Pulmonary Arterial Hypertension in Children: A Medical Update

Transcription

1 Symposium on Advances in Cardiology - I Pulmonary Arterial Hypertension in Children: A Medical Update Erika B. Rosenzweig and Robyn J. Barst Department of Pediatrics, Columbia University College of Physician & Surgeons, New York, NY USA ABSTRACT Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by a progressive pulmonary vasculopathy with ensuing right heart failure if left untreated. In the 1980 s, prior to the current treatment era, idiopathic pulmonary arterial hypertension (IPAH) carried a poor prognosis with a 10 month median survival for children after diagnosis. However, in 1995 continuous intravenous epoprostenol was approved for the treatment of severe PAH, improving hemodynamics, quality of life, exercise capacity, functional class and survival. In the past decade there have been further advances in the treatment of PAH; however, there is still no cure. While much of the groundbreaking clinical research has been performed in adults, children have also seen the benefits of PAH novel therapies. The target population among pediatric patients is expanding with the recent recognition of pulmonary hypertension as a risk factor for sickle cell disease patients. With rapid advances, navigating the literature becomes challenging. A comprehensive review of the most recent literature over the past year on available and emerging novel therapies as well as an approach to target pediatric populations provides insights into the management of pediatric PAH patients. [Indian J Pediatr 2009; 76 (1) : 77-81] esb14@ columbia. edu Key words : Pulmonery hypertension; Edothelin receptor antagonists; Prostacyclin analogues; Sickle cell disease TARGETED PAH THERAPY IN CHILDREN Epoprostenol is efficacious in IPAH and PAH associated with other conditions such as congenital heart disease (CHD), connective tissue disease, HIV infection, and portal hypertension. 1-8 While still considered the gold-standard for treatment of severe PAH, the delivery system is not without risk. Thus, the focus of PAH research in the past decade has been to develop alternative treatments that are less invasive and with fewer side effects. There are currently three major drug classes available for the long-term treatment of PAH: prostanoids, endothelin receptor antagonists, and phosphodiesterase 5 inhibitors. While none of these agents have been specifically approved for children, there is evidence that each can benefit the appropriate PAH child. Prostanoids Treprostinil Treprostinil (SQ/IV) is a prostacyclin analogue with a Correspondence and Reprint requests : Erika Berman Rosenzweig, MD, Pulmonary Hypertension center, Columbia University, College of Physicians and Surgeons, 3959 Broadway, BH - 2 North, New York, NY [Received December 12, 2008; Accepted December 12, 2008] longer half-life (elimination t ½ 4.4 hours and distribution t ½ ~40 minutes) than epoprostenol (t 1 / minutes that has been shown to be effective in PAH. 9 A recent clinical trial in adults evaluated the transition from IV epoprostenol to IV treprostinil after 12 wk and showed that there was no significant deterioration in hemodynamics or exercise capacity. 10 In 2007, Ivy DD et al 11 reported retrospectively the transition of 13 PAH children from IV epoprostenol to IV treprostinil; children (mean age 11 yr; range 3-17) were transitioned in the hospital over 24 hours and followed on IV treprostinil for 1.1 ± 0.5 yr. Baseline 6-minute walk test distance was 516 ± 115 m (n =9) with no change after transition. There were 2 deaths, and 2 patients transitioned to another therapy. Seven patients experienced 1 central-line infection. Despite a higher dose of treprostinil than epoprostenol, the side effects were less. The authors concluded that treprostinil provides an alternative therapy to epoprostenol in PAH children, with fewer side effects; however, evaluation of infection rates requires further exploration. In the authors' opinion, the use of treprostinil in children can be considered for a PAH patient who has been on a stable dose of IV epoprostenol with clinical improvement. This study illustrates that treprostinil appears well-tolerated in children as previously seen in adults. Given the small number of patients studied, Indian Journal of Pediatrics, Volume 76 January,

