CPAP: The New (old) Gold Standardfor Respiratory Management

Morgan Stanley Children’s HospitalColumbia University

Richard A. Polin M.D.

Disclosures

• I am a consultant forFisher & 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

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 toleratedB. 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.

Case

Modified from Thomas W & Speer CP Neonatology 2011

Immature Lung Genetic Predisposition

• Nitric oxide

• Diuretics

• SuperoxideDismutase

• GentleResuscitation

• Antenatalsteroids

• Surfactant

• Permissive Hypercapnia

• Permissive hypoxemia

• Caffeine

• Postnatal steroids

• Vitamin A

• CPAP

Lung Injury in the Neonate: Fundamental Concept

• If you don’t ventilate an infant,it’s hard to cause BPD!

CPAP is Controversial

Sharma A & Greenough. Acta Paediatrica 96: 1115-1117, 2007

Acute RDS WeaningIPPV 73% N/AHFO 2% N/AIMV N/A 13%A/C 4% 15%SIMV 13% 73%VG 5% 6%CPAP 2% N/A

Respiratory Support Strategies U.K.

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% 97% 95% 90% 86% 78% 65% 82%

Ventilation 96% 94% 89% 76% 61% 49% 40% 62%

CPAP 0% 3% 8% 18% 30% 36% 38% 26%

Stoll B et al Pediatrics 126: 443, 2010

N = 8575 VLBW infants (2003-2007)

Pulmonary Morbidity According to Gestational Age for VLBW Infants

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

Surfactant: Systematic Reviews-Mortality

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

“Simplicity is theUltimate sophistication”

KISS: Keep it simple stupid!

CPAP is an evidence-based treatment for preterm

infants with RDS

Gestational age N Death or BPD Air-leaks

CPAP/control 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%

Summary of CPAP Trials

Why is CPAP Only Marginally Betterthan 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

% SurfactantnCPAP/control

Duration ventilationnCPAP/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 @ median values** DR or NICU

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 33.3% 46.2% 25.9% 11.1%

A comparison of 3 periods before and after the routine application of nCPAP in ELBW infants with respiratory distress.

* First week of life

Aly et al. Pediatrics 114: 697, 2004

There’s a Learning Curve to Success with CPAP

Columbia Experience

• 4 year retrospective analysis(2008-11)

• 297 consecutive inborn infantsBW ≤ 1000 gm

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%

Respiratory Outcomes with CPAP 2008-2011

Time course of CPAP failure infirst 72 hr life

7.5Total Lung Sat PC80

Success Fail Success Fail

BALF Sat PC

Large Aggregate% Secreted

60

40

20

0

10

8

6

4

2

0

5.0

2.5

0.0

75

50

25

0

% %

(µm

ol/

kg

)

(µm

ol/

kg

)

A

C D

B

Mulrooney et al. Am. J Respir. Crit. Care Med. 171: 488, 2005

Surfactant pools were lower in lambsthat failed BCPAP

1.6.1 Studies without routine application of CDPBevilacqua 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

Study or Prophylactic Selective Risk Ratio Subgroup Events Total Events Total Weight M-H, Fixed,95% Cl

Risk RatioM-H, Fixed,95% Cl

1.1.2 Studies with routine application of CDPSupport 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 2 5Favors prophylactic Favors selective

1

Rojas & Soll 2010 unpublished

Prophylactic Surfactant vs. Selective Treatment of RDS Neonatal Mortality

1. Studies without routine applicationof 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

Favorsexperiments

Favorscontrol

Study or subgroupProphylactic

n/NSelective

n/N

Risk RatioM-H, Fixed,

95% Cl Weight

Risk RatioM-H, Fixed,

95% Cl

Prophylactic

Prophylactic surfactant vs. treatment of established respiratory distress in preterm infants,

Chronic lung disease or death

Intubation >> Surfactant >> Extubation

INSURE

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 weeksStudy assignment was made prior to delivery

Death or CLD At 36 Weeks Post Menstrual Age

36.5% 28.5% 30.5%

36.5%

50

40

30

20

10

0

% C

ases

Death or CLD

RR 0.78(95% CI 0.59,

1.03)

RR 0.83(95% CI 0.64,

1.09)

PS ISX NCPAP

28.5%30.5%

Rojas and Soll 2010 unpublished

Von Delivery Room Management Trial

VON-DRM

• In the nasal CPAP group 48% were managed without intubation and 54% without surfactant.

Bhatia et al Neonatology 2013

The Stable Microbubble Test forDetermining 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.

Mother Hispanic

Hypertension

Maternal diabetes

Antenatal steroids

Magnesium

GBS pos

GBS unknown

PPROM>18 hrsClinical

chorioamnionitisMaternal 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

Risk Factors: CPAP success vs. Failure

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 babieswho actually fail.

Yadav, Indian Journal of Pediatrics 2012

Mohammad-Bagher Turkish Journal of Pediatrics 2012Tagare Journal Tropical of Pediatrics 2013

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.

*Courtney et al J Perinatology 2011 **Lipsten et al J Perinatology 2005

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-CPAPvs. IFD**.

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.

0

10

20

30

40

50

60

70

80

14.1%

Ventilated for ≤14 days

28.6%

Bubble

CPAP

IFD CPAP

p=0.046

%*

IFD CPAPBubble CPAP

1.0

0.8

0.6

0.4

0.2

0.0

Cu

m S

urv

ival

Days CPAP Use

0 10 20 30 40 50 60

*% CPAP failure

Gupta S et al J Pediatr. 154: 645, 2009

Randomized controlled Trial of Post-extubation Bubble CPAP vs. Infant Flow

Driver in Preterm Infants with RDS

Pillow J, Hillman N, