Pulmonary Arterial Hypertension

Scientific Updates – January 2005

Compiled by

United Therapeutics Corporation

Severe paediatric pulmonary hypertension: new management strategies.

Arch Dis Child. 2005 Jan;90(1):92-8

Rashid A, Ivy D.

Queens Medical Centre, Nottingham, UK.

Pulmonary hypertension is a significant complication in many paediatric disease states. This article discusses current understanding of pulmonary hypertension and includes definition, diagnosis, and management. A description of the latest advances in targeted pharmacological therapy in children is also provided as well as impact on morbidity and mortality.

Publication Types:

· Review

Inhaled nitric oxide in pediatric cardiac surgery.

Int Anesthesiol Clin. 2004 Fall;42(4):93-100

Kawakami H, Ichinose F.

Department of Anesthesia and Critical Care, Massachusetts General Hospital, Boston 02114, USA.

Publication Types:

· Review

A rare consequence of uncorrected atrial septal defect: diffuse pulmonary artery aneurysms.

Tex Heart Inst J. 2004;31(3):328-9

Cevik C, Izgi C, Boztosun B.

Kosuyolu Heart & Research Hospital, Department of Cardiology, 81020 Istanbul, Turkey. drcihancevik00@yahoo.com

Publication Types:

· Case Reports

High frequency oscillatory ventilation in acute respiratory failure.

Paediatr Respir Rev. 2004 Dec;5(4):323-32

Ventre KM, Arnold JH.

Department of Anesthesia, Children's Hospital Boston and the Departments of Anaesthesia and Pediatrics, Harvard Medical School, Boston, MA, USA. kathleen.ventre@childrens.harvard.edu

High frequency oscillatory ventilation (HFOV) has emerged over the past 20 years as a safe and effective means of mechanical ventilatory support in patients with acute respiratory failure. During HFOV, lung recruitment is maintained by application of a relatively high mean airway pressure with superimposed pressure oscillations at a frequency of 3 to 15Hz, creating adequate ventilation using tidal volumes less than or equal to the patient's dead space volume. The physiologic rationale for the application of HFOV in the clinical arena comes from its ability to preserve end-expiratory lung volume while avoiding parenchymal overdistension at end-inspiration and theoretically limiting the potential for ventilator-associated lung injury. Data in the neonatal population suggests significant benefits in pulmonary outcomes when HFOV is applied with a recruitment strategy in preterm infants with respiratory distress syndrome (RDS). Use of HFOV in the paediatric and adult populations has not as yet been associated with significant improvements in clinically important outcome measures.

Publication Types:

· Review

· Review, Tutorial

Successful switch from inhalative iloprost to oral bosentan in portopulmonary hypertension associated with liver cirrhosis.

Wien Klin Wochenschr. 2004 Sep 30;116(17-18):627-30

Molnar C, Alber H, Colleselli D, Vogel W, Kahler CM.

Pneumology Service, Clinical Department of Internal Medicine, Innsbruck Medical University, Innsbruck, Austria.

Portopulmonary hypertension (PPHTN) is a rare complication of liver cirrhosis. Prostanoids have been shown to be effective in the treatment of PPHTN and have been used as a bridge to orthotopic liver transplantation. However, inhibition of platelet aggregation might be a limitation of prostacyclin therapy in patients with end-stage liver disease having an increased risk of bleeding from esophageal varices. The effect of oral bosentan, a dual endothelin-receptor antagonist in the reversal of PPHTN, is still unclear. We report a case of PPHTN (mean pulmonary artery pressure [mPAP] of 51 mmHg) that was successfully switched from inhalative iloprost to oral bosentan therapy. Hemodynamic and symptomatic improvements were maintained after a 12-month long-term treatment with inhalative iloprost as well as after single oral bosentan therapy. This is the first reported case of a successful switch from therapy with an inhalative prostacyclin analogue to oral bosentan in a patient suffering from PPHTN. Thus, oral bosentan therapy might be a promising new option for patients suffering from PPHTN.

Publication Types:

· Case Reports

Diagnosis of pulmonary embolism by acute right heart morphologic and hemodynamic changes observed during exercise stress echocardiography.

