also appears to have significant antiproliferative and chronic PAH, the final common pathway is a sustained antiplatelet aggregation properties. Studies have sug- elevation in PVR. Medical treatment for PAH should gested that the pathogenesis of PAH is in part related be directed toward lowering PVR by either potentiating to a deficiency of circulating prostacylin in the setting of pulmonary vasodilatation or inhibiting pulmonary decreased prostacyclin synthase expression.15,16 Chronic vasoconstriction. Calcium channel blockers (CCBs) administration of exogenous prostanoids has subse- are a class of agents known to produce vascular quently been shown to improve hemodynamics, exer- smooth muscle relaxation with resultant vasodilata- cise capacity, quality of life, and overall survival in tion. A substantial survival benefit was observed in early, nonrandomized studies using CCBs in patients There are currently 3 Food and Drug Administra- with PPH,10,11 but no randomized, controlled trials tion (FDA)–approved prostanoids available for treat- have borne this out. Most important, the improved ment of PAH. Epoprostenol was the first to be outcome associated with CCBs appears to be confined introduced, is the most investigated to date, and is thus to the very small subset of patients with evidence of the most widely used drug of its class. The 2 largest vasoreactivity during right-heart catheterization. All randomized, controlled trials with epoprostenol have patients with PAH and symptoms or disease severity been conducted in functionally limited patients (NYHA prompting consideration of treatment should undergo class III or IV, see Table 2) with IPAH and PAH asso- vasodilator testing. Vasodilator testing involves measur- ciated with scleroderma, respectively.19,20 Data from ing PVR before and after administration of a short- these studies demonstrate improvements in exercise acting vasodilating agent (typically inhaled nitric oxide, capacity, hemodynamic status, and survival (in IPAH) intravenous epoprostenol, or adenosine). A positive with epoprostenol administration as compared with response is defined as a fall in mean pulmonary artery conventional treatment. Further studies have shown pressure of at least 10 mm Hg to ≤ 40 mm Hg, with a the clinical benefit to be sustained over many years of stable or increased cardiac output when compared chronic therapy,21–23 and epoprostenol is currently with baseline values, and is associated with improved approved for use in NYHA class III and IV patients outcomes with long-term CCB therapy.12,13 Only 5% to with IPAH. Uncontrolled studies have also suggested 10% of all patients with PAH exhibit vasoreactivity dur- benefit in patients with PAH secondary to congenital ing right-heart catheterization; thus, CCBs are indi- heart disease, cirrhosis, and HIV. The typical starting cated in only a minority of PAH patients. Adverse dose is 1 to 2 ng/kg per min with subsequent gradual effects include worsening heart failure due to negative up-titration by 1 to 2 ng/kg per min until clinical inotropic effects; thus, CCBs should not be used in improvement is observed and sustained (“plateau patients with evidence of RHF. Furthermore, deaths dose”) or dose-limiting side effects develop.
have been reported following vasodilator testing with Despite its proven efficacy in certain clinical CCBs, likely due to their prolonged negative hemody- settings epoprostenol has several disadvantages.
namic effects.14 Because of the limited benefit and Significant side effects include flushing, jaw pain, the potential for adverse outcomes, CCBs, when used headaches, gastrointestinal distress, rashes, and throm- at all, should be titrated up gradually with judicious bocytopenia. It is an expensive therapy due to inherent monitoring for side effects. The choice of CCBs may drug costs and the complex administration system.
include amlodipine, diltiazem, or nifedipine; vera- Unstable at room temperatures it must be kept cold and pamil should be avoided due to its negative inotropic mixed on a daily basis. Epoprostenol requires continu- effects. CCBs should never be instituted empirically ous intravenous infusion, generally through a tunneled without evidence of vasoreactivity during right-heart catheter, and has an exceedingly short half-life (<6 min- utes). Interruption of the infusion can lead to abruptincreases in PVR, acute RHF, hemodynamic collapse,and death. Patients are also at risk for catheter-related Prostanoids
complications, such as pneumothorax, venous throm- Developed in the 1990s, prostacyclin analogues were bosis, cellulitis, and sepsis. Given these considerations, the first class of drugs introduced for the treatment use of epoprostenol involves a long-term commitment Seminars in Cardiothoracic and Vascular Anesthesia / Vol. 11, No. 2, June 2007 for the patient and medical team that requires thorough bypass) to prevent acute RHF in patients with pre- patient education, involvement of specialized person- existing PAH, has been described in case reports and nel, and frequent outpatient monitoring.
Treprostinil is an FDA-approved prostanoid with similar hemodynamic effects to epoprostenol,24 but it Endothelin Receptor Antagonists
has the advantage of a longer half-life (3 hours) andsubcutaneous administration. A 12-week, randomized, Endothelins are vasoactive peptides synthesized by placebo-controlled trial comparing subcutaneous tre- endothelial cells and are important mediators of vascu- prostinil to conventional therapy in 470 patients with lar tone. They also appear to have mitogenic properties IPAH and PAH associated with connective tissue dis- and induce cellular proliferation in many cell lines, ease and congenital heart disease (NYHA classes including vascular smooth muscle. The most important II–IV) showed an increased exercise capacity (as of these is endothelin-1 (ET-1), an isoform that appears measured by 6-minute walk) that appeared to be dose- to be elevated in the plasma of patients with IPAH or dependent, along with improvement in various hemo- PAH secondary to connective tissue disease.32 Two dynamic indices. These benefits were observed in all endothelin receptors have been identified, with differ- groups except for those patients with congenital heart ent locations and binding affinities for endothelin, and disease, a disparity attributed to the short study dura- thus with distinct physiologic activities. Endothelin tion.25 A subsequent multicenter, randomized study receptor A (ET ) exists on pulmonary vascular smooth limited to PAH with connective tissue disease further muscle cells and mediates a potent pulmonary vaso- supported the positive effect of treprostinil on exercise constrictor response when activated. Endothelin recep- capacity, symptoms, and hemodynamics, as compared tor B (ET ) is found predominantly on pulmonary with placebo.26 Although many of the reported side vascular endothelial cells with lesser expression on effects are similar to those caused by epoprostenol, a smooth muscle cells. Thus, ET function is more com- significant proportion of patients complain of dose- plex but appears to be primarily responsible for nitric limiting infusion site pain and erythema, which may oxide and prostacyclin-mediated pulmonary vasodilata- improve with time but can ultimately lead to cessation tion in the normal lung.33 Based on this knowledge, of therapy. Use of intravenous treprostinil obviates this endothelin receptor antagonists (ERAs), both nonse- concern while providing the benefits of prolonged lective and ET -specific, have been introduced to pro- drug effect. Initial data suggest that intravenous mote pulmonary vasorelaxation, with current evidence administration approximates subcutaneous delivery suggesting favorable therapeutic outcomes.
