Acute Pulmonary Vasodilator Testing Research Articles

Acute Pulmonary Vasodilator Testing and Long-Term Clinical Course in Segmental Pulmonary Vascular Disease.

Results of acute pulmonary vasodilator testing (AVT) and the outcome of medical therapy have not been described in patients with segmental pulmonary vascular disease (SPVD). We sought to compare the pulmonary vasodilatory effects of oxygen, oxygen with nitric oxide, and diltiazem, and to describe the clinical course of patients with SPVD and pulmonary hypertension. A retrospective review of 16 patients with pulmonary hypertension and SPVD involving 2-3 major lung segments who underwent AVT between January 2000 and December 2015 was performed. Baseline hemodynamic measurements were obtained with patients breathing ≤ 30% oxygen. AVT was performed using 100% oxygen, 100% oxygen with 20ppm nitric oxide, 21-35% oxygen, and 21-35% oxygen with intravenous diltiazem. The events associated with their long-term care were described. Nine of 16 patients were acutely responsive during AVT using the Sitbon criteria. The change in mean pulmonary artery pressure with oxygen or oxygen with nitric oxide (19 ± 12mmHg) was significantly greater than the change with diltiazem (7 ± 5mmHg). Pulmonary vasodilator therapy was initiated or escalated after AVT in 12 patients. Five patients subsequently experienced a decrease in mean pulmonary artery pressure or normalization in B-type natriuretic peptide. Three patients experienced adverse events associated with therapy. The actuarial survival was 94% over a period of 1-20years. This study suggests that AVT can be used to identify patients with SPVD who are reactive to oxygen, oxygen with nitric oxide, and diltiazem. Clinical improvement was temporally associated with pulmonary vasodilator therapy in some patients with few adverse effects.

Portopulmonary hypertension in children: a rare but potentially lethal and under-recognized disease.

Portopulmonary hypertension (PoPH) is defined by the combination of portal hypertension and precapillary pulmonary arterial hypertension (PAH). Very little is known about this process in pediatric patients but prognosis is generally poor. We review our institutional experience and report on five patients with pediatric PoPH. The median age of PoPH diagnosis was six years and PAH was 14 years. PAH diagnosis was made by echocardiogram in all patients, four of whom also had cardiac catheterization. The median mean pulmonary artery pressure (mPAP) was 48.5 mmHg (interquartile range [IQR] = 46–60) with a median pulmonary vascular resistance index (PVRi) of 9 WU*M2 (IQR = 8–22). All were acute pulmonary vasodilator testing non-responsive. All patients received targeted therapies. Three of five patients (60%) died despite an evidence-based approach to care. Of those who died, timing from the PoPH diagnosis to death ranged from three days to three years. Based upon our limited experience, PoPH is a disorder with significant mortality in childhood and challenges in treatment. Future research, focused on screening and early targeted treatment strategies, may alter the current dismal prognosis for these children.

Red blood cell distribution width predicts responsiveness of acute pulmonary vasodilator testing in patients with idiopathic pulmonary arterial hypertension

BackgroundRed blood cell distribution width (RDW) has been shown to predict clinical outcomes in cardiopulmonary vascular diseases. We investigated whether RDW is useful to predict responsiveness of acute pulmonary vasodilator testing in patients with idiopathic pulmonary arterial hypertension (IPAH). MethodsRDW was determined in 167 IPAH patients who underwent acute pulmonary vasodilator testing. All subjects were followed up for 20±10months. ResultsNineteen out of 167 patients (11.4%) were acute pulmonary vasodilator testing responders. Patients with lower RDW levels ≤13.65% (sensitivity 89.5%, specificity 52.7%; AUC: 0.747, 95% CI: 0.632 to 0.861) were more likely to have a positive response. Multivariate logistic regression analysis showed that RDW≤13.65% independently predicted responsiveness of vasodilator testing in patients with IPAH (OR 18.453, 95% CI 2.279–149.391, p=0.006). RDW correlated with disease severity evaluated by clinical parameters. Patients with increased RDW (>13.65%) had significantly increased risk of all-cause death (Log-rank p=0.007). ConclusionsRDW independently predicts responsiveness of acute pulmonary vasodilator testing in patients with IPAH. RDW is associated with disease severity and all-cause death.