J Am Soc Echocardiogr. 2004 Sep;17(9):1005-8

Ramanath VS, Lacomis JM, Katz WE.

Department of Internal Medicine, University of Pittsburgh Medical Center, Pennsylvania 15213-2582, USA.

In addition to the conventional means of diagnosing pulmonary embolism, resting echocardiography has sometimes been useful. We describe the case of a patient with a normal resting transthoracic echocardiogram, but with a markedly abnormal posttreadmill exercise echocardiogram revealing acute right ventricular dilatation, marked ventricular septal shift, and acute pulmonary hypertension. Pulmonary embolism was suspected and subsequently confirmed by chest computed tomographic angiography.

Publication Types:

· Case Reports

Oral sildenafil reduces pulmonary hypertension after cardiac surgery.

Ann Thorac Surg. 2005 Jan;79(1):194-7; discussion 194-7

Trachte AL, Lobato EB, Urdaneta F, Hess PJ, Klodell CT, Martin TD, Staples ED, Beaver TM.

Department of Surgery, Division of Thoracic and Cardiovascular Surgery, University of Florida College of Medicine, Gainesville, Florida 32611, USA.

BACKGROUND: Treatment of postoperative pulmonary hypertension with intravenous (IV) pulmonary vasodilators is hampered by the lack of selectivity. Inhaled nitric oxide produces selective pulmonary vasodilation; however, it requires a special device, and weaning can cause rebound. Oral sildenafil is a phosphodiesterase type V inhibitor. Sildenafil can produce sustained pulmonary vasodilatation in patients with hypoxic or primary pulmonary hypertension; however, experience with postoperative pulmonary hypertension is limited. We report our initial experience with eight patients who received oral sildenafil as adjunctive therapy for postoperative pulmonary hypertension METHODS: We reviewed the charts of eight adult patients with postoperative pulmonary hypertension who received oral sildenafil (25 to 50 mg) to facilitate weaning of IV (milrinone, nitroglycerine, and sodium nitroprusside) and inhaled (nitric oxide) pulmonary vasodilators. Hemodynamic data were recorded before and 30 and 60 minutes after the initial dose of sildenafil. RESULTS: After the initial dose of sildenafil, mean pulmonary artery pressure was reduced by 20% and 22% at 30 and 60 minutes, respectively (p < 0.05). Pulmonary vascular resistance index decreased by 49% and 44% at 30 and 60 minutes, respectively (p < 0.05). Sildenafil had no clinically significant effects on cardiac index, mean arterial pressure, or systemic vascular resistance. Subsequent doses of sildenafil were administered at regular intervals, allowing successful weaning of concomitant pulmonary vasodilators. CONCLUSIONS: Oral sildenafil is an effective agent for treatment of postoperative pulmonary hypertension and can be used to facilitate weaning of inhaled and IV pulmonary vasodilators.

Sustained symptomatic, functional, and hemodynamic benefit with the selective endothelin-A receptor antagonist, sitaxsentan, in patients with pulmonary arterial hypertension: a 1-year follow-up study.

Chest. 2004 Oct;126(4):1377-81

Langleben D, Hirsch AM, Shalit E, Lesenko L, Barst RJ.

Center for Pulmonary Vascular Disease, Room E-258, Sir Mortimer B. Davis Jewish General Hospital, 3755 Cote Ste Catherine, Montreal, Quebec, Canada H3T 1E2. david.langleben@mcgill.ca