pharmacokinetically,27 but long-term efficacy remains Bosentan is an oral, nonspecific ERA and is cur- rently the only FDA-approved drug for PAH treatment Iloprost is a prostacyclin analogue whose half-life in its class. The first randomized, placebo-controlled is intermediate to those of epoprostenol and trepros- trial of bosentan was performed in 32 patients with tinil. It is currently the only FDA-approved inhaled IPAH or PAH due to connective tissue disease and prostanoid available, with a hemodynamic effect lasting showed a statistically significant improvement in exer- approximately 90 minutes after administration. Patients cise capacity and pulmonary hemodynamics after 12 are required to perform 6 to 9 inhalations daily, each weeks of therapy.34 Subsequent follow-up performed at requiring 10 to 20 minutes to administer. This modality 1 year revealed that these benefits were sustained and circumvents many of the other disadvantages encoun- that long-term therapy was well-tolerated.35 BREATHE- tered by the intravenous or subcutaneous routes while 1 was a pivotal trial that randomly assigned 213 patients offering a moderate duration of action. In a pivotal trial with PAH (IPAH and PAH due to connective tissue dis- of 203 NYHA class III or IV patients with IPAH, PH ease) to placebo or 1 of 2 bosentan doses (125 mg due to chronic thromboembolic disease, or PH due to or 250 mg twice daily). After 16 weeks of therapy, connective tissue disease, patients were randomized to the bosentan group had an improvement in 6-minute receive inhaled iloprost or placebo. The treatment group walk distance, Borg dyspnea index, functional class, showed an improvement in the combined clinical end- as well as an increased time to clinical deterioration.
point composed of exercise capacity, functional class, Significant adverse events were rare at the lower dose, and lack of clinical deterioration.28 Additionally, the suc- and there was no clinical advantage gained by the cessful use of inhaled iloprost during cardiac surgery higher dose.36 More recently, a survival benefit has been (before and during weaning from cardiopulmonary reported in PAH patients on long-term therapy with Current Therapies for Pulmonary Arterial Hypertension / Takaoka et al bosentan (predominantly IPAH, NYHA class III and different doses of ambrisentan, it was found that IV), although poor baseline exercise capacity and NYHA there was a dose-independent improvement com- class IV were predictors of worse outcomes.37 While pared with baseline in all the endpoints: 6-minute most trials have focused primarily on IPAH, there are walk distance, functional class, Borg dyspnea index, some data to suggest that bosentan may confer similar hemodynamics, and subjective global assessment.
benefits in patients with portopulmonary hypertension The incidence and severity of side effects (mainly and those with chronic thromboembolic pulmonary elevated hepatic transaminases) was low overall, unrelated to dose, and decreased relative to bosen- Based on this evidence, bosentan is currently tan.43 Preliminarily, these selective ERAs represent a approved for the treatment of IPAH and PAH due to potentially attractive treatment modality with their connective-tissue disease with NYHA class III or IV longer durations of action, comparable efficacy, and symptoms. Clinical improvement may take up to 2 lower incidence of hepatic side effects when com- to 3 months after therapy initiation; thus, bosentan pared with bosentan. However, the data remain is not recommended as first-line monotherapy for limited, and more randomized studies of longer class IV PAH. Bosentan is generally well tolerated but can cause elevation in hepatic transaminases (greaterthan 3 times the upper limit of normal in approximately Phosphodiesterase-5 Inhibitors
10% of patients), mild anemia, diminished efficacy of oral contraception, and fetal teratogenesis. The rec- Phosphodiesterase-5 (PDE-5) is an enzyme respon- ommended starting dose is 62.5 mg twice daily with sible for the metabolism of intracellular cyclic an increase to the maintenance dose of 125 mg guanosine monophosphate (cGMP), which in turn twice a day after 1 month if tolerated. Liver enzyme is a second messenger that mediates vasodilatation abnormalities are rare at low doses, but monthly and antiproliferative activities in vascular smooth monitoring of liver function tests for the duration of muscle. PDE-5 is strongly expressed in the lung and increased PDE-5 gene expression and activity has Sitaxsentan is an oral, ET -selective ERA currently been observed in chronic PAH.44,45 Inhibition of this under investigation as another therapy for PAH. It overexpressed enzyme by specific PDE-5 inhibitors exhibits a greater affinity (6000-fold) for ET over ET increases the intracellular levels of cGMP and pro- and thus has the theoretical benefit of blocking ET - motes vasodilatory and antiproliferative effects and mediated vasoconstriction with concomitant sparing has been shown to be effective in patients with PAH.
