iNO talk

Persistent Pulmonary Hypertension of the NewbornA rational approach to implementation of inhaled Nitric Oxide : 

Persistent Pulmonary Hypertension of the NewbornA rational approach to implementation of inhaled Nitric Oxide Eddie Chang, MD Division of Neonatology Abington Memorial Hospital Abington, Pennsylvania Clinical Assistant Professor of Pediatrics Drexel University College of Medicine

Today’s Goals : 

Today’s Goals Define Persistent Pulmonary Hypertension of the Newborn Review Pathophysiology & Natural History of PPHN Introduce inhaled Nitric Oxide (iNO) Review clinical criteria for treatment with iNO. Review best practices for treatment strategies of PPHN. Optimal lung recruitment Consideration of Surfactant replacement HFOV + iNO Review Weaning

Timeline : 

Timeline 1960 1970 1980 1990 2000 Today Defining the Disease: PFC vs. PPH vs. PPHN Vasoconstriction:EDRF-mediated Inhaled Nitric Oxide Mechanical Ventilation of Newborns ECMO Surfactant for PPHN HFOV + iNO High Frequency Ventilation Adopted from: Cleary GM, Wiswell TE. Meconium-stained amniotic fluid and the meconim aspiration syndrome. Ped Clinics North Am. June 1998. 45(3), 511-529 Kinsella JP. Inhaled nitric oxide in the term newborn. Ear Hum Devel. (2008) 84, 709-716 DR Suctioning

Slide 4: 

PPHN Sepsis Meconium/Aspiration Syndromes Acidosis Idiopathic Systemic Inflammation Lung Hypoplasia Severe fetal Stress Lung Disease/Alveolar Hypoxia/Pneumonia/RDS

Slide 5: 

http://www.uihealthcare.com/depts/med/pediatrics/iowaneonatologyhandbook/pulmonary/images/p57total.gif

PPHN Subtypes : 

PPHN Subtypes Pulmonary vasoconstriction due to lung parenchymal diseases (MAS, RDS, or pneumonia) Remodeled pulmonary vasculature with normal lungs (idiopathic or “black-lung” PPHN Hypoplastic pulmonary vasculature (CDH) Steinhorn RH J Perinatology 2009

PPHN : 

PPHN Incidence of severe PPHN is ~ 0.2% of all live births MAS is the most common cause Steinhorn RH J Perinatology 2009

Slide 8: 

www.chw.edu

Slide 9: 

Pulmonary Vasoconstriction Decreased Pulmonary Blood Flow Alveolus Pulmonary Arteriole

Persistent Pulmonary Hypertension of the Newborn 1980-90s: Modern age of PPHN Management --> EDRF --> Nitric Oxide : 

Persistent Pulmonary Hypertension of the Newborn 1980-90s: Modern age of PPHN Management --> EDRF --> Nitric Oxide Furchgott and Zawadzki 1980: Acetylcholine-induced vasorelaxation was dependent on intact endothelium through Endothelium-Derived Relaxing Factor (EDRF) Palmer 1987: EDRF acted like Nitric Oxide (NO) Kinsella 1992: First showed selective vasodilator effect of inhaled NO in newborn lambs.

Nomenclature : 

Nomenclature Inhaled Nitric Oxide (iNO)--> Inhaled Nitrous Oxide (N2O)--> potent selective pulmonary vasodilator laughing gas anesthesia

Slide 12: 

Pulmonary Vasoconstriction Decreased Pulmonary Blood Flow Alveolus Pulmonary Arteriole

Slide 13: 

NO NO NO NO NO NO Pulmonary Vasodilation Increased Pulmonary Blood Flow Alveolus Pulmonary Arteriole

NO mechanism of action : 

NO mechanism of action L-Arginine turns into NO with the help of Nitric Oxide Synthase Endogenous NO helps Guanylate Cyclase change GTP to cGMP cGMP causes Vasodilation Vasodilation Endothelial Cell Smooth Muscle Cell Steinhorn RH J Perinatology 2009

iNO: Selective pulmonary vasodilation : 

iNO: Selective pulmonary vasodilation Location of activity is at the smooth muscle cell NO broken down in the blood stream No systemic vasodilation No systemic hypotension Monitor MetHgb on ABGs (should be <5)

iNO: V/Q Matching : 

iNO: V/Q Matching V/Q Matching Less iNO delivered to pulmonary arterioles associated with atelectatic alveoli More iNO to well-ventilated alveoli NO NO NO

iNO: V/Q Matching : 

iNO: V/Q Matching A: Airway obstruction/atelectasis + pulmonary vasoconstriction B: Airway obstruction/atelectasis + non-selective pulmonary vasodilation C: Airway obstruction/atelectasis + selective pulmonary vasodilation & V/Q Matching Wasted Cardiac Output--no gas exchange here

