CPAP: The New (old) Gold Standard for Respiratory Management Morgan Stanley Children’s Hospital Columbia University Richard A. Polin M.D.

Disclosures I am a consultant for Fisher & Paykel and Ikaria

Outline Rationale for use of CPAP as an initial mode of respiratory support in neonates with respiratory distress Differences in CPAP delivery systems Conclusions and Recommendations

Case A 0.75 kg infant is born following a 27 week gestation. The infant exhibits immediate signs of respiratory distress and is administered 30% O2 in the delivery room. He is given ampicillin and gentamicin and transported to the NICU. A chest x-ray demonstrates a ground glass appearance with air bronchograms. What should be done now? A. Intubate and administer surfactant; wean ventilation as tolerated B. Intubate, administer surfactant and rapidly extubate to NPCPAP (INSURE). C. Withhold surfactant. Place the infant IMV-NPCPAP. D. Withhold surfactant. Place on the infant on NPCPAP and observe.

Genetic Predisposition Immature Lung Genetic Predisposition Nitric oxide Diuretics Superoxide Dismutase Gentle Resuscitation Antenatal steroids Surfactant Permissive Hypercapnia Permissive hypoxemia Caffeine Postnatal steroids Vitamin A CPAP Modified from Thomas W & Speer CP Neonatology 2011

Lung Injury in the Neonate: Fundamental Concept If you don’t ventilate an infant, it’s hard to cause BPD!

CPAP is Controversial

Respiratory Support Strategies U.K. Acute RDS Weaning IPPV 73% N/A HFO 2% N/A IMV N/A 13% A/C 4% 15% SIMV 13% 73% VG 5% 6% CPAP 2% N/A 80% of 228 units in the UK responded. Sharma A & Greenough. Acta Paediatrica 96: 1115-1117, 2007

Pulmonary Morbidity According to Gestational Age for VLBW Infants Characteristic 22 wk 23 wk 24 wk 25 wk 26 wk 27 wk 28 wk Total Severe BPD 56% 39% 37% 26% 17% 13% 8% 18% Surfactant 97% 95% 90% 86% 78% 65% 82% Ventilation 96% 94% 89% 76% 61% 49% 40% 62% CPAP 0% 3% 30% 36% 38% N = 8575 VLBW infants (2003-2007) Stoll B et al Pediatrics 126: 443, 2010

Surfactant: Systematic Reviews-Mortality RR 95%CI NNT 95% CI Natural surfactant 0.86 0.76-0.98 50 20-1000 Multiple doses 0.63 0.39-1.02 14 7-1000 Prophylaxis 0.61 0.48-0.77 20 14-50 Early 0.87 0.77-0.99 33 17-1000 HL Halliday Journal of Perinatology 28: s47, 2008

Critique of the Surfactant Trials Low rates of exposure to antenatal steroids Infants randomized to control arms of these trials were routinely ventilated (without surfactant) rather than receiving CPAP 12

“Simplicity is the Ultimate sophistication” KISS: Keep it simple stupid!

CPAP is an evidence-based treatment for preterm infants with RDS

Summary of CPAP Trials Gestational age N Death or BPD Air-leaks CPAP/control Support 240/7-276/7 1316 47.8%/51.1% 6.8%/7.4% COIN 250/7-286/7 610 33.9%/38.9% 9.1%/3.0% VON 266/7-296/7 648 29.6%/36.5% 4.8%/5.4% Neocosur 800-1500g 256 13.7%/19.2% 3.1%/5.6% CURPAP 250/7-286/ 208 21.0%/21.9% 4.9%/9.5% Total 3038 29.2%/33.52% 5.7%/6.18%

Why is CPAP Only Marginally Better than Intubation/Surfactant? Inexperience with CPAP in the centers participating in RCTs Greater skill with other forms of respiratory support. Limited duration of ventilation in the RCTs Some CPAP delivery systems, may be more effective than others

% intubated** nCPAP/control % Surfactant nCPAP/control Duration ventilation nCPAP/control Support 87.0%100% 67.1%/98.9% 10 days / 13 days@ COIN 58%%/100% 38%/77% 3 days / 4 days VON 45%/98.6% 45%/98.2% 9.2 days / 12.5 days % ventilated Neocosur 26%/39% 12%/100%** 3.3 days / 4.3 days CURPAP 33%/31.4% 48.5%/100% 5.5 days / 5.4 days@ * CPAP vs. INSURE ** DR or NICU @ median values

There’s a Learning Curve to Success with CPAP A comparison of 3 periods before and after the routine application of nCPAP in ELBW infants with respiratory distress. Pre-CPAP Tercile 1 Tercile 2 Tercile 3 ENCPAP application 11.1% 17.6% 61.8% 66.7% CPAP failure* 18.2% 29.4% 11.8% 9.1% Surfactant 51.5% 48.0% 13.3% 33.3% BPD 46.2% 25.9% * First week of life Aly et al. Pediatrics 114: 697, 2004

Columbia Experience 4 year retrospective analysis (2008-11) 297 consecutive inborn infants BW ≤ 1000 gm

Respiratory Outcomes with CPAP 2008-2011 CPAP success@ CPAP failure Ventilated Started (n = 151) (n = 84) (n =62) Weeks 26.9 ± 1.8* 25.6 ± 1.3* 24.8 ± 1.5* Weight (g) 792.7 ± 136.1 723.1 ± 152. 658.6 ± 141.2 *P < .001 CPAP success vs. CPAP failure & ventilated vs. CPAP failure @ CPAP success rate 64%

Respiratory Outcomes with CPAP 2008-2011 CPAP success CPAP failure Ventilated Started (n = 151) (n = 84) (n =62) Oxygen at 28 days 31.8% 73.8% 72.9% Oxygen at 36 weeks 3.6% 15.4% 13.5% Severe BPD (NICHD) 23.9% 50.7% 54.0% Pneumothorax 3.2% 13.4% 8.1% Mortality 8.6% 22.6% 40.3% Death or O2 (36 wks) 11.9% 34.5% 48.4%

Time course of CPAP failure in first 72 hr life

Surfactant pools were lower in lambs that failed BCPAP 80 A Total Lung Sat PC 7.5 B BALF Sat PC 60 5.0 (µmol/kg) (µmol/kg) 40 2.5 20 0.0 10 C % Secreted 75 D Large Aggregate 8 50 Preterm lambs (130-136 days gestation) were delivered by cesarean section. The Lambs were intubated at birth and randomized to CMV, bubble CPAP 5 or bubble CPAP 8 (Fisher Paykel). Non-ventilated (gestational age-matched) served as controls. 6 % % 4 25 2 Success Fail Success Fail Mulrooney et al. Am. J Respir. Crit. Care Med. 171: 488, 2005

Prophylactic Surfactant vs Prophylactic Surfactant vs. Selective Treatment of RDS Neonatal Mortality Study or Prophylactic Selective Risk Ratio Subgroup Events Total Events Total Weight M-H, Fixed,95% Cl Risk Ratio M-H, Fixed,95% Cl 1.6.1 Studies without routine application of CDP Bevilacqua 1996 28 136 46 132 16.9% 0.59 [0.39, 0.89] Bevilacqua 1997 9 49 9 44 3.4% 0.90 [0.39, 2.06] Dunn 1991 9 62 8 60 3.0% 1.09 [0.45, 2.63] Egberts 1993 8 75 14 72 5.2% 0.55 [0.24, 1.23] Kattwinkel 1993 3 627 11 621 4.0% 0.27 [0.08, 0.96] Kendig 1991 23 235 40 244 14.2% 0.60 [0.37, 0.97] Merritt 1991 27 76 21 72 7.8% 1.22 [0.76, 1.95] Walti 1995 15 134 23 122 8.7% 0.59 [0.33, 1.08] Subtotal (95% Cl) 1394 1367 63.3% 0.69 [0.56, 0.85] Total events 122 172 1.1.2 Studies with routine application of CDP Support 2010 114 653 94 663 33.8% 1.23 [0.96, 1.58] Von 2010 10 209 8 221 2.8% 1.32 [0.53, 3.28] Subtotal (95% Cl) 862 884 36.7% 1.24 [0.97, 1.58] Total events 124 102 Total (95% Cl) 2256 2251 100.0% 0.89 [0.76, 1.04] Total events 246 274 .2 .5 1 2 5 Favors prophylactic Favors selective Rojas & Soll 2010 unpublished