STUDY OBJECTIVES: To examine the long-term efficacy and safety of the selective endothelin-A receptor (ET-A) antagonist, sitaxsentan sodium, after 1 year of therapy in patients with pulmonary arterial hypertension (PAH). DESIGN: The study was a Canadian, open-label extension of at least 1-year total of active therapy (sitaxsentan, 100 mg/d), following a preceding, blinded, 12-week placebo controlled trial of sitaxsentan (placebo, or sitaxsentan, 100 mg/d or 300 mg/d), which had then been followed by a blinded active-therapy continuation study (sitaxsentan, 100 mg/d or 300 mg/d). PATIENTS: Eleven patients with PAH were enrolled. The condition of one patient worsened at 7 months of therapy, and the patient transferred to epoprostenol therapy. The remaining 10 patients (idiopathic [n = 3], connective tissue disease [n = 3], congenital heart disease [n = 4]) completed the evaluation after 1 year of active therapy. INTERVENTIONS: The end points of the study included the 6-min walk test, World Health Organization (WHO) functional class, and cardiopulmonary hemodynamic parameters. RESULTS: After 1 year of sitaxsentan therapy, there were significant improvements in 6-min walk distance (50-m treatment effect), WHO functional class, and hemodynamics, as compared to baseline. There were no serious adverse events, and no instances of hepatotoxicity or bleeding. CONCLUSION: Long-term selective ET-A blockade with sitaxsentan sodium is safe and may improve exercise capacity, functional class, and hemodynamics in patients with PAH.

Natriuretic peptides, respiratory disease, and the right heart.

Chest. 2004 Oct;126(4):1330-6

Yap LB, Mukerjee D, Timms PM, Ashrafian H, Coghlan JG.

Department of Cardiology, Homerton University Hospital, Homerton Row, London E9 6SR, UK. lokyap@lycos.com

It is well-recognized that atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) are raised in conditions with ventricular volume and pressure overload. In addition to this established role in left ventricular congestive cardiac failure, there is good evidence that BNP has a diagnostic role in right ventricular (RV) dysfunction and pulmonary arterial hypertension (PAH). For example, BNP levels can be used to differentiate between dyspneic patients with pure respiratory defects and those with RV dysfunction. Studies in patients with PAH have demonstrated significant correlations between BNP levels and mean pulmonary arterial pressure as well as pulmonary vascular resistance. Additionally, BNP has a prognostic role in patients with RV pressure overload and pulmonary hypertension, and it offers a noninvasive test that can be used to guide therapy in patients with PAH. However, although measured plasma proBNP levels are raised in conditions with RV overload, its biological significance is still not well-understood. In this article, we review the general physiologic and potential therapeutic role of natriuretic peptides in respiratory disease, RV dysfunction, and PAH. Furthermore, we assess the various clues toward natriuretic peptide action coming from laboratory studies. ANP and BNP knockout mice develop cardiac fibrosis and hypertrophy. Potentiation of the natriuretic pathway has been shown to reduce cardiac hypertrophy and PAH. This is likely to take place as a result of increased intracellular cyclic guanosine monophosphate levels and subsequent pulmonary vasorelaxant activity. In view of this evidence, there may be a rationale for the therapeutic use of recombinant BNP or neutral endopeptidase inhibitors under conditions of RV dysfunction and PAH.

Publication Types:

· Review

· Review, Tutorial

New formula for predicting mean pulmonary artery pressure using systolic pulmonary artery pressure.

Chest. 2004 Oct;126(4):1313-7

Chemla D, Castelain V, Humbert M, Hebert JL, Simonneau G, Lecarpentier Y, Herve P.

Service EFCR, Broca 7, Hopital de Bicetre, 78 Rue du General Leclerc 94, 275 Le Kremlin Bicetre Cedex, France. denis.chemla@bct.ap-hop-paris.fr

STUDY OBJECTIVES: Mean pulmonary artery pressure (MPAP) and systolic pulmonary artery pressure (SPAP) are used interchangeably to define pulmonary hypertension (PH). We tested the hypothesis that the measurement of MPAP and SPAP is redundant in resting humans over a wide pressure range. DESIGN: Prospective, observational study. SETTING: Catheterization laboratory in a university hospital. PATIENTS: This study involved 31 patients, as follows: primary PH, nine patients; chronic pulmonary thromboembolism, seven patients; venous PH, six patients; and control subjects with normal pulmonary artery pressure, nine patients. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: High-fidelity pulmonary artery pressures were obtained when patients were at rest. Over the wide MPAP range that was under study (10 to 78 mm Hg), MPAP and SPAP were strongly related (r(2) = 0.98). Regression analysis performed on the first 16 subjects (test sample) allowed us to propose a formula (MPAP = 0.61 SPAP + 2 mm Hg), the accuracy of which was confirmed in the remaining 15 subjects (validation sample bias, 0 +/- 2 mm Hg). If PH was defined by an SPAP in excess of 30 or 40 mm Hg, this corresponded to an MPAP in excess of 20 or 26 mm Hg. If PH was defined by an MPAP of > 25 mm Hg, this corresponded to an SPAP of > 38 mm Hg. CONCLUSIONS: In resting humans, MPAP can be accurately predicted from SPAP over a wide pressure range. The new formula may help to refine the threshold pressure values used in the diagnosis of PH. Further studies are needed to test the hypothesis that our formula may allow the noninvasive prediction of MPAP from Doppler-derived SPAP values.

