Multicenter randomized controlled trial of the effects of inhaled nitric oxide therapy on gas exchange in children with acute hypoxemic respiratory failure.

OBJECTIVES AND BACKGROUND: To determine whether inhaled nitric oxide (iNO) therapy can attenuate the progression of lung disease in acute hypoxemic respiratory failure, we performed a multicenter, randomized, masked, controlled study of the effects of prolonged iNO therapy on oxygenation. We hypothesized that iNO therapy would improve oxygenation in an acute manner, slow the rate of decline in gas exchange, and decrease the number of patients who meet pre-established oxygenation failure criteria. STUDY DESIGN: A total of 108 children (median age 2.5 years) with severe acute hypoxemic respiratory failure from 7 centers were enrolled. After consent was obtained, patients were randomized to treatment with iNO (10 ppm) or mechanical ventilation alone for at least 72 hours. Patients with an oxygenation index >/=40 for 3 hours or >/=25 for 6 hours were considered treatment failures and exited the study. RESULTS: Patient age, primary diagnosis, pediatric risk of mortality score, mode of ventilation, and median oxygenation index (35 +/- 22 vs 30 +/- 15; iNO vs control; mean +/- SEM) were not different between groups at study entry. Comparisons of oxygenation indexes during the first 12 hours demonstrated an acute improvement in oxygenation in the iNO group at 4 hours (-10.2 vs -2.7, mean values; P <.014) and at 12 hours (-9.2 vs -2.8; P <.007). At 12 hours 36% of the control group met failure criteria in contrast with 16% in the iNO group (P <.05). During prolonged therapy the failure rate was reduced in the iNO group in patients whose entry oxygenation index was >/=25 (P <.04) and in immunocompromised patients (P <.03). CONCLUSIONS: We conclude that iNO causes an acute improvement in oxygenation in children with severe AHRF. Two subgroups (immunocompromised and an entry oxygen index >/=25) appear to have a more sustained improvement in oxygenation, and we speculate that these subgroups may benefit from prolonged therapy.

Neutrophil and cytokine activation with neonatal extracorporeal membrane oxygenation.

OBJECTIVE: To determine whether extracorporeal membrane oxygenation (ECMO), like cardiopulmonary bypass, produces systemic inflammatory responses that could potentiate organ injury in infants with respiratory failure. STUDY DESIGN: We evaluated the effects of neonatal ECMO on neutrophil surface adherence proteins, elastase release, and cytokine levels in blood samples from 15 patients before and during ECMO, and from banked blood and ECMO circuit blood before cannulation. Neutrophil elastase, tumor necrosis factor alpha, and interleukin types 1 beta, 6, and 8 were measured. Chest radiographs were evaluated by a radiologist using a lung injury score in blinded fashion. RESULTS: Primed ECMO circuit blood, in comparison with patient pre-ECMO blood, demonstrated marked up-regulation of CD11b (mean fluorescence intensity 1660 +/- 109 vs 361 +/- 81; p < 0.001 (mean +/- SEM)), shedding of L-selectin (mean fluorescence intensity 10 +/- 2 vs 89 +/- 38; p < 0.01), and elevated elastase levels (349 +/- 76 vs 154 ng/ml +/- 38; p < 0.001), consistent with neutrophil activation. During ECMO, neutrophil CD11b levels increased but L-selectin was not significantly shed. Concentrations of circulating neutrophil elastase increase significantly during ECMO. Corrected circulating quantities of interleukin-8 also rose significantly, but the responses of tumor necrosis factor alpha and interleukin-1 beta were minimal. Radiographic lung injury scores worsened with the initiation of ECMO (median score: 6 before ECMO vs 11 in first hour of ECMO; p = 0.012), in conjunction with indicators of neutrophil activation. CONCLUSION: Neonates with respiratory failure have activation of the inflammatory cascade. ECMO incites additional neutrophil and cytokine activation in association with early pulmonary deterioration. Routine leukodepletion of blood for circuit priming to remove activated neutrophils may be beneficial.

Interval between menarche and first sexual intercourse, related to risk of human papillomavirus infection.

The purpose of this investigation was to study the occurrence of human papillomavirus (HPV) infection in relation to the interval between menarche and first intercourse. Two hundred eight subjects, aged 13 to 21 years, were recruited from an ambulatory adolescent clinic. Patients were excluded if they had a history of genital warts or an abnormal Papanicolaou smear. All subjects completed a self-administered questionnaire regarding demographics and their menstrual, sexual, and contraceptive histories. HPV infection was determined by in situ hybridization or changes consistent with HPV on a Papanicolaou smear, or both. The prevalence of HPV infection was 19.2%. The average interval between menarche and onset of sexual activity was 26.6 months for those who were found to have HPV infection compared with 35.7 months for those whose test results were negative (p = 0.02). First sexual intercourse within 18 months of menarche was associated with a significant elevation of risk of HPV infection, in comparison with that in adolescents who postpone first intercourse 3 to 4 years after menarche. These data suggest that factors such as increased biologic vulnerability may play a role in HPV infections among adolescent women.