Inhaled Nitric Oxide Therapy

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Inhaled Nitric Oxide Therapy

• Marc Weiss, MD
• Loyola University Medical Center

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History

• 1980 -Furtchgott Zawicki demonstrate that
  Ach-induced vasorelaxation required intact
  endothelium. Coined endothelium-derived
  relaxation factor (EDRF)
• 1987 - Ignarro et al. show that EDRF and NO have
  identical pharmacologic properties (Nobel Prize,
  1998)
• 1992 - Roberts et al. Kinsella et al. report
  success of NO in babies with PPHN

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Properties of NO

• colorless odorless hydrophobic free radical
• half-life 3-5 seconds
• diffuses freely through cell membranes
• rapidly metabolized to nitrite and nitrate
• synthesized from arginine via nitric oxide
  synthase (NOS)
• inactivated in blood by binding to Hgb, forming
  methemoglobin

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Nitric Oxide Synthase (NOS)

• 3 isoforms, all use L-arginine as substrate
• endothelial (eNOS) and neuronal (nNOS)
• constitutive forms (cNOS)
• responsible for basal vasomotor tone
• activated by Ca influx
• produces NO in picomolar quantities
• stimulated by Ach, bradykinin, ATP, shear stress
• important in physiologic conditions

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Nitric Oxide Synthase (NOS)

• Inducible NOS (iNOS)
• not normally active
• Ca - independent
• produces NO in nanomolar quantities
• stimulated by IL-1, IFN?, TNFa in hours
• inhibited by glucocorticoids, IL-4, IL-10
• important in pathophysiologic conditions

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Action of NO in Smooth Muscle

• Within smooth muscle cells, NO binds to the heme
  moiety of soluble guanylate cyclase.
• This generates cGMP from GTP.
• cGMP activates protein kinases which
  dephosphorylate myosin light chains, preventing
  myosin-actin interactions.

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Action of NO in Smooth Muscle

• cGMP also leads to a decrease in intracellular
  Ca and increase in permeability of the K
  channel, leading to hyper-polarization of the
  cell membranes.
• Both mechanisms lead to vasorelaxation

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Other Actions of NO

• Potent platelet inhibitor
• decreased adhesion
• increased disaggregation
• Inhibition of vascular smooth muscle cell
  proliferation
• Immunomodulation
• Gene toxicity

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Endothelin

• Endothelin (ET) is a potent 21 amino acid
  vasoconstricting polypeptide.
• ET is made in endothelial cells
• Plays an important role in modulating fetal and
  transitional circulations
• Promotes cellular proliferation
• NO and PgI inhibit ET release

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Persistent Pulmonary Hypertension of the Newborn

• Fetal circulation is marked by high degree of
  pulmonary vasoconstriction
• Failure of postnatal drop in PVR, or
  redevelopment of elevated PVR, leads to R ? L
  shunting at the FO and DA
• Management includes hyperoxygenation,
  hyperventilation, alkalosis, systemic BP support,
  and non-specific vasodilators

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PPHN Pathophysiology

• Infants with PPHN have elevated circulating and
  endothelial cellular ET
• Some also have vascular smooth muscle
  proliferation
• Hypoxia increases ET release and inhibits NO
  release.
• ? decreased NOS activity
• ? L-arginine deficiency

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Toxicology

• NO is an oxidizing free radical
• NO2 is even more toxic
• OSHA limits NO - 25 ppm NO2 - 3 ppm
• NO prolongs bleeding time in rabbits by 30
• Methemoglobinemia
• Peroxynitrites - lipid peroxidation
• Possible damage to SAPs

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NO in PPHN Roberts et al Lancet 1992

• 7 trials of NO in 6 patients with PPHN
• 10 minutes at 20, 40, 80 ppm
• Increase in
• pO2 41 ? 116 (5/7)
• SaO2 88 ? 97 (6/7)

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NO in PPHNKinsella et al Lancet 1992

• 9 infants w/ PPHN meeting ECMO criteria
• NO for 15 min each at 10 and 20 ppm, then 24 H
• 30 min saw OI from 60 to 20, O2 from 41 to 103
• 24 H saw OI from 57 to 9, O2 from 38 to 154
• No change in pCO2, pH, BP
• None needed ECMO

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NO in ECMO ReferralsFiner et al J Ped 1994

• 23 consecutive ECMO referrals, OI gt 20
• Random schedule of 5, 10, 20, 40, 80 ppm
• OI lt 25 4/8 responded, 2 ECMO - both died
• OI 25-40 5/8 responded, 4 ECMO
• OI gt 40 4/7 responded, 5 ECMO
• no dose differences
• PPHN 10/13 no PPHN 3/10 responded

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Acute Response in PPHNDay et al Pediatrics 1996

• 50 babies with PPHN, OI gt 25
• if OI lt 40, randomized to 20 ppm NO
• Randomized arm
• NO had improved OI, pO2, pH, pCO2, ductal shunt
• ECMO 5/11 control vs. 1/11 NO
• Total OI gt 40 23/33 responded, 3 late failure
• poor response in pulmonary hypoplasia

