ABSTRACT
BACKGROUND: Safe, effective therapy is needed for pediatric pulmonary arterial hypertension. METHODS AND RESULTS: Children (n=235; weight ≥8 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 mean±SE percent change in PV(O(2)) for the 3 doses combined versus placebo was 7.7±4.0% (95% confidence interval, -0.2% to 15.6%; P=0.056). 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.
Subject(s)
Hypertension, Pulmonary/drug therapy , Piperazines/administration & dosage , Sulfones/administration & dosage , Administration, Oral , Adolescent , Child , Child, Preschool , Dose-Response Relationship, Drug , Double-Blind Method , Exercise Test/drug effects , Hemodynamics/drug effects , Humans , Hypertension, Pulmonary/physiopathology , Infant , Oxygen Consumption/drug effects , Piperazines/adverse effects , Purines/administration & dosage , Purines/adverse effects , Sildenafil Citrate , Sulfones/adverse effectsABSTRACT
Classic pathology textbooks claim that acute splenitis reflects septic states, nevertheless, the evidence upon which that association is based remains unclear. We assessed the occurrence of acute splenitis, as an indicator of systemic infection, in 34 autopsies performed in patients in whom the cause of death was due to multiple organ dysfunction syndrome, secondary to sepsis (group A); and in 37 cases of death by non-infectious causes (group B). These necropsies were done during the period January 31, 1999-December 31, 2000, at the Pathology Department of the Hospital General del Sur "Dr. Pedro Iturbe", Maracaibo, Venezuela. Acute splenitis was observed in 79% of the cases in group A, whereas it was absent in group B (p < 0.001). Thirty three (97%) of the patients of group A did not receive antibiotic therapy, and died within the first 24 hours following admission. Our results suggest that based on a proper clinical-pathological correlation, non-specific acute splenitis constitutes a finding that reflects a septic state, at least in cases that do not receive anti-microbial therapy.