Risk Ratio M-H, Fixed, 95% Cl Risk Ratio M-H, Fixed, 95% Cl Prophylactic surfactant vs. treatment of established respiratory distress in preterm infants, Chronic lung disease or death Risk Ratio M-H, Fixed, 95% Cl Prophylactic Risk Ratio M-H, Fixed, 95% Cl Prophylactic n/N Selective n/N Study or subgroup Weight Studies without routine application of CPAP Dunn 1991 16/62 12/60 3.1% 1.29 [0.67, 2.49] Subtotal (95% Cl) 62 60 3.1% 1.29 [0.67, 2.49] Total events 16 (Prophylactic), 12 (Selective) 2. Studies with routine application of CPAP Dunn 2011 76/208 67/220 16.4% 1.29 [0.92, 1.57] Support 2010 353/653 323/663 80.6% 1.11 [1.00, 1.23] Subtotal (95% Cl) 861 883 96.9% 1.12 [1.02, 1.24] Total events 429 (Prophylactic), 390 (Selective) Total (95% Cl 923 943 100.0% 1.13 [1.02, 1.25] Total events 445 (Prophylactic), 402 (Selective) 0.5 0.7 1 1.5 2 Favors experiments Favors control

Intubation >> Surfactant >> Extubation INSURE Intubation >> Surfactant >> Extubation

VON Delivery Room Management (DRM) Groups Intubation, prophylactic surfactant administration with subsequent stabilization on ventilator support (PS Group) Intubation, prophylactic surfactant administration and rapid extubation to NCPAP (ISX Group) Early stabilization on NCPAP and selective intubation and surfactant administration for clinical indications (NCPAP Group) Gestational age 26+0 to 29+6 weeks Study assignment was made prior to delivery 27

Von Delivery Room Management Trial Death or CLD At 36 Weeks Post Menstrual Age 50 40 30 20 10 RR 0.83 (95% CI 0.64, 1.09) RR 0.78 (95% CI 0.59, 1.03) 36.5% % Cases 30.5% 28.5% 36.5% 28.5% 30.5% Death or CLD PS ISX NCPAP Rojas and Soll 2010 unpublished 28

VON-DRM In the nasal CPAP group 48% were managed without intubation and 54% without surfactant. 29

The Stable Microbubble Test for Determining CPAP Success Stable microbubbles were counted in gastric aspirates taken at 1 hour of age in 68 infants (mean GA 28 weeks) who received CPAP from birth. Infants who failed had a lower GA and higher FiO2 on admission to the NICU 8 microbubbles/mm3 had a sensitivity of 53%, a specificity of 100% a positive predictive value of of 100% and a negative predictive value of 60% for predicting CPAP success. Bhatia et al Neonatology 2013

Risk Factors: CPAP success vs. Failure Mother Hispanic Hypertension Maternal diabetes Antenatal steroids Magnesium GBS pos GBS unknown PPROM>18 hrs Clinical chorioamnionitis Maternal fever Intrapartum Antibiotics Fetal distress Multiple birth Vaginal delivery SGA <10th %tile BWT<750 g Male Apgar <5 (1min) Apgar <5 (5min) Severe RDS (CXR) GA (wks) BWT (g) Initial fiO2 (%) 1st ABG (min) pH pCO2 pO2 BE AaDO2 PaO2/fiO2

Performance of Composite Variables   Sensitivity Specificity PPV NPV Severe RDS + (GA≤26 wk) 27.4 98.7 92 29 Severe RDS + (pH≤7.27) 10 99.2 88.9 37.1 Severe RDS + (AaDO2>180) 11.2 63.4 81.8 36.6 Severe RDS+ (paO2/fiO2≤100) 19.3 68.2 84.2 31.8

Summary Based on the data from our NICU from the past 4 years (2008-11), if we have a baby with Severe RDS by CXR The probability of CPAP failure is 82%. With Severe RDS and (GA≤ 26 wks) The probability of CPAP failure is 92% These criteria will identify ¼-⅓ of the babies who actually fail.

Is Bubble CAP Equivalent to or Superior to Other Methods of Delivering CPAP Tagare et al 2013. (n = 145, mean GA 32 weeks) Bubble (B) CPAP vs. Ventilator (V) CPAP. 82.5% of infants in the BCPAP group vs. 63.2% in the VCPAP met success criteria. Mohammad-Bagher et al 2012. (n =161 mean GA ~ 30 weeks) BCPAP vs. Medinjet system (variable flow CPAP system) No significant differences in the duration of CPAP use. Yadav et al 2011 (n = 32, mean GA ~ 28 weeks) BCPAP vs. VCPAP. No significant difference in the rate of extubation failure. Tagare study: Success was defined as reduced CPAP pressures (< 4 cm H2O) and O2 < 30% CPAP), clinical improvement or no need for CPAP or ventilation for 72 hours. Yadav, Indian Journal of Pediatrics 2012 Tagare Journal Tropical of Pediatrics 2013 Mohammad-Bagher Turkish Journal of Pediatrics 2012