Acute Pulmonary Vasodilator Testing With Inhaled Treprostinil in Children With Pulmonary Arterial Hypertension

Acute pulmonary vasodilator testing (AVT) is essential to determining the initial therapy for children with pulmonary arterial hypertension (PAH). This study aimed to report the initial experience with inhaled treprostinil used for AVT in children with PAH and to evaluate the hemodynamic change after inhaled treprostinil compared with inhaled nitric oxide. This prospective cohort study was designed for 13 children who underwent AVT with inhaled treprostinil or oxygen plus inhaled nitric oxide (iNO) during catheterization. Inhaled treprostinil was delivered during cardiac catheterization by adapting the Optineb ultrasonic nebulizer via either a flow-inflating bag or the manual mode of the anesthesia system. The median age of the patients was 10 years (range 4-17 years). The etiologies of PAH included idiopathic PAH and associated PAH. All the patients tolerated inhaled treprostinil without marked clinical worsening and received six or nine breaths (36 or 54 μg) of treprostinil. The median of the total treprostinil doses was 1.53 μg/kg (range 0.71-2.89 μg/kg). Inhaled treprostinil was administrated via an endotracheal tube (n = 8), anesthesia mask (n = 3), or laryngeal mask airway (n = 2). Inhaled nitric oxide (iNO) and inhaled treprostinil significantly decreased the mean pulmonary artery pressure and the pulmonary vascular resistance index compared with baseline. Three adverse events were reported after inhaled treprostinil, including cough and mild to moderate hypotension with higher doses. All adverse events resolved without any intervention. This study report is the first to describe the use of inhaled treprostinil for AVT in children with PAH. In this small pediatric cohort, inhaled treprostinil was effectively delivered and well tolerated and may be useful for AVT.

Right-Heart Function Related to the Results of Acute Pulmonary Vasodilator Testing in Patients with Pulmonary Arterial Hypertension Caused by Connective Tissue Disease

Acute pulmonary vasodilator testing is important for patients with pulmonary arterial hypertension, but little is known about the predictors of response to such testing. Forty-eight patients (mean age, 41.3 ± 11.6 years; 91.7% women) with pulmonary arterial hypertension associated with connective tissue diseases who underwent right-heart catheterization and acute pulmonary vasodilator testing were prospectively recruited. Echocardiography was performed before and immediately after testing. There were 14 responders (29.2%) to acute pulmonary vasodilator testing. Responders had lower pulmonary vascular resistance, higher peak systolic velocity of the lateral tricuspid valve annulus (right ventricular [RV] S') and tricuspid annular plane systolic excursion, and smaller RV end-diastolic area. After vasodilator testing, mean pulmonary artery pressure and pulmonary vascular resistance decreased significantly in both groups, cardiac index increased significantly in responders, and RV function improved significantly in nonresponders. Receiver operating characteristic curve analysis identified an optimal cutoff value for RV S' of ≥10.5 cm/sec to predict response, with sensitivity of 71% and specificity of 71%. There were more responders among patients with RV S' ≥ 10.5 cm/sec (45.5% vs 15.4%, P = .02). On multivariate logistic regression analysis, RV S' ≥ 10.5cm/sec emerged as an independent predictor of response (odds ratio, 4.58; 95% confidence interval, 1.18-17.79; P = .02). Right-heart function is better in responders to acute pulmonary vasodilator testing than in nonresponders among patients with pulmonary arterial hypertension associated with connective tissue diseases, and pulmonary vasodilators may improve RV function in nonresponders and cardiac index in responders. RV S' is a simple and clinically useful tool for predicting the results of pulmonary vasodilator testing.