of the nitric oxide and prostacylin-mediated vasodilata- Sildenafil is a potent, highly selective PDE-5 tion produced by B-receptor binding. A randomized, inhibitor, and evidence to date appears to support placebo-controlled trial (STRIDE-1) was performed its role as an effective pulmonary vasodilator with over 3 months in 178 patients with PAH (IPAH, PH improvements in exercise capacity, symptom scores, due to congenital heart disease, PH due to connective and hemodynamics after drug administration. Until tissue disease) and NYHA class II–IV symptoms.
recently, the available data for sildenafil remained Although the difference in the primary endpoint of limited to case reports and small, nonrandomized tri- maximum oxygen consumption was not statistically sig- als.46–49 However, in a recent report of a randomized, nificant, there was an improvement in exercise capac- placebo-controlled trial (SUPER-1, presented as an ity, functional class, and hemodynamic parameters in oral abstract), sildenafil administered to PAH patients the sitaxsentan group compared with placebo group.40 over 12 weeks resulted in an increase in 6-minute A 1-year follow-up of patients on chronic therapy sug- walk distance and improved NYHA functional class.
gests that the benefits are sustained and the drug is These benefits were observed within days of drug well tolerated with no serious adverse outcomes.41 administration, unlike the delayed effect often seen More recent data have suggested that sitaxsentan can with bosentan. The drug was well tolerated and the improve exercise capacity and functional class in primary side effects were relatively mild (headaches, patients with PAH in a manner similar to bosentan but epistaxis).50,51 Furthermore, a recent small, double- with a trend toward less hepatotoxicity.42 blinded study of patients with PAH (IPAH and PAH Ambrisentan is another long-acting, oral, ET - due to connective-tissue disease; NYHA class III) specific ERA currently being studied for use in PAH.
randomized to either sildenafil or bosentan therapy In a recent 12-week, double-blinded study using 4 demonstrated that improvements in exercise capacity Seminars in Cardiothoracic and Vascular Anesthesia / Vol. 11, No. 2, June 2007 Summary of FDA-Approved Medical Therapies indwelling line, storage; short half-life; catheter-related risks were greater in patients treated with sildenafil com- there has been interest in defining the benefit of pared with bosentan with an increase in cardiac index combination medical therapy. It is biologically plau- that was similar in both groups.52 A recent observa- sible that combining drug classes with distinct tar- tional study of the acute and chronic effects of silde- gets in the pathogenesis of PAH would produce an nafil found that, in addition to its potent vasodilation, additive or synergistic effect. Unfortunately, there sildenafil can produce long-term symptomatic are few data to date to support this theoretical ben- improvement when administered on a chronic basis.53 efit. The combination of prostanoids and endothelin Sildenafil is the only FDA-approved drug in its antagonists has been studied in a few small, class, and the recommended starting dose is 20 mg prospective, nonrandomized trials, which have gen- orally 3 times a day. Importantly, sildenafil has been erally shown an improvement in exercise capacity, shown to cause profound refractory hypotension functional status, and subjective symptoms with few when given in the setting of nitrates of any form.
adverse events.56,57 The only randomized study of Therefore, the concurrent use of these agents is prostanoid–ERA combination therapy to date is the contraindicated. Other recently introduced long-act- BREATHE-2 trial, which enrolled 33 patients with ing PDE-5 inhibitors are currently under investiga- PAH who had initially been treated with intravenous tion for the treatment of PAH. Tadalafil offers the epoprostenol for 16 weeks and who were subse- theoretical advantage of a longer half-life, allowing quently randomized to receive either bosentan or once daily drug administration. Although it appears placebo. Although there was a nonsignificant trend to have similar selective pulmonary vasodilatory toward greater improvement in pulmonary hemody- effects, preliminary data suggest that it does not namics and clinical status in patients who received improve oxygenation as sildenafil does.54 While the combination therapy, there was also a higher inci- current medical literature is limited to anectodal dence of adverse events when compared with the experience,55 studies are under way to evaluate the efficacy of tadalafil in the treatment of PAH.
The addition of sildenafil to either prostanoid or ERA monotherapy has also undergone limited study.
Two small trials have been done in PAH patients Combination Therapy
who exhibited clinical deterioration while on long- Given the growing body of evidence supporting the term prostanoid monotherapy (inhaled iloprost, available drugs as monotherapy for PAH (Table 3), intravenous epoprostenol). The addition of sildenafil Current Therapies for Pulmonary Arterial Hypertension / Takaoka et al was well tolerated and appeared to lead to improve- whom a specific procedure is indicated. Atrial sep- ments in exercise capacity and pulmonary hemody- tostomy (AS) may serve as palliation or as a bridge to namics with chronic drug administration.59–61 Likewise, more definitive treatment, such as lung transplanta- the addition of sildenafil to patients on bosentan who tion, while pulmonary thromboendarterectomy (PTE) experienced a decline in exercise tolerance resulted in offers a potential surgical cure for patients with an increase in 6-minute walk distance after 3 months CTEPH. Transplantation has been a mainstay of surgi- of sildenafil therapy; this benefit was sustained with cal treatment for PAH since the 1980s; the first suc- no notable adverse effects.62 However, there are con- cessful heart–lung transplant was performed on a cerns that drug–drug interactions may limit the use of woman with pulmonary vascular disease due to sildenafil–bosentan combination therapy. However, IPAH.65 Since then, lung and heart–lung transplanta- combination therapy presents a promising therapeutic tion have been used in the treatment of PAH in the option for patients who are either refractory to, or who event of failed medical and other surgical interven- deteriorate on, appropriate monotherapy. Although the tions. Detailed data and recommendations for these data remain limited, more studies may provide better surgical therapies and interventions for PAH have been evidence to substantiate the perceived benefit of com- Adjunctive Therapy
Historically, patients with IPAH and a patent foramen There are a variety of adjunctive measures commonly ovale (PFO) awaiting transplantation were observed to used in the management of PAH which are not well- have a survival advantage over those without a PFO.67 validated by evidence but are generally accepted to be This finding suggested that the creation of an intra- of clinical benefit. All patients with known PAH should atrial right-to-left shunt could decompress the right be anticoagulated with warfarin to an international ventricle and increase left ventricular preload, thereby normalized ratio of 1.5–2.5, as these patients are at increasing systemic blood flow and improving systemic increased risk of thrombosis due to a variety of factors: oxygen transport, despite arterial oxygen desaturation.