Elevated basic fibroblast growth factor levels in patients with pulmonary arterial hypertension.

Chest. 2004 Oct;126(4):1255-61

Benisty JI, McLaughlin VV, Landzberg MJ, Rich JD, Newburger JW, Rich S, Folkman J.

Karp Family Research Building Room 11213.1, Children's Hospital Boston, 300 Longwood Avenue, Boston, MA 02115-5737, USA. jacques.benisty@childrens.harvard.edu

STUDY OBJECTIVES: Cellular growth in the vascular wall, including endothelial and smooth-muscle cell proliferation, is recognized as a component of the obstructive vasculopathy observed in the small vessels of the lungs in pulmonary arterial hypertension (PAH). We hypothesized that angiogenic growth factors may have a role in the molecular mechanisms underlying this cellular proliferation. DESIGN: Case-control study. SETTING: Multicenter, tertiary care hospitals. PARTICIPANTS: We studied 117 patients with PAH and 60 control subjects. MEASUREMENTS: We measured levels of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) in the blood and urine of these subjects using an enzyme-linked immunoassay. RESULTS: Median levels of urinary and plasma bFGF were significantly higher in patients with PAH compared to normal control subjects. There was a difference in levels of urine and plasma bFGF according to etiology of pulmonary hypertension, with the highest levels seen in patients with primary pulmonary hypertension. Levels of urine or plasma VEGF were not significantly different between patients and control subjects. CONCLUSION: Patients with PAH have substantial alterations in urine and plasma levels of bFGF. This molecule may have a role as a mitogenic factor in the endothelial and smooth-muscle cell proliferation seen in PAH.

Publication Types:

· Multicenter Study

Lung biopsy diagnosis of operative indication in secundum atrial septal defect with severe pulmonary vascular disease.

Chest. 2004 Oct;126(4):1042-7

Yamaki S, Kumate M, Yonesaka S, Maeda K, Endo M, Tabayashi K.

Japanese Research Institution of Pulmonary Vasculature, 40-1 Usagisaku, Shiroishi, Miyagi Pref., Japan 989-0228. syamaki@ff.iij4u.or.jp.

OBJECTIVE: Surgical indication was determined by lung biopsy in 91 patients with secundum atrial septal defect (ASD) and severe pulmonary hypertension > 70 mm Hg of pulmonary arterial peak pressure and/or pulmonary vascular resistance of > 8 U/m(2). METHODS AND RESULTS: Pulmonary vascular disease (PVD) in ASD was classified into four types: (1) Musculoelastosis consisting of longitudinal muscle bundles and elastic fibers; surgery is indicated no matter how severely the peripheral small pulmonary arteries are occluded. Surgery was performed in all of the 20 patients, and the postoperative course was uneventful. (2) Plexogenic pulmonary arteriopathy: surgery is indicated for a PVD index < or = 2.3. Surgery was performed in 25 of the 32 patients. The remaining seven patients for whom surgery was not indicated are under follow-up observation. No deaths have occurred among the 32 patients. (3) Thromboembolism of small pulmonary arteries: Surgery is indicated for all such cases. Surgery was indicated in all of the five patients. (4) Mixed type of plexogenic pulmonary arteriopathy and musculoelastosis: Surgery is indicated if the collateral is not observed. Surgery was performed in 15 of the 25 patients. The remaining 10 patients for whom surgery was not indicated are under follow-up observation. Nine of these 91 patients associated with primary pulmonary hypertension were eliminated from this study. CONCLUSION: No deaths due to PVD occurred among the 82 patients who underwent lung biopsy diagnosis. Lung biopsy diagnosis is concluded to be very effective.

