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Inhaled Nitric Oxide in Premature Infants with The Respiratory Distress Syndrome

Inhaled Nitric Oxide in Premature Infants with The Respiratory Distress Syndrome. New England Journal of Medicine Nov. 27, 2003. Abstract. Background: Inhaled NO improves gas exchange, decreases pulmonary vascular lability, reduces pulmonary inflammation

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Inhaled Nitric Oxide in Premature Infants with The Respiratory Distress Syndrome

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  1. Inhaled Nitric Oxide in Premature Infants with The Respiratory Distress Syndrome New England Journal of Medicine Nov. 27, 2003

  2. Abstract • Background: • Inhaled NO improves gas exchange, decreases pulmonary vascular lability, reduces pulmonary inflammation • The hypothesis that inhaled NO would decrease the incidence of chronic lung disease & death in premature infants with RDS

  3. Abstract • Methods: • A randomized, double blind ,placebo controlled study of the effect of inhaled NO during the first week of life on the incidence of chronic lung disease & death in infants < 34 wks on mechanical ventilation for RDS • Infants were randomized in two groups : inhaled NO vs. inhaled oxygen placebo for 7 days, further randomization into 2 ventilatory modes.

  4. Abstract • Results: • 207 premature infants were enrolled • In NO group 51 infants( 48.6%) died or had Chronic lung disease, in the placebo group 65 infants ( 63.7%) • No significant difference in the the overall incidence of IVH & periventricular leukomalacia, but NO group had a lower incidence of severe IVH & PVL ( 12.4% vs. 23.5 %) • Type of ventilation had no significant effect on the outcome .

  5. Abstract • Conclusion: • The use of inhaled nitric oxide in premature infants with RDS decreases the incidence of chronic lung disease & death.

  6. methods • Criteria for eligibility: • Premature infants < 72 hrs old • < 34 weeks gestation • BW < 2000 gm • Received a clinical diagnosis of RDS • Required tracheal intubation, mechanical ventilation & exogenous surfactant . • Infants were excluded if they had major congenital malformations or hydrops fetalis

  7. Study design & randomization • Five 250 g birth wt categories were used • Treatment with NO was initiated at 10ppm by continuous inhalation for the first day ( 12-24 hrs) followed by 5ppm for 6 days. • When study gas was discontinued it was resumed if PaO2 dropped > 15 % & dose was decreased by 1 ppm Q 6 hrs • Respiratory therapist was responsible for changing & handling study gas.

  8. Ventilator strategies • Decisions about ventilation were made by clinicians according to the usual protocol. • The oxygenation index = • 100 * FiO2 * MAP/PaO2 • IMV was initiated at rate= 40 Bpm , PEEP= 4-6 , Pip sufficient to inflate the chest . • HFV : MAP 2 cm H2O above the required pressure for initial stabilization. • MAP adjusted to keep lung inflated at 9 post. Ribs. • PaO2 = 50-90 mmHg • PaCO2 =35-55 mmHg

  9. Infants < 1250 gm birth wt received prophylactic indomethacin to prevent or attenuate PDA • Ventilatory mode was changed according to clinical condition & the study gas was stopped . • Parents could withdraw their infants at any time • Infants who were extubated within 7 days had treatment stopped 1 hr before extubation

  10. Hypotheses & outcome • Primary outcome measure : death or chronic lung disease. • CLD was diagnosed in ifants who required O2 as their usual daily therapy at 36 wks + chest radiograph of persistent parenchymal disease. • Infants who died before discharge or by 6 months of age were included in the analysis.

  11. Additional analysis to understand the influence of ventilator strategy ,severity of lung disease, birth wt on the effects of INO. • To asses bleeding( complication of NO): pulmonary hemorrhage ,severe IVH PVL. • Complications of chronic lung disease: interstitial emphysema & pneumothorax.. • Incidence of symptomatic PDA was tracked. • Duration of ventilation & hospitalization were measured variables as well. • ROP & NEC , sepsis & hydrocephalus were tracked.

  12. Safety monitoring • Daily methemoglobin level : • The monitoring committee was informed if any level exceeded 5%. • If levels were confirmed to be > 5 infants would have study gas stopped.