dilated right-sided heart chambers, sluggish pulmonary AS has been used as a palliative treatment in patients blood flow, venous insufficiency, and sedentary with advanced disease based on its potential to decom- lifestyle. This practice is supported by the finding of press the failing right ventricle and increase cardiac in situ thrombosis in pathologic specimens of PAH index. It is indicated in severely symptomatic patients and the demonstration of a survival benefit with long- with PAH who are unresponsive to medical treatment, term anticoagulation.10,63 Supplemental oxygen is also including those who are NYHA class III or IV, have a recommended if necessary to maintain saturations ≥ history of recurrent syncope, or present with “refrac- 90%, as hypoxemia is known to be a potent pulmonary tory” RHF.68 Because procedural mortality can be high, vasoconstrictor and can exacerbate underlying PAH.
AS should be done only at institutions with significant Fluid retention is a common problem manifested by experience in performing this procedure and only in findings such as edema and ascites; diuretics can selected patients with severe PAH who have failed decrease preload and improve right ventricular function with resultant symptomatic relief and improved qualityof life. Digoxin can also be used in the setting of RHF, and it has been shown to produce modest increases in PTE provides a potential surgical cure for PAH result- ing from chronic pulmonary thromboembolism affect-ing the central pulmonary arteries (main, lobar, Surgical Treatment Options
segmental). Selection of appropriate patients for thiscomplex surgery relies on ascertainment of the presence Although many effective medical therapies have of surgically accessible thrombus using various radi- been recently introduced for the treatment of PAH, ographic imaging techniques,69,70 including ventilation- catheter-based and surgical interventions still play perfusion (VQ) scanning and pulmonary angiography.
an important role in the management of PAH is Basic criteria suggested for selection of patients under- some patients. The rationale for these interventions going PTE are: (1) NYHA class III or IV symptoms; (2) is based on the identification of a PAH patient in a preoperative PVR > 300 dynes cm-5; (3) surgically Seminars in Cardiothoracic and Vascular Anesthesia / Vol. 11, No. 2, June 2007 accessible thrombus (in the main, lobar, or segmental for this increased afterload by undergoing concentric pulmonary arteries) as determined by all appropriate hypertrophy to maintain adequate cardiac output and radiographic studies; and (4) no severe comorbidities.71,72 regulate right atrial pressures. However, chronic expo-sure to this pressure overload eventually results in RVremodeling and chamber dilatation that, in turn, leads Lung and Heart–Lung Transplantation
to diminished myocardial perfusion and tricuspid Lung transplantation and heart–lung transplantation regurgitation.77 These pathophysiologic alterations cul- may offer definitive therapy for PAH patients in whom minate in RV myocardial dysfunction with increased all other medical and surgical therapies have failed.
right atrial pressures and systemic venous congestion, The selection of appropriate candidates for transplan- most significantly impacting the hepatic, renal, and tation is critical to its success as a therapy, and detailed splanchnic vascular beds, and resulting in end-organ guidelines for the selection of candidates for lung dysfunction. This dysfunction is further exacerbated by transplantation have been published previously.73 In poor organ perfusion and oxygenation as RV failure general, transplantation should not be considered compromises left-sided cardiac output. Furthermore, until after the failure of medical therapy, factoring into PAH patients with chronic RV failure can rapidly account the time needed to complete a transplant decompensate when challenged by any number of evaluation and the time spent on the transplant list intercurrent illnesses, such as infection, myocardial awaiting suitable organs. PAH patients with NYHA ischemia, dysrhythmia, thromboembolic disease, or class III or IV symptoms should be referred for trans- anemia.78 Treatment of acute, decompensated RHF plant evaluation while their response to therapy is starts with the identification and treatment of any pre- being evaluated. Transplant procedures currently cipitating factors, then centers around the optimization being performed on patients with PAH are single lung of RV preload, afterload, and contractility with the goal (SLT), bilateral lung (BLT), and combined heart–lung of maintaining end-organ oxygenation and perfusion.
(HLT) transplantation.74 In PAH patients undergoingtransplantation, higher rates of reperfusion edema Preload Optimization
have been shown to occur in SLT versus BLT proce-dures, likely due to enhanced blood flow to the trans- Although a small subset of PAH patients with decom- planted lung. Increased blood flow and worse pensated RHF are preload-dependent and may benefit reperfusion injury have been implicated in prolonged from cautious fluid resuscitation, the majority present mechanical ventilation and protracted intensive care with evidence of elevated right atrial pressures, central unit stays in PAH patients undergoing SLT.75,76 On the venous congestion, and fluid overload. Volume loading basis of these findings, most centers prefer BLT in these patients with acute RHF may lead to worsening PAH patients. For patients with PAH due to simple RV dilatation and tricuspid regurgitation, resulting in congenital heart disease (eg, atrial septal defect), the a further decrease in myocardial function and cardiac recommended procedure is BLT with cardiac repair, output. Thus, volume therapy should generally be whereas patients with complex congenital heart dis- avoided in PAH-related acute RHF; instead, treatment ease (eg, ventriculoseptal defect, Tetralogy of Fallot, of volume overload should be initiated with diuretic aortopulmonary window, transposition of the great therapy. Not infrequently, diuretic resistance may vessels) generally require combined heart–lung trans- occur due to renal and splanchnic venous congestion; plantation. However, the best transplant procedure for in some cases, hemofiltration (typically with inotropic patients with PAH will ultimately depend on individual patient characteristics and the availability of appropri-ate organs for transplantation.