Outcome of Pediatric Patients With Pulmonary Arterial Hypertension in the Era of New Medical Therapies

Little is known about the effects of "second-generation drugs" (prostanoids, endothelin receptor antagonists, 5-phosphodiesterase inhibitors) in children with pulmonary arterial hypertension (PAH). This study describes the outcome of a national cohort of children with PAH in an era when these drugs became available. From 1993 to 2008, 52 consecutive children with idiopathic PAH (n = 29) or systemic-to-pulmonary shunt-associated PAH (n = 23) underwent baseline and follow-up assessments. Treatment was initiated depending on functional class, acute pulmonary vasoreactivity response, and drug availability. Observed survival was evaluated depending on time of diagnosis in relation to second-generation drug availability and subsequently compared to calculated predicted survival. Children for whom second-generation drugs were available had improved survival compared to their predicted survival (1-, 3-, and 5-year survival rates 93%, 83%, and 66% vs 79%, 61%, and 50%, respectively). However, this improved survival was observed only in patients for whom second-generation drugs became available during their disease course. No improved survival was observed in patients for whom drugs were available already at diagnosis. Baseline variables associated with decreased survival included higher functional class, higher pulmonary-to-systemic arterial pressure ratio, lower cardiac index, and higher serum levels of N-terminal pro-brain natriuretic peptide and uric acid. After start of second-generation drugs, functional class, 6-minute walking distance, and N-terminal pro-brain natriuretic peptide improved but gradually decreased after longer follow-up. In conclusion, survival of pediatric PAH seemed improved since the introduction of second-generation drugs only in selected patients for whom these drugs became available during their disease course. Start of second-generation drugs initially induced clinical improvements, but these effects decreased after longer follow-up.

Polymorphism in the Angiotensin II Type 1 Receptor ( AGTR1) is Associated With Age at Diagnosis in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a rare, lethal disease associated with single gene disorders, connective tissue disease, exposures to anorexigens, and often, idiopathic etiology. Genes can modify the risk of PAH: (1) monogenic disorders associated with PAH are incompletely penetrant, and (2) not all patients with associated conditions at increased risk for PAH develop the disease. The renin angiotensin aldosterone system (RAAS) provides a set of candidate genes that could modulate pulmonary vascular disease similar to its effects on renal and peripheral vasculature. We studied 247 patients with PAH, comprising 177 with idiopathic PAH (IPAH), 63 with PAH/connective tissue disease (CTD), and 7 with PAH associated with anorexigens. Patients were genotyped for 5 common polymorphisms in angiotensinogen (AGT), angiotensin-converting enzyme (ACE), cardiac chymase A (CMA1), angiotensin II type 1 receptor (AGTR1), and aldosterone synthase (CYP11B2). Genotypes were tested for associations with age at diagnosis, hemodynamic parameters at diagnosis, and/or response to acute pulmonary vasodilator testing at diagnosis. Associations were demonstrated for AGTR1 and age at diagnosis in IPAH (p = 0.005). Homozygotes for the 1166C allele (n = 13) were associated with an age at diagnosis 26 years later than those with A/A (n = 139) or A/C (n = 90) genotypes. No associations were demonstrated for AGT, ACE, CMA1, or CYP11B2. The 1166C polymorphism in AGTR1 appears to be associated with a later age at diagnosis in IPAH, suggesting that this pathway could be involved in the biologic variability that is known to occur in PAH.

What might be learned from acute pulmonary vasodilator testing in portopulmonary hypertension?