Publication Types:

· Case Reports

BMPR2 mutations in pulmonary arterial hypertension with congenital heart disease.

Eur Respir J. 2004 Sep;24(3):371-4

Roberts KE, McElroy JJ, Wong WP, Yen E, Widlitz A, Barst RJ, Knowles JA, Morse JH.

Dept of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA.

The aim of the present study was to determine if patients with both pulmonary arterial hypertension (PAH), due to pulmonary vascular obstructive disease, and congenital heart defects (CHD), have mutations in the gene encoding bone morphogenetic protein receptor (BMPR)-2. The BMPR2 gene was screened in two cohorts: 40 adults and 66 children with PAH/CHD. CHDs were patent ductus arteriosus, atrial and ventricular septal defects, partial anomalous pulmonary venous return, transposition of the great arteries, atrioventicular canal, and rare lesions with systemic-to-pulmonary shunts. Six novel missense BMPR2 mutations were found in three out of four adults with complete type C atrioventricular canals and in three children. One child had an atrial septal defect and patent ductus arteriosus; one had an atrial septal defect, patent ductus arteriosus and partial anomalous pulmonary venous return; and one had an aortopulmonary window and a ventricular septal defect. Bone morphogenetic protein receptor 2 mutations were found in 6% of a mixed cohort of adults and children with pulmonary arterial hypertension/congenital heart defects. The current findings compliment recent reports in mouse models implicating members of the bone morphogenetic protein/transforming growth factor-beta pathway inducing cardiac anomalies analogous to human atrioventricular canals, septal defects and conotruncal congenital heart defects. The small number of patients studied and the ascertainment bias inherent in selecting for pulmonary arterial hypertension require further investigation.

Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2.

Eur Respir J. 2004 Sep;24(3):353-9

Humbert M, Barst RJ, Robbins IM, Channick RN, Galie N, Boonstra A, Rubin LJ, Horn EM, Manes A, Simonneau G.

Hopital Antoine Beclere, Assistance Publique, Hopitaux de Paris, Universite Paris-Sud, 157 rue de la porte de Trivaux, 92140, Clamart, France. marc.humbert@abc.ap-hop-paris.fr

The efficacy and safety of combining bosentan, an orally active dual endothelin receptor antagonist and epoprostenol, a continuously infused prostaglandin, in the treatment of pulmonary arterial hypertension (PAH) was investigated. In this double-blind, placebo-controlled prospective study, 33 patients with PAH started epoprostenol treatment (2 ng.kg(-1)min(-1) starting dose, up to 14+/-2 ng.kg(-1)min(-1) at week 16) and were randomised for 16 weeks in a 2:1 ratio to bosentan (62.5 mg b.i.d for 4 weeks then 125 mg b.i.d) or placebo. Haemodynamics, exercise capacity and functional class improved in both groups at week 16. In the combination treatment group, there was a trend for a greater (although nonsignificant) improvement in all measured haemodynamic parameters. There were four withdrawals in the bosentan/epoprostenol group (two deaths due to cardiopulmonary failure, one clinical worsening, and one adverse event) and one withdrawal in the placebo/epoprostenol group (adverse event). This study showed a trend but no statistical significance towards haemodynamics or clinical improvement due to the combination of bosentan and epoprostenol therapy in patients with pulmonary arterial hypertension. Several cases of early and late major complications were reported. Additional information is needed to evaluate the risk/benefit ratio of combined bosentan-epoprostenol therapy in pulmonary arterial hypertension.

Publication Types:

· Clinical Trial

· Multicenter Study

· Randomized Controlled Trial

Combination therapy for pulmonary arterial hypertension: still more questions than answers.

Eur Respir J. 2004 Sep;24(3):339-40

Hoeper MM, Dinh-Xuan AT.

Publication Types:

· Editorial

Interventricular Septal Configuration at MR Imaging and Pulmonary Arterial Pressure in Pulmonary Hypertension.