2 Erika B. Rosenzweig and Robyn J. Barst however, the clinician must follow the transitioned patient cautiously for clinical deterioration and/or side effects including central line bloodstream infections. Furthermore, aggressive up-titration is necessary without standardized guidelines in place; i.e., dose of treprostinil is equivalent to ~1.5-4 times the dose of epoprostenol for equivalent efficacy. Inhaled prostanoids Iloprost is a chemically stable prostacyclin analogue with a minute half-life, which can be used for IV or inhaled administration. 12 The hemodynamic efficacy and side effects of IV iloprost are similar to IV epoprostenol. Inhaled iloprost therapy is an appealing approach for PAH management given its selectivity for the pulmonary vascular bed with less systemic side effects; however, the delivery system prohibits the outpatient use in young children. The focus for iloprost use in children has been its use in the critical care setting in which there are now several case reports of pediatric iloprost use. In 15 children with PAH related to CHD, acute inhaled iloprost was as effective as inhaled nitric oxide in selectively lowering pulmonary vascular resistance. 13 More recently, in a center without inhaled nitric oxide (ino) available, the use of aerosolized iloprost for postoperative pulmonary hypertensive crises (PHC) was evaluated in 12 high risk children undergoing congenital heart surgery. 14 Children had hemodynamic monitoring to identify postoperative PHC after CHD repair. PHC was defined as an acute rise in pulmonary artery pressures causing cardiopulmonary compromise reflected by systemic arterial oxygen desaturation and systemic hypotension. If conventional medical treatment failed to prevent postoperative PHC, children were administered aerosolized iloprost (0.5 μg/kg). Eight of the 12 children had one or more episodes of PHC, secondary to pulmonary vasoreactivity. All responded to aerosolized iloprost, as demonstrated by a fall in PAPm from 48 ± 15 to 30 ± 8 mmhg (mean +/- SD; p = 0.012) and an increase in systemic arterial oxygen saturation from 82 ± 17 to 93 ± 12 % (p = 0.012) with no significant effect on systemic blood pressure 59 ± 12 to 64 ± 10 mmhg (p = 0.16). Authors concluded that in a medical setting with limited access to ino, inhaled iloprost is an effective alternative to ino for postoperative PHC in children undergoing congenital heart surgery. In the authors opinion, this small study demonstrates the potential utility of inhaled iloprost in the critical care setting for children with acute pulmonary hypertensive crises. While the short duration of action of iloprost and delivery system is a drawback for children in the outpatient setting, the role of inhaled iloprost in the critical care setting appears to be receiving greater recent attention. Further studies with larger numbers of patients and possibly other forms of PAH are warranted. Endothelin Receptor Antagonists (ERA) Endothelin-1, one of the most potent vasoconstrictors identified to date, 15 has been implicated in the pathobiology of PAH. Endothelin-1 expression, production, and concentration in plasma and lung tissue are elevated in PAH patients and inversely correlated with prognosis Bosentan is an oral endothelin receptor antagonist approved (2001) for the treatment of WHO functional class III and IV PAH patients > 12 yr old. Ambrisentan, an ET A selective ERA, was approved in 2007 for WHO functional class II-IV PAH patients. The data with endothelin receptor antagonists in children, however is limited. In 2005 we 20 published early experience with bosentan in children with a subsequent study by Haworth et al 21 supporting safety and apparent efficacy. In the year 2007, van Loon et al 22 looked at the long term effects of bosentan in adults vs children with PAH associated with systemic-to-pulmonary shunts to determine whether the short-term response persists. They studied bosentan efficacy (WHO functional class, systemic arterial oxygen saturation, and 6 minute walk distance) in 30 PAH-CHD patients (20 adults and 10 children) at short-term (4 months) and long-term (2.7 years); 87% of the patients had classic Eisenmenger syndrome. Although there was short-term improvement in both adults and children, at longer term follow up, there was progressive decline in efficacy with both groups. The deterioration appeared most pronounced in the pediatric patients who appeared to have more severe disease at baseline. During 2007 there were several other case reports on the use of bosentan in children. Kageyama et al 23 performed a study to elucidate the pathophysiological roles of endothelin (ET)-1 in patients with PAH associated with CHD and compared the plasma levels of ET-1 between children with and without Down syndrome; 32 children aged mth were included. Patients were classified into two groups: with Down syndrome (Group D, n = 16); and without Down syndrome (Group ND, n = 16). Plasma ET-1 levels were measured preoperatively, during cardiopulmonary bypass (CPB), minutes after CPB, and 2, 6 and 24 h after CPB discontinuation. Plasma ET-1 levels were significantly higher in Group D than in Group ND at all times except for immediately after CPB termination. In both groups, peak ET-1 values were obtained 6 h after CPB. At 24 hr after CPB, ET-1 concentrations returned to pre-cpb baseline levels in Group ND, but not in Group D. The preoperative pulmonary to systemic pressure ratio and ET-1 concentration correlated both before and after CPB in 78 Indian Journal of Pediatrics, Volume 76 January, 2009

