Background-Safe, effective therapy is needed for pediatric pulmonary arterial hypertension. Methods and Results-Children (nϭ235; weight Ն8 kg) were randomized to low-, medium-, or high-dose sildenafil or placebo orally 3 times daily for 16 weeks in the Sildenafil in Treatment-Naive Children, Aged 1-17 Years, With Pulmonary Arterial Hypertension (STARTS-1) study. The primary comparison was percent change from baseline in peak oxygen consumption (PV O 2 ) for the 3 sildenafil doses combined versus placebo. Exercise testing was performed in 115 children able to exercise reliably; the study was powered for this population. Secondary end points (assessed in all patients) included hemodynamics and functional class. The estimated meanϮSE percent change in PV O 2 for the 3 doses combined versus placebo was 7.7Ϯ4.0% (95% confidence interval, Ϫ0.2% to 15.6%; Pϭ0.056). PV O 2 , functional class, and hemodynamics improved with medium and high doses versus placebo; low-dose sildenafil was ineffective. Most adverse events were mild to moderate in severity. STARTS-1 completers could enter the STARTS-2 extension study; patients who received sildenafil in STARTS-1 continued the same dose, whereas placebo-treated patients were randomized to low-, medium-, or high-dose sildenafil. In STARTS-2 (ongoing), increased mortality was observed with higher doses. Conclusions-Sixteen-week sildenafil monotherapy is well tolerated in pediatric pulmonary arterial hypertension. Percent change in PV O 2 for the 3 sildenafil doses combined was only marginally significant; however, PV O 2 , functional class, and hemodynamic improvements with medium and high doses suggest efficacy with these doses. Combined with STARTS-2 data, the overall profile favors the medium dose. Further investigation is warranted to determine optimal dosing based on age and weight. Clinical Trial Registration-http://www.clinicaltrials.gov. Unique identifier: NCT00159913. (Circulation. 2012;125:324-334.)

As far as we are aware, ours is the first epidemiologic study concerning the frequency and type of congenital cardiac disease found in Guatemalan children with Down's syndrome. The high frequency of patency of the arterial duct, and the differential distribution of the cardiac malformations associated with Down's syndrome among Guatemalan children, differ from what has been reported in the United States of America, Europe, and Asia. This difference warrants further research.

Background— In 1997, an effort was made to disseminate US pediatric cardiac surgical practices to create a new comprehensive program in Guatemala. The objective of this study was to describe the improvement of the program by exploring the reduction in risk-adjusted in-hospital mortality. Methods and Results— A retrospective cohort study of surgical procedures performed in Guatemala from February 1997 to July 2004 was conducted. Data were divided into 3 time periods (1997 to 1999, 2000 to 2002, and 2003 to 2004) and compared with a US benchmark (2000 Kids’ Inpatient Database of 27 states and 313 institutions). The risk adjustment for congenital heart surgery (RACHS-1) method was used to adjust for case mix. Mortality rates, standardized mortality ratios, and 95% confidence intervals were calculated. A total of 1215 surgical procedures were included. Median age was 3.1 years (range, 1 day to 17.9 years). The overall mortality was 10.7% (n=130). The RACHS-1 method showed better discrimination than in prior reports (area under receiver operating characteristic curve=0.854). A decreasing trend in mortality rate was observed in every RACHS-1 risk category over the 3 time periods. When compared against the US benchmark, the reduction in risk-adjusted mortality was noted by a decrease of standardized mortality ratio from 10.0 (95% confidence interval, 7.2 to 13.7) in 1997–1999, to 7.8 (95% confidence interval, 5.9 to 10.0) in 2000–2002, and to 5.7 (95% confidence interval, 3.8 to 8.3) in 2003–2004. Conclusions— In a short time period, mortality after congenital heart surgery has been reduced substantially in Guatemala. Measurement of risk-adjusted mortality is a useful method to assess pediatric cardiac program improvement in the developing world.

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