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Four Patterns of ResponseGoldman et al
Pediatrics 1996

• 25 consecutive with PPHN
• NO at 20 ppm for 20 min
• 8 non-responders - 1/2 died
• 36 early failures - 3/9 died
• 44 sustained responders -all lived
• 12 prolonged dependence - all died
• OI gt 40 6/18 sustained response

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NO in RDSSkimming et al J Ped 1996

• 23 preterm infants with RDS
• Randomized to 5 vs 20 ppm for 15 min

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NO and HFOVKinsella et al J Ped 1997

• 205 infants RDS, MAS, iPPHN, CDH
• randomized to HFOV vs NO/CV, w/ XO
• 125 crossed to HFOV/NO - 32 success
• Best with MAS, RDS

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NO in PPHNRoberts et al NEJM 1997

• 58 infants with PPHN, pO2 lt 55 no CDH
• Randomized to NO at 80 ppm
• Short term (20 min) success 7 vs. 53
• Long term ECMO 71 vs. 40
• Of the responders, 25 went on to ECMO
• No baseline difference for responders vs.
  non-responders

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NO in Term Resp FailureNINOS NEJM 1997

• 235 infants gt 34 wk, OI gt 25, no CDH
• randomized to NO at 20 ppm
• Primary outcome Death and/or ECMO
• no XO
• DX
• PPHN 17 RDS 10
• MAS 48 Pneumonia/sepsis 20

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NO in Term Resp FailureNINOS NEJM 1997

• Only 20 of those without a complete response to
  20 ppm had a response to 80 ppm
• Could not prove a subgroup effect by dx or OI

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NO in CDHNINOS Pediatrics 1997

• 53 infants with CDH, OI gt 25
• same protocol

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NO in PPHNDavidson (Ohmeda) Pediatrics 1998

• 155 pts, term, pO2 40 -100, PPHN
• Randomized to C, 5, 20, 80 ppm
• short term (24H) improved OI, pO2

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NO Protocol

• Indications
• Term or near-term infant (gt 34 weeks)
• Evidence of PPHN
• Optimal pre-NO management
• A-a DO2/OI
• 550-600 for 2 hours or gt 600 for 1 hour, or
• OI
• gt20 for 2 hours or gt 25 for 1 hour

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Pre-NO Management

• Open-lung ventilation
• Mild hypocarbia/alkalosis
• Good systemic BP
• Volume
• Pressors
• Surfactant if indicated
• Sedation paralysis

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Oxygenation Status

• A-a DO2
• FiO2 x (Patm 47) (1.25x PCO2) PaO2
• Oxygenation Index
• MAP x FiO2 x 100/PaO2

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iNO Set Up
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iNO Set Up
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iNO Set Up
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NO Protocol

• Initiate iNO at 20 ppm
• ABG in 20-30 min
• Response gt20 improvement in PaO2
• If no response, wean off iNO
• If response, maintain iNO for 6 12 hrs

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NO Protocol - Monitoring

• Monitor ABG q 4-6 hours
• Check methemoglobin at 8 and then every 24 hours
• Decrease iNO if metHb gt 5
• Continuos monitoring of NO2
• Decrease iNO if NO2 gt 5 ppm
• Clinical bleeding

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Weaning

• After 6-12 hours, begin FiO2 and ventilator
  weaning
• When FiO2 lt 0.60, wean iNO
• Wean by 5 ppm every hour until dose is 5 ppm,
  then wean in hourly steps of 1 ppm
• If deteriorates, go back to previous step wait
  for 4 hours

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• Inhaled NO may be an effective adjuvant therapy
  for PPHN, but only as part of an overall clinical
  strategy that cautiously manages parenchymal lung
  disease, cardiac performance, and systemic
  hemodynamics.
• Abman Kinsella

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iNO and the Preterm

• Utilizing another property of NO
  anti-inflammatory activity
• Preterm infant with immature lungs (Hyaline
  Membrane Disease) is at risk for chronic lung
  disease.
• Could iNO help prevent the progression to CLD?

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iNO in Preterm Infants Undergoing Mechanical
Ventilation

• Ballard, et al NEJM 2006
• lt1250 grams, on vent, given surfactant
• 7-21 post-natal days
• 20 ppm, 24 day duration (weaned)
• Blinded, placebo controlled

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iNO in Preterm Infants Undergoing Mechanical
Ventilation

• iNO 294 control 288
• Survival without BPD
• iNO 43.9
• Control 36.8
• Also saw decreased LOS and time on O2

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iNO in Preterm Infants with Respiratory Failure

• Kinsella, et al. NEJM 2006
• lt 34 weeks, lt 1250 grams, on ventilator
• iNO at 5 ppm begun at 30 hours
• Maintained until extubation or 21 days
• Blinded, placebo controlled

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iNO in Preterm Infants with Respiratory Failure

• iNO 398 control 395
• Survival without BPD
• iNO 28.4
• Control 24.7 (no difference)
• Subgroup analysis benefit in the 1000-1250 gram
  group only

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