Radiology. 2005 Jan 5; [Epub ahead of print

Roeleveld RJ, Marcus JT, Faes TJ, Gan TJ, Boonstra A, Postmus PE, Vonk-Noordegraaf A.

Departments of Pulmonology and Physics and Medical Technology, VU University Medical Center/Institute of Cardiovascular Research ICaR-VU, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands. a.vonk@vumc.nl.

PURPOSE: To investigate whether a relationship exists between septum shape and systolic pulmonary arterial pressure (PAP) in patients with pulmonary hypertension. MATERIALS AND METHODS: Study protocol was approved by institutional ethics review committee; all patients gave informed consent. Right-sided heart catheterization with vasodilator testing was performed in 39 adult subjects suspected of having pulmonary hypertension. There were 11 men and 28 women, aged 21-75 years (mean, 46 years). Only two patients showed favorable response to vasodilators, defined by a decrease in PAP of more than 20%. Synchronous right- and left-ventricular pressure measurements and four-chamber magnetic resonance (MR) imaging were used to identify timing of maximal leftward ventricular septal bowing within cardiac cycle. Septal bowing was evaluated with MR, measured on short-axis cine heart images, and expressed as curvature (reciprocal of radius). Curvature was quantified on one image (the one that showed the most severe distortion of normal septal shape). The relationship between systolic PAP and septal curvature was tested with linear regression analysis. P < .05 was considered to indicate a statistically significant difference. RESULTS: Of 39 subjects, 37 had pulmonary hypertension. Maximal distortion of normal septal shape was found during right ventricular relaxation phase. Systolic PAP was proportional to septal curvature: r = 0.77 (P < .001), slope = -114.7, and intercept = 67.2. In the two vasodilator responsive subjects, a significant reduction of leftward ventricular septal bowing was observed in response to reduction of right ventricular pressure. CONCLUSION: In 37 patients with pulmonary hypertension, systolic PAP higher than 67 mm Hg may be expected when leftward curvature is observed. Supplemental material: radiology.rsnajnls.org/cgi/content/full/2343040151/DC1 (c) RSNA, 2005.

Different mechanisms for changes in glucose uptake of the right and left ventricular myocardium in pulmonary hypertension.

J Nucl Med. 2005 Jan;46(1):25-31

Kluge R, Barthel H, Pankau H, Seese A, Schauer J, Wirtz H, Seyfarth HJ, Steinbach J, Sabri O, Winkler J.

Department of Nuclear Medicine, University of Leipzig, Leipzig, Germany.

In patients with pulmonary hypertension (PH) the right ventricular (RV)-to-left ventricular (LV) ratio of fatty acid uptake is reduced. In animal studies, such a finding was combined with an increased glucose uptake in RV myocardium. The aim of this study was to measure the metabolic rates of glucose uptake for the RV and LV myocardium in patients in relationship to parameters of RV and LV function. METHODS: Thirty patients with PH underwent PET with (18)F-FDG and SPECT with (99m)Tc-tetrofosmine. The metabolic rate of glucose uptake was determined for RV and LV myocardium using the method of Patlak. A right heart catheter, thermodilution, and Doppler sonography were used to characterize RV and LV function. From these methods, the stroke work of both ventricles and the RV Tei index were calculated. RESULTS: RV-to-LV ratios of (18)F-FDG-uptake increased with rising pulmonary arteriolar resistance (PAR). With increasing PAR, the metabolic rate of glucose uptake of the left ventricle decreased (r = -0.547; P < 0.01) together with LV stroke work (r = -0.838; P < 0.001). The metabolic rate of glucose uptake of the right ventricle, however, correlated neither with RV stroke work (r = 0.124) nor with PAR (r = 0.189) but with the Tei index (r = 0.78; P < 0.001). CONCLUSION: Increasing right-to-left ratios of glucose uptake with an increasing pressure load in the right ventricle in PH are caused mainly by a significant reduction in the LV metabolic rate of glucose uptake. This is obviously due to a reduced energy demand of the LV myocardium caused by reduced stroke work. An increased metabolic rate of glucose uptake in the right ventricle presumably indicates RV impairment, correlating with the Tei index, which is an established prognostic parameter for cardiac dysfunction and poor survival.

l-Arginine attenuates acute pulmonary embolism-induced oxidative stress and pulmonary hypertension.

