Inhaled Nitric Oxide in Premature Infants with The Respiratory Distress Syndrome

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Inhaled Nitric Oxide in Premature Infants with
The Respiratory Distress Syndrome

• New England Journal of Medicine
• Nov. 27, 2003

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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

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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 lt 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.

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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 .

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Abstract

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

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methods

• Criteria for eligibility
• Premature infants lt 72 hrs old
• lt 34 weeks gestation
• BW lt 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

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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 gt 15 dose was decreased by 1 ppm
  Q 6 hrs
• Respiratory therapist was responsible for
  changing handling study gas.

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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

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• Infants lt 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

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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.

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• 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.

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Safety monitoring

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

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Results

• From Oct. 1998 Oct 2001 , 207 premature infants
  underwent randomization.
• The birth wt distribution 72 infants( 34.8 ) lt
  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.

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• 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.

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• 36 Infants were successfully extubated during the
  treatment period received study gaslt 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.

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• 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.

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

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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.

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• 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.

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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 .

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• 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.

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• 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.

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• 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.

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• 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 .

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• 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 gt 10 days .

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• 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.

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