In the current issue of Liver Transplantation, Ricci et al.1 report their results of acute pulmonary vasodilator (VD) testing with inhaled nitric oxide (NO), intravenous prostacyclin (PGI2), and oral isosorbide-5-mononitrate (Is-5-MN) in patients with portopulmonary hypertension (POPH). PGI2 elicited greater reductions in mean pulmonary artery pressure (11.8%) and pulmonary vascular resistance (24%) than NO (5.7% and 11%, respectively). The mechanisms were largely due to a 28% drop in systemic vascular resistance and a 17% increase in cardiac index, although another important difference in hemodynamic response may have been the route of administration. Intravenous administration delivers medication directly to the endothelial cell while diffusion to the vascular smooth muscle cell is required when medication is inhaled. Is-5-MN decreased mean pulmonary artery pressure by 25.6% and pulmonary vascular resistance by 21.5% without systemic changes. Overall, 6 of 19 patients (32%) had decreased mean pulmonary artery pressure <35 mmHg and would have been considered potential liver transplantation candidates. VD, vasodilator; POPH, portopulmonary hypertension; PAH, pulmonary artery hypertension. Traditionally, acute VD testing has been used to determine which patients might have a beneficial response to oral vasodilator therapy (calcium antagonists) as initial treatment for pulmonary artery hypertension (PAH).2, 3 What is a positive VD response? What does it mean? The definition continues to evolve over time and, 2 definitions were used in the current study. In general, a positive VD response identifies patients who have a more favorable hemodynamic profile, such as having vasoconstriction as the predominant mechanism for the increased pulmonary artery pressures.4 Approximately 10% of patients with PAH will have such a positive VD response.5 Several medications are available for acute pulmonary VD testing and which to use depends largely on availability, cost, and convenience. Acute pulmonary VD testing in POPH specifically, has fallen out of favor because these patients do not tolerate calcium channel blockers, which worsen edema and portal hypertension by increasing the hepatic vein portal pressure gradient.6 Unique and varying hemodynamic patterns exist in POPH compared to other forms of PAH and, pressure-flow-volume-resistance relationships may influence therapeutic approaches.7 High-flow states and excess volumes exist in POPH and may be rare in other forms of PAH. What happens to these vascular relationships in response to acute VD testing in POPH and are they prognostic? In the current series, for example, baseline pulmonary artery occlusion pressures were normal; however, we do not know what happened to the individual pulmonary artery occlusion pressures in response to the acute administration of NO compared with PGI2 or Is-5-MN. Given the small sample size, the individual patient data, including the responses of pulmonary artery occlusion pressure and transpulmonary gradient (mean pulmonary artery pressure–pulmonary artery occlusion pressure) rather than the overall median responses of pulmonary vascular resistance and cardiac index would have been helpful. Medications of different classes may influence these vascular relationships in different ways and these interactions may clinically be relevant and are important to understand. It is intuitive that not all patients experience the same response to the same medication, thus the purpose of combining medications with different mechanisms of action.8 One important point that deserves emphasis is that patients who do not respond to acute VD testing may still respond to medications for PAH. In other words, a negative VD challenge should not preclude treatment. This goes beyond acute vasodilatation and involves more complex issues of vascular remodeling. Intimal proliferation and vascular smooth muscle hypertrophy both cause luminal obliteration and obstruction to arterial blood flow. Current therapies for PAH act to prevent or reverse this remodeling while calcium channel blockers and Is-5-MN are pure vasodilators. The authors ask whether acute pulmonary VD testing might have a relevant role in developing a therapeutic strategy for patients with POPH who might ultimately be candidates for liver transplantation. This is a question that must be answered in all severities of pulmonary hypertension to truly understand the pressure-volume-flow-resistance interactions and responses to varying medications in POPH. Indeed, with the development of mechanistically different therapies for PAH, it is time to reevaluate the role of acute pulmonary VD testing and its potential influence on medication selection and outcomes in POPH with or without liver transplantation.

Assessment of acute pulmonary vascular reactivity in portopulmonary hypertension

The role of acute pulmonary vasodilator testing in portopulmonary hypertension (PoPH), a current contraindication for orthotopic liver transplantation (OLT), has not been thoroughly elucidated. The purpose of this work was to analyze the results of acute vasodilator testing with inhaled nitric oxide (NO), to compare them with intravenous epoprostenol (PGI(2)), and to investigate the acute effects of the oral vasodilator isosorbide-5-mononitrate (Is-5-MN), in patients with PoPH. A total of 19 patients with PoPH (male/female = 9/10) were studied. Pulmonary hemodynamic measurements were performed at baseline and during NO inhalation (40 ppm); additionally, 15 patients were tested with PGI(2) (2-12 mug/kg/minute) and 8 were tested with Is-5-MN (20-40 mg). Inhaled NO reduced pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) by 5.7% and 11.0%, respectively. PGI(2) elicited greater reductions in PAP (11.8%) and PVR (-24.0%), and produced a 28% drop in systemic vascular resistance (SVR) and a 17% increase in the cardiac index (CI). Is-5-MN reduced PAP by 25.6% and PVR by 21.5%, without systemic changes. There was good agreement between the response to PGI(2) and Is-5-MN: 6 patients of the whole series (32%) decreased PAP >20% from baseline, reaching a final value < or = 35 mmHg, the current limit for OLT. In conclusion, acute vasodilator testing has a relevant role in PoPH, as it identifies one-third of patients able to reach a more favorable hemodynamic situation, which can be determinant for their management. For vasodilator testing, PGI(2) is more suitable than NO in PoPH. Is-5-MN exerts a selective effect on pulmonary circulation in patients who had already responded to PGI(2).