Afterload Reduction
Measures to decrease PVR, and thus RV afterload, are Treatment of Acute Decompensated
essential to bring about improvements in myocardialoxygen demand, RV filling, and ultimately cardiac out- Right-Heart Failure
put.79 Hypoxemia, acidemia, hypercarbia, endogenous As PAH progresses, the increasing PVR presents or exogenous vasoconstrictors, and increased sympa- greater demands on right ventricular (RV) function.
thetic tone all increase PVR and should be corrected The thin-walled right ventricle initially compensates if identified. Once reversible causes of pulmonary Current Therapies for Pulmonary Arterial Hypertension / Takaoka et al vasoconstriction are addressed, vasodilator therapy to elucidate the effects of levosimendan in acute RHF in can be initiated. Systemic vasodilators such as sodium nitroprusside, nitroglycerin, and hydralazine effec-tively decrease both pulmonary as well as systemic vas-cular resistance. As such, these agents can also lead Adjunctive Measures
to decreased arterial oxygenation owing to impairment In addition to the optimization of RV preload, afterload, of hypoxic pulmonary vasoconstriction with worsening and contractility, there are a variety of adjunctive ther- of VQ matching, decreased right coronary artery per- apeutic modalities that are used to preserve end-organ fusion with myocardial ischemia, systemic hypoten- perfusion and oxygenation. Supplemental oxygen is sion, and decreased organ perfusion.79,80 administered when indicated to prevent hypoxia- To avoid these adverse systemic effects, selective mediated pulmonary vasoconstriction and to maintain pulmonary vasodilators have been used for RV after- adequate tissue oxygenation. Severe respiratory insuffi- load reduction. The most investigated agent is nitric ciency may require mechanical ventilation, which can oxide (NO), which acts directly on pulmonary smooth worsen RHF by increasing transpulmonary pressures muscle to cause localized vasodilatation only in venti- and thus RV outflow impedance. Ventilatory support lated areas as it is rapidly inactivated when bound by should be delivered with the lowest respiratory rate hemoglobin. Thus, PVR is decreased with increased and positive end-expiratory pressure settings possible RV output, VQ matching is improved, and systemic to minimize increases in PVR and transpulmonary vascular resistance is unchanged.81 A subsequent study in critically ill patients with pulmonary hypertension Vasopressor therapy with agents that possess and acute RHF showed that NO therapy led to both inotropic and vasoconstrictor properties may improvement in various hemodynamic parameters, occasionally be used in the treatment of acute RHF but no survival benefit was demonstrated.82 The previ- or to address hypotension caused by inotropes such ously discussed pulmonary vasodilators epoprostenol as dobutamine or milrinone. Epinephrine, norepi- and iloprost may also be useful in the treatment of nephine, and high-dose dopamine are direct vasocon- acute RHF; however, data on the use of these agents strictors, with some inotropic activity, that increase arterial blood pressure, improve coronary artery perfu-sion, but also increase afterload. In 1 study, norepi- Inotropic Support
nephrine was shown to increase right coronary arteryperfusion pressure with concomitant improvement in Positive inotropic agents are commonly administered RV function as compared with the selective α-adrenergic to improve myocardial function and RV output once agonist phenylephrine.86 Vasopressin, an agent with afterload reduction is accomplished. Dobutamine and potent vasopressor (and some inotropic) properties, milrinone are 2 commonly used drugs that increase has been shown to effectively treat milrinone-induced intracellular calcium, which in turn enhances myocar- hypotension without adversely affecting either pul- dial contractility. However, this inotropic activity occurs monary artery pressures or cardiac output.87 at the expense of increased oxygen consumption by themyocardium with the potential for ischemia, arrhyth-mia, and systemic vasodilatation with hypotension, Conclusions
which may require vasopressor support.79 Calcium sen-sitizers are a new class of inotropes that appear to aug- Although PAH remains a challenging entity, recent ment myocardial contractility without increasing advances in the understanding of its pathophysiol- intracellular calcium concentrations, thus improving ogy have led to the development of new medical systolic function without impairing diastole. Levosimen- treatments that have significantly impacted the dan is the primary drug in this class currently under long-term outcome of this disease. Agents such as investigation and preliminarily has been shown to prostanoids, ERAs, and PDE inhibitors, when com- induce dilatation of both the pulmonary and systemic bined with traditional measures such as anticoagu- vasculatures, with improved hemodynamic status, and lation, supplemental oxygen, and diuretics, have led without any apparent adverse effect on myocardial oxy- to an improvement in not only physiologic indices gen demand.83,84 However, the available data pertain to but quality of life and survival. When indicated, AS, chronic left heart failure, and further studies are needed PTE, and organ transplantation can be also be used Seminars in Cardiothoracic and Vascular Anesthesia / Vol. 11, No. 2, June 2007 with benefit in the treatment of selected patients with 13. Sitbon O, Humbert M, Jais X, et al. Long-term response to PAH. Despite these advances, acute decompensated calcium channel blockers in idiopathic pulmonary arterial RHF remains a common and potentially fatal compli- hypertension. Circulation. 2005;111:3105-3111.
cation of chronic PAH. Although the management of 14. Partanen J, Nieminen M, Luomanmaki K. Death in a RHF remains controversial, a rational approach based patient with primary pulmonary hypertension after 20mg of nifedipine [correspondence]. N Engl J Med. 1993; on underlying pathophysiology can be used to optimize cardiac output and thus maintain end-organ perfusion 15. Christman B, McPherson C, Newman J, et al. An imbal- and oxygenation. Future advances in the understanding ance between the excretion of thromboxane and prosta- and management of chronic PAH as well as acute RHF cyclin metabolites in pulmonary hypertension. N Engl J will hopefully result in improved functional capacity, quality of life, and survival in patients with PAH.