  13. Results • From Oct. 1998 – Oct 2001 , 207 premature infants underwent randomization. • The birth wt distribution: 72 infants( 34.8 % ) < 750 gm , 57 ( 27.5 % ) weighed 751 to 100 g , 33 ( 15.9 % ) weighed 1001 to 1250 g , 18 ( 8.7 % ) weighed 1251 to 1500 g , 27 ( 13.0 %) weighed more than 1500 g.

  14. Of the 207 premies: 2 died before receiving any study medication, one never received any study gas , 5 other infants the assigned mode of ventilation was changed because of worsening clinical condition . • 3 infants had elevated methemoglobin levels , none exceeded 7 % non were high on reevaluation. • Nitrogen dioxide was never elevated.

  15. 36 Infants were successfully extubated during the treatment period & received study gas< 7 days. • 20 of these were in placebo group , one developed subsequent chronic lung disease. • Among the 16 other infants who were in NO group , one developed chronic lung disease.

  16. Inhaled nitric oxide group : 51 of 105 (48.6 % )died or had chronic lung disease , compared to 65 of 102 infants ( 63.7 % ) in the placebo group • The mode of ventillation had no significant effect on the primary outcome. • No significant interaction was observed between the type of the study gas & birth wt subgroup.

  17. As compared with placebo gas , inhaled NO significantly decreased the risk of the primary outcome by 47%in infants whose oxygenation index was below the median . • This disease – severity – specific interaction is significant.

  18. Secondary outcomes • The incidence of pulmonary hemorrhage did not differ significantly between the 2 groups. • The overall incidence of IV hemorrhage & PVL did not differ significantly between the two groups, however inhaled NO decreased the incidence of severe IVH & PVL.

  19. The incidence of pneumothorax , pulmonary interstitial emphysema , & symptomatic PDA did not differ significantly between groups. • No significant difference in other complications of prematurity ( NEC , late onset sepsis, Retinopathy of prematurity & hydrocephalus ) • Among the infants who survived , the median duration of mechanical ventilation was 16 days in No group compared to 28.5 days in the placebo group • Hospitalization was 65 days & 76 days respectively.

  20. discussion • In this study , early treatment with with inhaled NO improved long term pulmonary outcomes in premature infants with RDS , decreasing the incidence of chronic lung disease & death. • In addition inhaled NO decreased the incidence of severe IVH & PVL , the primary cause of serious long term neurologic disability .

  21. Analysis of data according to the mode of ventilation showed a significant decrease in the primary outcome in the INO group with Intermittent mandatory ventilation but not in the group with high frequency oscillatory ventilation. • NO is an important mediator of normal lung development & pulmonary vascular tone & is important in optimizing ventilation perfusion matching.

  22. NO did not prevent IVH & PVL but it decreased its severity. • No decreases right ventricular afterload , attenuating venous stasis & subsequent infarction of the germinal matrix arteriovenous rete. • No also prevents platelet aggregation & decreases venous thrombosis.

  23. Safety Of NO :bleeding , methemoglobenemia & oxidative stress. • No incresased bleeding time in adults & term infants . • Methemoglobenemia has been reported in term infants treated with high concentrations of NO , but not in infants receiving less than 20 ppm.

  24. Other NO dependent processes are enhancement f pulmonary surfactant activity , inhibition of neutrophil infiltration , inhibition of cytokines & prevention of neuromuscularization & airway remodelling. • Additional studies are required to define the sub groups of prematures who would benifet of inhaled NO & to determine the optimal dose & duration of therapy .

  25. Inhaled NO could subject the lung to increased oxydative stress , contributing to a variety of lung injuries. • elevated levels of 3-nitrotyrosine may be present in lung lavage fluid from infants after prolonged exposure to NO > 10 days .

  26. In conclusion , when initiated soon after birth , treatment with low dose inhaled NO reduces the incidence of chronic lung disease & death among premature infants with RDS . • The use of NO may also decrease the risk of severe IVH & PVL , which are important neonatal complications associated with prematurity.

  27. THANK YOU!

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