Issue Highlights

HomeCirculationVol. 111, No. 23Issue Highlights Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBIssue Highlights Originally published14 Jun 2005https://doi.org/10.1161/circ.111.23.3015Circulation. 2005;111:3015ALDOSTERONE SYNTHASE INHIBITOR AMELIORATES ANGIOTENSIN II–INDUCED ORGAN DAMAGE, by Fiebeler et al.Aldosterone has been shown to contribute to angiotensin II–induced end-organ damage, and clinical studies have confirmed the benefit of adding aldosterone antagonists to angiotensin-converting enzyme inhibitor agents to prevent adverse remodeling. Angiotensin II increases circulating levels of aldosterone levels as well as de novo tissue synthesis of aldosterone by stimulating aldosterone synthase (CYP11B2); however, it is unknown which source of aldosterone plays a greater role in tissue remodeling and damage. In these studies, Fiebeler et al examine this question by utilizing both FAD286, a novel CYP11B2 inhibitor, and adrenalectomy in transgenic rats overexpressing human renin and angiotensinogen genes. Using these models, they are able to isolate the source of aldosterone that modulates some of the adverse cardiac and renal effects associated with hyperaldosteronism. See p 3087.LONG-TERM RESPONSE TO CALCIUM CHANNEL BLOCKERS IN IDIOPATHIC PULMONARY ARTERIAL HYPERTENSION, by Sitbon et al.Characteristics of patients with idiopathic pulmonary arterial hypertension (IPAH) who benefit from long-term calcium channel blockers (CCBs) are unknown. Sitbon and colleagues performed acute pulmonary vasodilator testing with epoprostenol or nitric oxide during initial right heart catheterization in 557 IPAH patients. Acute responders were treated initially with oral CCB. Long-term CCB responders were defined as those being in functional class I or II after at least 1 year on CCB monotherapy. Among the 70 patients (12.6%) who displayed acute pulmonary vasoreactivity and received CCB therapy, 38 (6.7%) improved long term. Long-term CCB responders had less severe disease at baseline and displayed a more pronounced fall in mean pulmonary artery pressure during acute vasodilator testing. Of note, long-term CCB responders represented less than 10% of IPAH patients evaluated in a pulmonary vascular referral center. These data suggest that routine administration of CCB as first-line therapy in IPAH patients may be ill advised. See p 3105.APOLIPOPROTEIN E MIMETIC PEPTIDE DRAMATICALLY LOWERS PLASMA CHOLESTEROL AND RESTORES ENDOTHELIAL FUNCTION IN WATANABE HERITABLE HYPERLIPIDEMIC RABBITS, by Gupta et al.Elevated high-density lipoprotein (HDL) levels are associated with a reduction in the frequency of cardiovascular events. To develop new drugs for the treatment of atherosclerosis, investigators have been evaluating the therapeutic properties of HDL components in both animal models of vascular disease and patients with coronary atherosclerosis. However, some of these agents are structurally complex and difficult to produce. In this issue of Circulation, Gupta et al analyze the atheroprotective properties of a synthetic peptide containing the arginine-rich receptor-binding domain of ApoE fused to an amphipathic helical peptide that possesses ApoA-I–like properties. A single administration of the dual-domain peptide dramatically reduces plasma cholesterol levels and improves vascular reactivity in a dyslipidemic rabbit model. These improvements coincide with a reduction in markers of oxidative stress that are associated with vascular inflammation. These data suggest that this HDL-mimetic peptide could make ‘good‘ cholesterol better and have utility for the treatment of atherosclerosis. See p 3112.Visit http://www.circ.ahajournals.org:Cardiology Patient PageHow to Respond to an Implantable Cardioverter-Defibrillator Shock. See p e380.Images in Cardiovascular MedicineReversible Right Ventricular Hypertrophy Due to Cardiac Sarcoidosis. See p e383. Download figureDownload PowerPointThree-Dimensional Imaging in Rupture of Papillary Muscle After Acute Myocardial Infarction. See p e385.Angiosarcoma of the Pericardium: A Fatal Disease. See p e388.CorrespondenceSee p e390. Previous Back to top Next FiguresReferencesRelatedDetails June 14, 2005Vol 111, Issue 23 Advertisement Article InformationMetrics https://doi.org/10.1161/circ.111.23.3015 Originally publishedJune 14, 2005 PDF download Advertisement