Is Bubble CAP Equivalent to or Superior to Other Methods of Delivering CPAP Courtney et al 2011 (n = 18, mean GA ~ 28 weeks) B- CPAP vs. V-CPAP crossover trial. Transcutaneous O2 was higher in the B-CPAP group, but work of breathing was identical*. Lipsten et al 2011 (n = 18, < 1500 grams) Both B-CPAP and IFD increased inspiratory work of breathing. Resistive work of breathing was greater with B-CPAP vs. IFD**. *Courtney et al J Perinatology 2011 **Lipsten et al J Perinatology 2005

Randomized controlled Trial of Post-extubation Bubble CPAP vs Randomized controlled Trial of Post-extubation Bubble CPAP vs. Infant Flow Driver in Preterm Infants with RDS Gupta et al 2009 (n=140, mean GA ~ 27 weeks) BCPAP vs. Infant Flow Driver IFD). No significant differences in the rate of post extubation failure; however, in infants intubated < 14 days, infants on BCPAP had a significantly lower extubation failure rate.

Randomized controlled Trial of Post-extubation Bubble CPAP vs Randomized controlled Trial of Post-extubation Bubble CPAP vs. Infant Flow Driver in Preterm Infants with RDS 1.0 0.8 0.6 0.4 0.2 0.0 IFD CPAP Bubble CPAP p=0.046 Cum Survival %* 28.6% 14.1% In infants ventilated for ≤14 days, B-CPAP was associated with a significantly higher rate of successful extubation for 72 hours. Bubble CPAP IFD CPAP 0 10 20 30 40 50 60 Days CPAP Use Ventilated for ≤14 days *% CPAP failure Gupta S et al J Pediatr. 154: 645, 2009

Bubble CPAP enhances lung volume and gas exchange in preterm lambs Preterm lambs (133 days gestation) were intubated and randomized to bubble CPAP (8 or 12 liters/min) or constant pressure CPAP (ventilator). There were no physiological or biological advantages of 8L/min vs. 12L/min. Pillow J, Hillman N, Moss TJM, Polglase, Bold G, Beaumont, C Ikegami M & AH Jobe AJRCCM 2008

Bubble CPAP enhanced ventilation 7.5 Bubble CPAP Constant Pressure CPAP 100 * * ** * * 7.4 ** 80 7.3 60 PaCO2 (mmHg) pH 7.2 40 7.1 20 7.0 30 60 90 120 150 30 60 90 120 150 Time (min) Time (min) Pillow J, Hillman N, Moss TJM, Polglase, Bold G, Beaumont, C Ikegami M & AH Jobe AJRCCM 2008

Bubble CPAP improved oxygenation * 400 300 PaO2 (mmHg) 200 Bubble CPAP Constant Pressure CPAP 100 30 60 90 120 150 Time (min) Pillow J, Hillman N, Moss TJM, Polglase, Bold G, Beaumont, C Ikegami M & AH Jobe AJRCCM 2008

Bubble CPAP enhanced O2 extraction 10 p=0.045 8 6 % O2 extraction 4 2 Constant Pressure Bubble 8 L/min Bubble 12 L/min Pillow J, Hillman N, Moss TJM, Polglase, Bold G, Beaumont, C Ikegami M & AH Jobe AJRCCM 2008

Physiological Explanation of the Advantages of Bubble CPAP The more efficient utilization of inspired O2 in the bubble CPAP groups are suggestive of increased airway patency.

Concerns about Bubble CPAP BCPAP may be most effective when lung compliance is low (early in RDS) The amount of positive airway pressure constantly fluctuates around a mean (immersing the expiratory limb to a depth of 5 cm will deliver pressures ranging from 3-7). In a test lung system, condensate forming in the expiratory limb, dramatically increased the amplitude of the pressure oscillations (when the pressure was set at 8 cm H2O, the oscillations were as high as 13 cm H2O).* *Younquist et al Respiratory case 2013

CPAP: Conclusions Early use of CPAP with subsequent selective surfactant administration in extremely preterm infants results in lower rates of BPD/death when compared to treatment with prophylactic or early surfactant therapy (LOE 1). If it is likely that respiratory support with a ventilator will be needed, early administration of surfactant followed by rapid extubation, is preferable to prolonged ventilation (LOE 1).

Recommendation for Preterm Infants with RDS Preterm infants with RDS weighing < 1500 gms. should be allowed time to demonstrate if they can achieve acceptable ventilation and oxygenation on CPAP. During that time period, these infants must be monitored closely. If ventilation is not improving or oxygenation is worsening, or inadequate with an FiO2 of 60%, these infants should be intubated. Should infants < 26 weeks gestation receive prophylactic surfactant?