3 Pulmonary Arterial Hypertension in Children: A Medical Update both groups. The authors concluded that pre- and postoperative plasma ET-1 concentrations reflect preand postoperative PH in both groups. Specific features in Down syndrome could be associated with greater ET perturbations (than in ND patients) and might cause persistent increases in ET concentration thereby prolonging mechanical ventilation. Ambrisentan, a propanoic acid type-a selective endothelin receptor antagonist, has also been shown to improve exercise capacity and delay clinical worsening in PAH patients. 24 Ambrisentan was FDA approved in 2007 for treatment of WHO functional class II-IV PAH adults. There is currently no data on the use of ambrisentan in children, although this may be a treatment option for children in the future by offering similar clinical and hemodynamic benefit to bosentan with less associated acute hepatotoxicity. Phosphodiesterase Inhibitors In chronic PAH, phosphodiesterase type 5 gene expression and activity are increased, 25 resulting in decreased cgmp levels. Phosphodiesterase type 5 inhibitors prevent the breakdown of cyclic GMP thereby raising cyclic GMP levels resulting in pulmonary vasodilation. While sildenafil has been approved for the treatment of WHO II-IV PAH in adults, 26 the data in children remains limited to case reports. In 2007 there were several case reports on the use of sildenafil in the pediatric population. We will review the most noteworthy. Raja SG et al 27 reported the effects of escalating doses of sildenafil on hemodynamics and gas exchange in children with PAH associated with CHD. This was a prospective, observational study of 10 children with PAH due to CHD in the intensive care unit on ino after cardiac surgery. The study patients received sildenafil every 4 h via gastric tube in incremental doses of 0.5 mg/kg, 1 mg/kg, 1.5 mg/kg, and 2.0 mg/kg in addition to ino until extubation. Hemodynamic and arterial blood gas measurements were obtained before (baseline) and 60 minutes after sildenafil. All doses of sildenafil caused significant reductions in pulmonary artery pressure with no significant effect on systemic arterial or central venous pressures. No significant dose effects were seen. The authors concluded that for the treatment of PAH in children with CHD, 0.5 mg/kg dose of sildenafil every 4 hr is as effective as a 2.0 mg/kg dose every 4 h. However, a larger dose-ranging and pharmacokinetic study of sildenafil in children with PAH and CHD is needed to validate the safety and efficacy of the dose-range and interval suggested. Noori et al 28 retrospectively evaluated the effects of 2 weeks of sildenafil therapy in 7 neonates with persistant pulmonary hypertension of the newborn associated with a congenital diaphragmatic hernia (CHD) who failed ino therapy. Right ventricular output increased with no significant increase in left ventricular output h after initiation of sildenafil with the increases sustained throughout the study. Echocardiographic indices of pulmonary hypertension were consistent with decreases in pulmonary vascular resistance. There was no significant change in systemic blood pressure or left ventricular shortening fraction. Ventilatory index and the need for ino appeared to decrease in the five surviving infants. These preliminary findings suggest that sildenafil may improve cardiac output by reducing pulmonary hypertension in patients with CDH refractory to ino. Although both authors studied different subgroups with PAH, e.g., CHD vs. CDH, both studies attempted to better understand how to use sildenafil in the pediatric critical care setting. There has been a rapid increase in the number of case reports describing the use of sildenafil in critically ill pediatric patients in Clearly, further pharmacokinetic studies with larger numbers of patients are warranted. Unfortunately, designing an appropriate study is challenging given the heterogeneous nature of pediatric PAH patients in the critical care setting. In 2007, Nagendran et al 29 looked at surgical specimens from 9 patients including those with right ventricular hypertrophy(rvh). They reported that although PDE5 is not expressed in the myocardium of the normal human right ventricle, mrna and protein are markedly upregulated in hypertrophied RV myocardium. PDE5 also is upregulated in rats with RVH. PDE5 inhibition significantly increased contractility, measured in the perfused heart and isolated cardiomyocytes in RVH, but not normal RV. PDE5 inhibition increased cgmp and camp in RVH but not in normal RV. In the authors' opinion, despite a small sample size, these data highlight one rationale for why PAH patients may benefit from sildenafil. Further studies looking at clinical indicators of RV function and cardiac output could expand upon this preliminary data. TARGETED PAH TREATMENT POPULATIONS IN PEDIATRICS: SICKLE CELL DISEASE (SCD) In 2007, there were several publications which investigated/reported the incidence of PH in children with SCD. These reports came on the heels of a publication by Gladwin M et al. which reported a significant association between PH and death in adult SCD patients. 30 Suell MN et al. 31 reported the prevalence of PH among adolescents with SCD. Using a tricuspid regurgitant (TRV) jet peak velocity of 2.5 m/s as a screening test for PH, the authors retrospectively reviewed echocardiograms and clinical data of Indian Journal of Pediatrics, Volume 76 January,

