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

2. Disclosures
I am a consultant for Fisher & Paykel and Ikaria

4. 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

5. 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.

6. 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

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

8. CPAP is Controversial

9. Respiratory Support Strategies U.K.
Acute RDS Weaning
IPPV % N/A HFO % N/A IMV N/A % A/C % % SIMV % % VG % % CPAP % N/A
80% of 228 units in the UK responded.
Sharma A & Greenough. Acta Paediatrica 96: , 2007

10. 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 ( )
Stoll B et al Pediatrics 126: 443, 2010

11. Surfactant: Systematic Reviews-Mortality
RR %CI NNT % CI
Natural surfactant
Multiple doses
Prophylaxis
Early
HL Halliday Journal of Perinatology 28: s47, 2008

12. 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

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

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

15. 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 g
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%

16. 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

17. % intubated** nCPAP/control
% Surfactant nCPAP/control
Duration ventilation nCPAP/control
Support
87.0%100%
67.1%/98.9%
10 days / 13
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
* CPAP vs. INSURE
** DR or NICU
@ median values

18. 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

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

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

21. Respiratory Outcomes with CPAP 2008-2011
CPAP success CPAP failure Ventilated Started
(n = 151) (n = 84) (n =62)
Oxygen at 28 days % % 72.9%
Oxygen at 36 weeks 3.6% % 13.5%
Severe BPD (NICHD) % % 54.0%
Pneumothorax % % 8.1%
Mortality % % %
Death or O2 (36 wks) % % %

22. Time course of CPAP failure in first 72 hr life

23. Surfactant pools were lower in lambs that failed BCPAP80 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 ( 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

24. 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 % 0.59 [0.39, 0.89]
Bevilacqua % 0.90 [0.39, 2.06]
Dunn % 1.09 [0.45, 2.63]
Egberts % 0.55 [0.24, 1.23]
Kattwinkel % 0.27 [0.08, 0.96]
Kendig % 0.60 [0.37, 0.97]
Merritt % 1.22 [0.76, 1.95]
Walti % 0.59 [0.33, 1.08]
Subtotal (95% Cl) % 0.69 [0.56, 0.85]
Total events
1.1.2 Studies with routine application of CDP
Support % 1.23 [0.96, 1.58]
Von % 1.32 [0.53, 3.28]
Subtotal (95% Cl) % [0.97, 1.58]
Total events
Total (95% Cl) % [0.76, 1.04]
Total events .2 .5 1 2 5
Favors prophylactic
Favors selective
Rojas & Soll 2010 unpublished

25. 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 / / % [0.67, 2.49] Subtotal (95% Cl) % [0.67, 2.49] Total events 16 (Prophylactic), 12 (Selective)
2. Studies with routine application of CPAP Dunn / / % [0.92, 1.57] Support / / % [1.00, 1.23]
Subtotal (95% Cl) % [1.02, 1.24] Total events 429 (Prophylactic), 390 (Selective)
Total (95% Cl % [1.02, 1.25] Total events 445 (Prophylactic), 402 (Selective)
Favors experiments
Favors control

26. Intubation >> Surfactant >> Extubation
INSURE
Intubation >> Surfactant >> Extubation

27. 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

28. 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

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

30. 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

31. 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

32. 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

33. Summary
Based on the data from our NICU from the past 4 years ( ), 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.

34. Is Bubble CAP Equivalent to or Superior to Other Methods of Delivering CPAP
Tagare et al (n = 145, mean GA 32 weeks) Bubble (B) CPAP vs. Ventilator (V) CPAP % of infants in the BCPAP group vs. 63.2% in the VCPAP met success criteria.
Mohammad-Bagher et al (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

35. 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

36. 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.

37. 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
Days CPAP Use
Ventilated for ≤14 days
*% CPAP failure
Gupta S et al J Pediatr. 154: 645, 2009

38. 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

39. 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

40. 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

41. Bubble CPAP enhanced O2 extraction10
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

42. 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.

43. 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

44. 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).

45. 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?