Long-Term Response to Calcium Channel Blockers in Idiopathic Pulmonary Arterial Hypertension

Characteristics of patients with idiopathic pulmonary arterial hypertension (IPAH) who benefit from long-term calcium channel blockers (CCB) are unknown. Acute pulmonary vasodilator testing with epoprostenol or nitric oxide was performed in 557 IPAH patients. Acute responders, defined by a fall in both mean pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) >20%, received long-term oral CCB. Patients who benefit from long-term CCB were defined as those being in New York Heart Association (NYHA) functional class I or II after at least 1 year on CCB monotherapy. Among the 70 patients who displayed acute pulmonary vasoreactivity (12.6%; 95% CI, 9.8% to 15.3%) and received CCB therapy, only 38 showed long-term improvement (6.8%; 95% CI, 4.7% to 8.9%). Long-term CCB responders had less severe disease at baseline than patients who failed. During acute vasodilator testing, long-term CCB responders displayed a more pronounced fall in mean PAP (-39+/-11% versus -26+/-7%; P<0.0001), reaching an absolute value of mean PAP lower than that measured in patients who failed (33+/-8 versus 46+/-10 mm Hg; P<0.0001). After 7.0+/-4.1 years, all but 1 long-term CCB responders were alive in NYHA class I or II, with a sustained hemodynamic improvement. In the group of patients who failed on CCB, the 5-year survival rate was 48%. Long-term CCB responders represent <10% of IPAH patients evaluated in a pulmonary vascular referral center. During acute vasodilator testing, these patients showed significantly lower levels of both mean PAP and PVR, which reached near-normal values.

Combined effects of nitric oxide and oxygen during acute pulmonary vasodilator testing

OBJECTIVESWe compared the ability of inhaled nitric oxide (NO), oxygen (O2) and nitric oxide in oxygen (NO+O2) to identify reactive pulmonary vasculature in pulmonary hypertensive patients during acute vasodilator testing at cardiac catheterization.BACKGROUNDIn patients with pulmonary hypertension, decisions regarding suitability for corrective surgery, transplantation and assessment of long-term prognosis are based on results obtained during acute pulmonary vasodilator testing.METHODSIn group 1, 46 patients had hemodynamic measurements in room air (RA), 100% O2, return to RA and NO (80 parts per million [ppm] in RA). In group 2, 25 additional patients were studied in RA, 100% O2and 80 ppm NO in oxygen (NO+O2).RESULTSIn group 1, O2decreased pulmonary vascular resistance (PVR) (mean ± SEM) from 17.2 ± 2.1 U·m2to 11.1 ± 1.5 U·m2(p < 0.05). Nitric oxide caused a comparable decrease from 17.8 ± 2.2 U·m2to 11.7 ± 1.7 U·m2(p < 0.05). In group 2, PVR decreased from 20.1 ± 2.6 U·m2to 14.3 ± 1.9 U·m2in O2(p < 0.05) and further to 10.5 ± 1.7 U·m2in NO+O2(p < 0.05). A response of 20% or more reduction in PVR was seen in 22/25 patients with NO+O2compared with 16/25 in O2alone (p = 0.01).CONCLUSIONSInhaled NO and O2produced a similar degree of selective pulmonary vasodilation. Our data suggest that combination testing with NO+O2provides additional pulmonary vasodilation in patients with a reactive pulmonary vascular bed in a selective, safe and expeditious fashion during cardiac catheterization. The combination of NO+O2identifies patients with significant pulmonary vasoreactivity who might not be recognized if O2or NO were used separately.