16. Tuder R, Cool C, Geraci M, et al. Prostacyclin synthase expression is decreased in lungs from patients withsevere pulmonary hypertension. Am J Respir Crit Care References
17. McLaughlin V, Shillington A, Rich S. Survival in primary 1. Burrows F, Klinck J, Rabinovitch M, Bohn D. Pulmonary pulmonary hypertension: the impact of epoprostenol ther- hypertension in children: perioperative management. Can apy. Circulation. 2002;106:1477-1482.
Anaesth Soc J. 1986;33:606-628.
18. Sitbon O, Humbert M, Nunes H, et al. Long-term intra- 2. Rodriguez R, Pearl R. Pulmonary hypertension and venous epoprostenol infusion in primary pulmonary major surgery. Anesth Analg. 1998;87:812-815.
hypertension: prognostic factors and survival. J Am Coll 3. Ramakrishna G, Sprung J, Ravi B, Chandrasekaran K, McGoon M. Impact of pulmonary hypertension on the 19. Barst R, Rubin LJ, Long W, et al. A comparison of contin- outcomes of noncardiac surgery. J Am Coll Cardiol.
uous intravenous epoprostenol (prostacyclin) with con- ventional therapy for primary pulmonary hypertension.
4. Barst RJ, McGoon M, Torbicki A, et al. Diagnosis and The Primary Pulmonary Hypertension Study Group. N differential assessment of pulmonary arterial hyperten- Engl J Med. 1996;334:296-302.
sion. J Am Coll Cardiol. 2004;43(Suppl):40-47.
20. Badesch D, Tapson V, McGoon M, et al. Continuous 5. Rubin L. Introduction: diagnosis and management of pul- intravenous epoprostenol for pulmonary hypertension due monary arterial hypertension: ACCP evidence-based clini- to the scleroderma spectrum of disease: a randomized, cal practice guidelines. Chest. 2004;126(Suppl):7-10.
controlled trial. Ann Intern Med. 2000;132:425-434.
6. Simonneau G, Galie N, Rubin LJ, et al. Clinical classi- 21. Barst R, Rubin L, McGoon M, et al. Survival in primary fication of pulmonary hypertension. J Am Coll Cardiol.
pulmonary hypertension with long-term continuous intra- venous prostacyclin. Ann Intern Med. 1994;121:409-415.
7. McGoon M, Gutterman D, Steen V, et al. Screening, 22. Shapiro S, Oudiz R, Cao T, et al. Primary pulmonary early detection, and diagnosis of pulmonary arterial hypertension: improved long-term effects and survival hypertension. Chest. 2004;126(Suppl):14-34.
with continuous intravenous epoprostenol infusion. J 8. Chu J, Kao P, Faul J, Doyle R. High prevalence of Am Coll Cardiol. 1997;30:343-349.
autoimmune thyroid disease in pulmonary arterial 23. McLaughlin V, Genthner D, Panella M, et al. Reduction in hypertension. Chest. 2002;122:1668-1673.
pulmonary vascular resistance with long-term epoprostenol 9. Badesch D, Abman S, Ahearn G, et al. Medical therapy for (prostacyclin) therapy in primary pulmonary hypertension.
pulmonary arterial hypertension: ACCP evidence-based N Engl J Med. 1998;338:273-277.
clinical practice guidelines. Chest. 2004;126(Suppl):35-62.
24. McLaughlin V, Gaine S, Barst R, et al. Efficacy and 10. Rich S, Kaufmann E, Levy P. The effect of high doses of safety of treprostinil: an epoprostenol analog for primary calcium-channel blockers on survival in primary pul- pulmonary hypertension. J Cardiovasc Pharmacol. 2003; monary hypertension [abstract]. N Engl J Med. 1992; 25. Simonneau G, Barst R, Galie N, et al. Continuous sub- 11. Ogata M, Ohe M, Shirato K, et al. Effects of a combi- cutaneous infusion of treprostinil, a prostacyclin ana- nation therapy of anticoagulant and vasodilator on the logue, in patients with pulmonary arterial hypertension: long-term prognosis of primary pulmonary hypertension.
a double-blind, randomized, placebo-controlled trial.
Am J Respir Crit Care Med. 2002;165:800-804.
12. Sitbon O, Humbert M, Ioos V, et al. Who benefits from 26. Oudiz R, Schilz R, Barst R, et al. Treprostinil, a prosta- long-term calcium-channel blocker therapy in primary cyclin analogue, in pulmonary arterial hypertension pulmonary hypertension [abstract]. Am J Respir Crit associated with connective tissue disease. Chest. 2004; Current Therapies for Pulmonary Arterial Hypertension / Takaoka et al 27. Laliberte K, Arneson C, Jeffs R, Hunt T, Wade M.
42. Barst R, Langleben D, Badesch D, et al. The STRIDE-2 Pharmacokinetics and steady-state bioequivalence of Trial: does selectivity matter in endothelin antagonism treprostinil sodium (Remodulin) administered by the for PAH? [abstract]. Proc Am Thorac Soc. 2005;2:A300.
intravenous and subcutaneous route to normal volun- 43. Galie N, Badesch D, Oudiz R, et al. Ambrisentan ther- teers. J Cardiovasc Pharmacol. 2004;44:209-214.
apy for pulmonary arterial hypertension. J Am Coll 28. Olschewski H, Simonneau G, Galie N, et al. Aerosolized iloprost randomized study group: inhaled iloprost for 44. Hanson K, Burns F, Rybalkin S, et al. Developmental severe pulmonary hypertension. N Engl J Med. 2002; changes in lung cGMP phosphodiesterase-5 activity, pro- tein, and message. Am J Respir Crit Care Med. 1998;157: 29. Langer F, Wilhelm W, Tscholl D, et al. Intraoperative inhalation of the long-acting prostacyclin analog iloprost 45. Hanson K, Ziegler J, Rybalkin S, et al. Chronic pulmonary for pulmonary hypertension. J Thorac Cardiovasc Surg.
hypertension increases fetal lung cGMP phosphodi- esterase activity. Am J Physiol. 1998;275:L931-L941.