The Patient : 

The Patient DOL#0 newborn 41 wk gestation male born to a 21 year old G1P0 whose labor is complicated by meconium-stained amniotic fluid. PNL: O+/Ab-/HepBNR/VDRL NR/RI/GBS unknown Delivery Course: Mother given PCN for “GBS unknown status” 2 hours PTD. Delivered via NSVD. ET suctioned after birth for MSAF, poor tone, poor cry. Required brief PPV but appeared improved. Apgars 5/6/8. To NBN

The Phone Call at 2am : 

The Phone Call at 2am Our patient in the NBN is grunting, flaring, and looks really bad. Oxygen Saturation is in the 70s on 100% blow-by oxygen Sounds pretty bad… we’ll be right there

The Patient : 

The Patient 97 degrees HR 180 RR 80 SaO2 86% on 100% BBO2 Mean BP 32 Physical Exam: lethargy, tachypnea, grunting, flaring, poor capillary refill. + nonspecific crackles in all lung fields

DDx : 

DDx Sepsis Pneumonia or Aspiration Syndrome Congenital Heart Disease RDS Systemic Inflammatory Syndrome PPHN?

Workup : 

Workup Physical Exam CBC, CRP Series Blood Cx ABG Chest XR ECHO (r/o Structural Heart Dz)

CXRs in PPHN : 

CXRs in PPHN LEFT: Aspiration Syndrome/Pneumonia-->PPHN RIGHT: “Black Lung” or Idiopathic PPHN (Congenital Cardiac Disease also a possibility)

Interventions : 

Interventions Consider Respiratory Support Ventilation if non-invasive support is insufficient If poor lung recruitment on CXR consider ventilation with HFOV Target “normal” lung inflation 8-10 ribs For FT or near term infants target 8-10 Hz. Target “normal” ABGs (discourage respiratory alkalosis) Intravascular Fluid Resusc & Vasopressor Support Aggressively maintain good clinical perfusion especially when on HFOV & significant Mean Airway Pressures. Small Heart on CXR? Consider Correction of Significant Metabolic Acidosis Caution against overcorrection--? underlying hypoperfusion Antibiotics Consider Surfactant If signs of lung process, surfactant can be beneficial in secondary surfactant deficiency

Interventions : 

Interventions Optimize oxygen delivery (Anemia?) Consider Sedation/Paralytics (Only if needed) If used, aggressively manage secondary hypotension Consider inhaled Nitric Oxide If PaO2s low despite optimal respiratory lung recruitment and on 100% FiO2. OI > 25 with evidence of PHTN (eg FiO2 100%, MAP 15, PaO2 < or = 60mmHg) OI 15-25: there may be benefit (OI 15= PaO2 95mmHg) Only if it is unlikely Structural Cardiac Dz--iNO contraindicated in: Coarctation of the Ao, Critical AS, Interrupted Ao Arch, TAPVR, HLHS Notify ECMO Center of potential transfer Consider prompt transfer after iNO and if poor response in PaO2 (<10mmHg) despite: Optimization of lung recruitment Optimization of cardiovascular support OI=FIO2 * MAP/PaO2

Intervention : 

Intervention Strongly consider transfer if: No improvement in PaO2 OI progressively increasing from 25-35 despite optimal therapy. Consider transfer if unable to wean > 3-5 days Consider undiagnosed structural heart disease

PPHN Clinical Evidence : 

PPHN Clinical Evidence iNO usage NINOS CINRGI Adjunctive therapy HFOV Surfactant

Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. The Neonatal Inhaled Nitric Oxide Study Group (NINOS). : 

Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. The Neonatal Inhaled Nitric Oxide Study Group (NINOS). 235 patients Blinded prospective multicenter study > 34 wks EGA No structural heart disease OI > 25 twice over 15 min. iNO decreased “death or ECMO” compared to control (46% vs. 64%) Non-responders at 20ppm rarely ever respond at 80ppm Ehrenkranz et al. NINOS NEJM. 1997 Feb 27;336(9):597-604

Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. Clinical Inhaled Nitric Oxide Research Group (CINRG). : 

Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. Clinical Inhaled Nitric Oxide Research Group (CINRG). 248 patients Blinded prospective multicenter study >34 wks OI>25 x 2 Differed from NINOS study because they limited iNO to 20ppm or less. iNO decreased “death or ECMO” compared to control (38% vs. 64%) CDH pts. probably do not benefit from iNO relative to the other etiologies of PPHN Clark et al. NEJM 2000 Feb 17;342(7):469-74.