Nitric Oxide. 2005 Feb;12(1):9-14. Epub 2004 Dec 23

Souza-Costa DC, Zerbini T, Metzger IF, Rocha JB, Gerlach RF, Tanus-Santos JE.

Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil.

l-Arginine is substrate for nitric oxide (NO) synthesis and produces pulmonary vasodilatory effects in patients with pulmonary hypertension and in hypoxic animals. We hypothesized that l-arginine would attenuate the increase in oxidative stress and the pulmonary hypertension observed during acute pulmonary embolism (APE). Using an isolated lung perfusion rat model of APE, we examined whether l-arginine (0, 0.1, 0.5, 3, and 10 mmol/L) attenuates the pulmonary hypertension induced by the injection of 6.6 mg/kg of 300 microm Sephadex microspheres into the pulmonary artery. Thiobarbituric acid reactive species (TBA-RS) and nitrite/nitrate (NO(x)) concentrations were measured in lung perfusate to assess oxidative stress and NO production. l-Arginine (0.5, 3, and 10 mmol/L) attenuated (all P<0.05) APE-induced pulmonary hypertension by about 50%. The protective effect of l-arginine was completely reversed by inhibition of NO synthesis with l-NAME (4 mmol/L). In addition, l-arginine (0.5-10 mmol/L) blunted the increase in TBA-RS observed after APE. NO(x) tended to increase only when l-arginine (10 mmol/L) was added to the lung perfusate of non-embolized lungs. Taken together, these findings suggest that l-arginine attenuates APE-induced pulmonary hypertension through antioxidant mechanisms involving increased NO synthesis.

Neonatal thyrotoxicosis and persistent pulmonary hypertension necessitating extracorporeal life support.

Pediatrics. 2005 Jan;115(1):e105-8

Oden J, Cheifetz IM.

Pediatric Endocrinology and Diabetes, Duke Children's Hospital, Durham, North Carolina 27710, USA. oden0003@mc.duke.edu

We report a case of neonatal Graves' disease involving an infant with severe persistent pulmonary hypertension (PPHN) associated with neonatal thyrotoxicosis that necessitated extracorporeal membrane oxygenation. Hyperthyroidism, although uncommon in the newborn period, has been associated with pulmonary hypertension among adults. The exact mechanisms responsible for this effect on pulmonary vascular pressure are not well understood. Recent studies have provided evidence that thyrotoxicosis has direct and indirect effects on pulmonary vascular maturation, metabolism of endogenous pulmonary vasodilators, oxygen economy, vascular smooth muscle reactivity, and surfactant production, all of which may contribute to the pathophysiologic development of PPHN. Therefore, because PPHN is a significant clinical entity among term newborns and the symptoms of hyperthyroidism may be confused initially with those of other underlying disorders associated with PPHN (eg, sepsis), it would be prudent to perform screening for hyperthyroidism among affected newborns.

Successful treatment of ARDS and severe pulmonary hypertension in a child with Bordetella pertussis infection.

Wien Klin Wochenschr. 2004 Nov 30;116(21-22):760-2

Skladal D, Horak E, Fruhwirth M, Maurer H, Simma B.

Pediatric Intensive Care Unit, University Children's Hospital, Innsbruck, Austria.

Infection with Bordetella pertussis can cause severe illness with neurological and pulmonary complications in children. Pulmonary hypertension is an early sign of potentially fatal disease and can cause failure of conventional respiratory therapy in severe acute respiratory distress syndrome (ARDS). We report a 4 1/2-year-old boy with B. pertussis infection who developed severe ARDS and pulmonary hypertension. Because of severe neurological signs the patient did not qualify for extracorporal membrane oxygenation (ECMO). After conventional ventilation, surfactant and high frequency oscillation ventilation (HFOV) failed, treatment with nitric oxide (NO) improved oxygenation, allowing recovery without the need for ECMO. The patient survived with few sequelae. Thus, this treatment may be an option in high-r