30. Rex S, Busch T, Vettelschoss M, de Rossi L, Rossaint R, 46. Bharani A, Mathew V, Sahu A, et al. The efficacy and tol- Buhre W. Intraoperative management of severe pul- erability of sildenafil in patients with moderate-to-severe monary hypertension during cardiac surgery with pulmonary hypertension. Indian Heart J. 2003;55:55-59.
inhaled iloprost. Anesthesiology. 2003;99:745-747.
47. Sastry B, Narasimhan C, Reddy N, et al. A study of clin- 31. Schroeder R, Wood G, Plotkin J, Kuo P. Intraoperative use ical efficacy of sildenafil in patients with primary pul- of inhaled PGI2 for acute pulmonary hypertension and monary hypertension. Indian Heart J. 2002;54:410-414.
right ventricular failure. Anesth Analg. 2000;91:291-295.
48. Ghofrani H, Schermuly R, Rose F, et al. Sildenafil for 32. Stewart D, Levy R, Cernacek P, Langleben D. Increased long-term treatment of nonoperable chronic thromboem- plasma endothelin-1 in pulmonary hypertension: marker or bolic pulmonary hypertension. Am J Respir Crit Care Med.
mediator of disease? Ann Intern Med. 1991;114:464-469.
33. Pepke-Zaba J, Morrell N. The endothelin system and its 49. Michelakis E, Tymchak W, Lien D, et al. Oral sildenafil is role in pulmonary arterial hypertension (PAH). Thorax.
an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with 34. Channick R, Simonneau G, Sitbon O, et al. Effects of the inhaled nitric oxide. Circulation. 2002;105:2398-2403.
dual endothelin-receptor antagonist bosentan in patients 50. Doyle R. Early Diagnosis and Treatment of Pulmonary with pulmonary hypertension: a randomized placebo con- Arterial Hypertension. Medscape Pulmonary Medicine trolled study [abstract]. Lancet. 2001;358:1119-1123.
2005. Available at:
35. Sitbon O, Badesch D, Channick R, et al. Effects of the dual 51. Hill N. Therapeutic Options for the Treatment of Pulmonary endothelin receptor antagonist bosentan in patients with Hypertension. Medscape Pulmonary Medicine 2005. Avail- pulmonary arterial hypertension: a 1-year follow-up study.
able at:
52. Wilkins M, Paul G, Strange J, et al. Sildenafil versus 36. Rubin LJ, Badesch D, Barst R, et al. Bosentan therapy Endothelin Receptor Antagonist for Pulmonary Hyper- for pulmonary arterial hypertension. N Engl J Med.
tension (SERAPH) study. Am J Respir Crit Care Med.
37. McLaughlin V, Sitbon O, Badesch D, et al. Survival with 53. Preston I, Klinger J, Houtches J, Nelson D, Farber H, Hill first-line bosentan in patients with primary pulmonary N. Acute and chronic effects of sildenafil in patients with hypertension. Eur Respir J. 2005;25:244-249.
pulmonary arterial hypertension. Respir Med. 2005;99: 38. Hoeper M, Halank M, Marx C, et al. Bosentan therapy for portopulmonary hypertension. Eur Respir J. 2005; 54. Ghofrani H, Voswinckel R, Reichenberger F, et al.
Differences in hemodynamic and oxygenation responses to 39. Hughes R, George P, Parameshwar J, et al. Bosentan in three different phosphodiesterase-5 inhibitors in patients inoperable chronic thromboembolic pulmonary hyper- with pulmonary arterial hypertension: a randomized tension. Thorax. 2005;60:707.
prospective study. J Am Coll Cardiol. 2004;44:1488-1496.
40. Barst R, Langleben D, Frost A, et al. Sitaxsentan therapy 55. Palmieri E, Affuso F, Fazio S, Lembo D. Tadalafil in pri- for pulmonary arterial hypertension. Am J Respir Crit mary pulmonary arterial hypertension. Ann Intern Med.
41. Langleben D, Hirsch A, Shalit E, Lesenko L, Barst R.
56. Hoeper M, Taha N, Bekjarova A, Gatzke R, Spiekerkoetter E.
Sustained symptomatic, functional, and hemodynamic Bosentan treatment in patients with primary pulmonary benefit with the selective endothelin-A receptor antago- hypertension receiving nonparenteral prostanoids [abstract].
nist, sitaxsentan, in patients with pulmonary arterial Eur Respir J. 2003;22:330-334.
hypertension: a 1-year follow-up study. Chest. 2004;126: 57. Seyfarth H, Pankau H, Hammerschmidt S, Schauer J, Wirtz H, Winkler J. Bosentan improves exercise tolerance Seminars in Cardiothoracic and Vascular Anesthesia / Vol. 11, No. 2, June 2007 and Tei index in patients with pulmonary hypertension and pulmonary thromboendarecterectomy. World J Surg.
prostanoid therapy [abstract]. Chest. 2005;128:709-713.
58. Humbert M, Barst R, Robbins I, et al. Combination of 73. International guidelines for the selection of lung transplant bosentan with epoprostenol in pulmonary arterial hyper- patients. The American Society for Transplant Physicians tension: BREATHE-2. Eur Respir J. 2004;24:353-359.