Randomized, multicenter trial of inhaled nitric oxide and high-frequency oscillatory ventilation in severe, persistent pulmonary hypertension of the newborn. : 

Randomized, multicenter trial of inhaled nitric oxide and high-frequency oscillatory ventilation in severe, persistent pulmonary hypertension of the newborn. 205 infants Stratified to primary disease category CDH are poor responders Randomized to iNO with CMV or HFOV Crossover design included iNO + HFOV iNO + HFOV improves PaO2 more than either alone or iNO+Conventional Ventilation Kinsella et al. J Peds 1997 Jul;131(1 Pt 1):55-62.

Meconium Aspiration Syndrome & GBS : 

Meconium Aspiration Syndrome & GBS Primary Prevention Secondary Prevention

PPHN: Prevention : 

PPHN: Prevention Primary prevention (OB Practice Changes) Prevention of post-dates delivery (1997-1998 ACOG) Decreased incidence of MAS and subsequent PPHN Active screening for GBS and Intrapartum Antibiotic Prophylaxis (1993, revised 1996 CDC) Decreased incidence of GBS sepsis & associated PPHN Intrapartum fetal monitoring/active management of labor Secondary prevention Active management of infants born through MSAF (Carson 1976) Active management of depressed MSAF infants (Wiswell 2000)

MAS: Changing Incidence 1990-1998 : 

MAS: Changing Incidence 1990-1998 Four-fold decrease in MAS (5.8% to 1.5% of pts born through MSAF) 33% decrease in births >41wks 33% increase in births 38-39 wks 3-fold increased diagnosis of NRFHT Universal early U/S for dating vs. sporadic U/S previously Increased C/S rate Implementation of IAP for GBS No change in OB or neonatal DR airway management Yoder et al., Changing obstetric practices associated with decreasing incidence of meconium aspiration syndrome. Obst Gyn 99(5 part 1). May 2002, 721-739 IAP Deliver by 41wks

GBS Sepsis & Changing Incidence : 

GBS Sepsis & Changing Incidence Before 1993 2 in 1000 live births After 1998 0.2 to 0.5 in 1000 live births Approximately 1600 cases per year (80 deaths per year) 1996 CBC GBS Consensus Guidelines

Neonatal Early-onset Group B Streptococcal Disease in the Era of Intrapartum Chemoprophylaxis: Residual Problems: Michigan Experience : 

Neonatal Early-onset Group B Streptococcal Disease in the Era of Intrapartum Chemoprophylaxis: Residual Problems: Michigan Experience Intrapartum chemoprophylaxis for GBS has been associated with a decrease in GBS infection & need for ECMO GBS (17-->3); ECMO (17-->0) Pinto, Soskolne E, Pearlman MD, Faix RG. J Perin (2003) 23, 265-271.

Surfactant Use : 

Surfactant Use

Evidence for Surfactant Use in MAS: Cochrane Meta-analysis : 

Evidence for Surfactant Use in MAS: Cochrane Meta-analysis 4 randomized controlled trials 326 infants Pt. requiring mechanical ventilation In infants with MAS, surfactant administration may reduce the severity of respiratory illness improves oxygenation decreases the number of infants with progressive respiratory failure (PPHN) requiring support with ECMO Cocharane Database Systemic Reviews. 2007 Jul 18;(3):CD002054

How about Surfactant for non-MAS PPHN? Should we use surfactant for PPHN with GBS sepsis? : 

How about Surfactant for non-MAS PPHN? Should we use surfactant for PPHN with GBS sepsis? FIO2 PaO2:FIO2 ratio MAP Hertig E. Surfactant Treatment of Neonates with Respiratory Failure and GBS Infection. Pediatrics 106(5) 2000, 957 Criticism: No Good Control Group Conclusion: Improvement in oxygenation with Surfactant in GBS similar to that seen in RDS. More likely to need multiple doses

Surfactant Summary : 

Surfactant Summary In MAS, surfactant Improves oxygenation, severity of respiratory distress, and “need for ECMO” In near- or FT-infants with respiratory insufficiency secondary to pneumonias and GBS infection, surfactant Probably improves oxygenation