4 Erika B. Rosenzweig and Robyn J. Barst adolescents followed at the Texas Children s Sickle Cell Center. Of the 80 adolescents with SCD and echocardiogram data, 21 (26%) had a TRV of 2.5 m/s. Of these 21 patients with PH, 12 (57%) had an echocardiogram performed during an inpatient stay for vaso-occlusive crisis (n = 6), acute chest syndrome (n = 4), fever (n = 1), or seizures (n = 1), and 9 (43%) had an echocardiogram performed as an outpatient in a baseline state of health. Although increases in estimated right ventricular systolic pressure (RVSP) were frequent in this adolescent cohort, clinical symptoms were rare. Nelson SC et al 32 also reported prospectively on the prevalence of PH in children with SCD. 31% of children 10 years of age had evidence consistent with PH by Doppler echocardiography. Factors associated with suspected PH were male sex and elevated reticulocyte count. Based on their findings, the authors recommend screening all SCD children for PH starting at the age of 10 years. In the Suell MN et al, article, while 26% of adolescents with SCD had a TRV 2.5m/s, more than half of the patients with elevated TRV measurements were studied during an acute crisis. While little is known about the effects of acute chest crisis or vasoocclusive crisis on pulmonary vasoreactivity, a recent study reported that with severe acute chest episodes pulmonary arterial pressures appear to increase 33 (with a concomitant increase in ET levels) and thus the impact on TRV should be considered. The Nelson SC et al. study, however supports the high overall prevalence of PH in adolescents with SCD. Onyekwere OC et al 34 looked at children and adolescents with SCD to determine whether increased pulmonary artery pressures would be found in SCD children and adolescents, especially those with a history of pulmonary complications: e.g., acute chest syndrome, obstructive sleep apnea, and reactive airway disease. Fifty-two SCD children, 23 of whom had underlying pulmonary disease, were screened for PH, defined as a TRV 2.5 m/s. Twenty-four (46.15%) SCD patients had increased estimated RVSP (i.e., TRV 2.5 m/s), and 6 (11.5%) appeared to have significant PH (i.e., TRV 3.0 m/s). Pulmonary disease was not significantly associated with PH (odds ratio 2.80 with confidence intervals 0.88 to 8.86; p = ). As in adult SCD patients with PH, this complication is correlated with the degree of hemolysis as manifested by higher lactate dehydrogenase (LDH) and bilirubin levels, lower hemoglobin and hematocrit levels, associated with Hb-SS phenotype. However, after statistical adjustment for age and sex, increased serum LDH was no longer associated with PH. The authors concluded that further studies are needed to clarify the prevalence and mechanisms of PH in pediatric and adolescent patients with SCD. In contrast, in a study of the role of hemolysis and PH in pediatric patients with SCD, Liem RI et al 35 prospectively examined the relationship between TRV and laboratory markers of hemolysis in 51 children and young adults with SCD at baseline and found significant correlations between TRV and lactate dehydrogenase (LDH), hemoglobin (Hb), reticulocyte count and aspartate aminotransferase (AST). LDH, reticulocyte and AST were significantly higher and Hb was significantly lower in subjects with TRV 2.5 m/ sec. The authors concluded that hemolysis significantly contributes to TRV elevation in children and young adults with SCD. In the authors opinion, there appears to be an association between markers of hemolysis and the occurrence of significant PH in SCD children as previously described in adults. This finding may be important in helping physicians identify SCD patients who may be at higher risk for PH and thus consider screening those patients with echocardiography more frequently. CONCLUSION Recent therapeutic advances have significantly improved the prognosis for children with PAH. However, pediatric PAH continues to be a serious condition which is extremely challenging to manage. Much of our treatment strategy is adapted from adult data due to constraints in studying children. The data in children is often limited to case reports as many of those described here. Thus, the reader needs to be cautious about the interpretation of such small uncontrolled studies. 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