(ASTP)/American Thoracic Society(ATS)/European Respi- 59. Ghofrani H, Rose F, Schermuly R, et al. Oral sildenafil as ratory Society(ERS)/International Society for Heart and long-term adjunct therapy to inhaled iloprost in severe pul- Lung Transplantation(ISHLT). Am J Respir Crit Care Med.
monary arterial hypertension. J Am Coll Cardiol. 2003; 74. Hertz M, Mohacsi P, Taylor D, et al. The registry of the 60. Stiebellehner L, Petkov V, Vonbank K, et al. Long-term International Society of Heart and Lung Transplantation: treatment with oral sildenafil in addition to continuous twentieth official report. J Heart Lung Transplant. 2003; IV epoprostenol in patients with pulmonary arterial hypertension. Chest. 2003;123:1293-1295.
75. Boujoukos A, Martich G, Vega J, et al. Reperfusion 61. Wilkens H, Guth A, Konig J, et al. Effect of inhaled iloprost injury in single lung transplant recipients with pul- plus oral sildenafil in patients with primary pulmonary monary hypertension and emphysema. J Heart Lung hypertension. Circulation. 2001;104:1218-1222.
62. Hoeper M, Faulenbach C, Golpon H, Winkler J, Welte 76. Cooper J, Patterson G, Trulock E. Results of single and T, Niedermeyer J. Combination therapy with bosentan bilateral lung transplantation in 131 consecutive recipi- and sildenafil in idiopathic pulmonary arterial hyperten- ents. Washington University Lung Transplant Group. J sion. Eur Respir J. 2004;24:1007-1010.
Thorac Cardiovasc Surg. 1994;107:460-470.
63. Fuster V, Steele P, Edwards W, Gersh B, McGoon M, 77. Guarracino F, Cariello C, Danella A, et al. Right ven- Frye R. Primary pulmonary hypertension: natural his- tricular failure: physiology and assessment. Minerva tory and the importance of thrombosis. Circulation.
78. De Marco T, Chatterjee K. Refractory heart failure: a ther- 64. Rich S, Seidlitz M, Dodin E, et al. The short-term apeutic approach. J Intensive Care Med. 1996;11:121-148.
effects of digoxin in patients with right ventricular dys- 79. Mebazaa A, Karpati P, Renaud E, Algotsson L. Acute right function from pulmonary hypertension. Chest. 1998; ventricular failure—from pathophysiology to new treat- ments. Intensive Care Med. 2004;30:185-196.
65. Reitz B, Wallwork J, Hunt S, et al. Heart-lung transplanta- 80. Packer M. Vasodilator therapy for primary pulmonary tion: successful therapy for patients with pulmonary vascu- hypertension: limitations and hazards. Ann Intern Med.
lar disease. N Engl J Med. 1982;306:557-564.
66. Doyle R, McCrory DC, Channick R, Simonneau G, Conte 81. McNeil K, Dunning J, Morrell N. The pulmonary physician J. Surgical treatments/interventions for pulmonary arterial in critical care: 13. The pulmonary circulation and right hypertension. Chest. 2004;126(Suppl):63-71.
ventricular failure in the ITU. Thorax. 2003;58:157-162.
67. Glanville A, Burke C, Theodore J, et al. Primary pulmonary 82. Borade S, Christenson J, O’Connor M, Lavoie A, hypertension; length of survival in patients referred for Pohlman A, Hall J. Response to inhaled nitric oxide in heart-lung transplantation. Chest. 1987;91:675-681.
patients with acute right heart syndrome. Am J Respir 68. Kerstein D, Levy P, Hsu D, et al. Blade balloon atrial Crit Care Med. 1999;159:571-579,.
septostomy in patients with severe primary pulmonary 83. Ukkonen H, Saraste M, Akkila J, et al. Myocardial effi- hypertension. Circulation. 1995;91:2028-2035.
ciency during levosimendan infusion in congestive heart 69. Bergin C, Sirlin C, Hauschildt J, et al. Chronic throm- failure. Clin Pharmacol Ther. 2000;68:522-531.
boembolism: diagnosis with helical CT and MR imaging 84. Slawsky M, Colucci W, Gottlieb S. Acute hemodynamic with angiographic and surgical correlation. Radiology.
and clinical effects of levosimendan in patients with severe heart failure. Circulation. 2000;102:2222-2227.
70. Bergin C, Hauschildt J, Brown M, et al. Identifying the 85. Piazza G, Goldhaber S. The acutely decompensated right cause of unilateral hypoperfusion in patients suspected to ventricle: pathways for diagnosis and management. Chest.
have chronic pulmonary thromboembolism: diagnostic accuracy of helical CT and conventional angiography.
86. Hirsch L, Rooney M, Wat S, Kleinmann B, Mathru M.
Norepinephrine and phenylephrine effects on right ven- 71. Moser K, Daily P, Peterson K, et al. Thromboendarterec- tricular function in experimental canine pulmonary tomy for chronic, major-vessel thromboembolic pul- embolism. Chest. 1991;100:796-801.
monary hypertension: immediate and long-term results 87. Gold J, Cullilnane S, Chen J, et al. Vasopressin in in 42 patients. Ann Intern Med. 1987;107:560-565.
the treatment of milrinone-induced hypotension in 72. Gilbert T, Gaine S, Rubin L, Sequireira A. Short severe heart failure [abstract]. Am J Cardiol. 2000;85: outcome and predictors of adverse events following


Allegra gabriele m

Beato Gabriele M. Allegra OFM (1907-1976) 1. La beatificazione di Padre Gabriele Allegra, nella festa dei Santi Arcangeli Michele, Gabriele e Raffaele, è un grande dono che il Santo Padre fa alla Chiesa intera, all’Ordine dei Frati Minori Francescani, e, in particolare, alla Sicilia, terra di antichissima tradizione cristiana, largamente benedetta dal Signore con la santità e la testim

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