Timeline : 

Timeline 1960 1970 1980 1990 2000 Today Defining the Disease: PFC vs. PPH vs. PPHN Vasoconstriction:EDRF-mediated Inhaled Nitric Oxide Mechanical Ventilation of Newborns ECMO Surfactant for PPHN HFOV + iNO High Frequency Ventilation Adopted from: Cleary GM, Wiswell TE. Meconium-stained amniotic fluid and the meconim aspiration syndrome. Ped Clinics North Am. June 1998. 45(3), 511-529 Kinsella JP. Inhaled nitric oxide in the term newborn. Ear Hum Devel. (2008) 84, 709-716 DR Suctioning GBS IAP & Neonatal Surveillance Avoidance of >41wk delivery

What’s next for PPHN? : 

What’s next for PPHN?

NO mechanism of action : 

NO mechanism of action L-Arginine turns into NO with the help of Nitric Oxide Synthase Endogenous NO helps Guanylate Cyclase change GTP to cGMP cGMP causes Vasodilation Vasodilation Endothelial Cell Smooth Muscle Cell

What else causes Vasodilation? : 

Sildenefil Milrinone Steinhorn RH J Perinatology 2009 What else causes Vasodilation? Phosphodiesterase Inhibitors can act synergistically with iNO

Future directions in PPHN : 

Future directions in PPHN Phosphodiesterase inhibitors potentiate cGMP or cAMP which cause vasodilation Sildenifil has been shown to act synergistically with iNO Milrinone infusion has been used successfully in term newborns perioperatively after cardiac surgery to decrease PHTN without systemic hypotension Caution in preterm infants (case reports of intracranial bleeds) Recombinant human Superoxide dismutase Steinhorn RH J Perinatology 2009 Hofman et al. Efficacy and safety of milrinone in preventing low cardiac output syndrome in infants and children after corrective surgery for congenital heart disease. Circulation 2003; 107, 996-1002

Weaning Ventilatory Support & iNO : 

Weaning Ventilatory Support & iNO Weaning should be inspired by the deliberate slow caution of the turtle. If in doubt with weaning, fall on the side of SLOW

Weaning : 

Weaning Keep PaO2 > 80-100mmHg Wean only FiO2 by 2-5% per hour to a goal of 60-65% only as tolerated (PaO2> 80-100mmHg). In the first 12 hours go slow--CAUTION is the best policy (remember the turtle).

Weaning : 

Weaning If FiO2 < 60-65% and/or iNO for 48hrs: Attempt to wean iNO to 15ppm (for each wean keep PaO2 80-100) If tolerated, after some time of stability, wean iNO to 10ppm. If tolerated, wean FiO2 by 2-5% per hour to goal of 40%

Weaning : 

Weaning If FiO2 < 40 or iNO for > 48hrs Attempt to wean iNO to 5ppm, then to 2 ppm, 1 ppm, then off. Reassess tolerance to each wean May use SaO2 to assess weaning tolerance If ANY WEAN is not tolerated, increase setting to previously tolerated level & don’t wean again for at least 8 hrs.

PPHN: Goals of TreatmentBuying Time : 

PPHN: Goals of TreatmentBuying Time Supportive care until underlying pathology runs its course Meet metabolic demands--feed the engine Get rid of metabolic waste Preserve function

PPHN: Goals of TreatmentBuying Time : 

PPHN: Goals of TreatmentBuying Time Time for resolution of systemic inflammation, sepsis, vascular remodeling of hypertrophy, etc. Pulmonary vasodilation & oxygenation Feeding the engine--efficient (VQ matching) delivery of oxygen from alveoli to tissues Scrubbing the waste--providing tissue to alveolar delivery of CO2 Decreasing PHTN decreases right heart afterload--preservation of function Potential decrease in the wear-and-tear on R Heart fxn--decrease in eventual R heart failure. Decreased time of ventilatory support Potential decrease in CLD

Summary : 

Summary Persistent Pulmonary Hypertension of the Newborn is the final common pathway for many conditions PPHN is characterized by pulmonary vasoconstriction or hypoplastic vasculature Inhaled Nitric Oxide (iNO) one part of a multifaceted intervention in PPHN. Reviewed clinical criteria for treatment with iNO. Reviewed best practices for treatment strategies of PPHN. Optimal lung recruitment Consideration of Surfactant replacement HFOV+iNO MAS management Future therapies Reviewed weaning from iNO--WEAN SLOWLY!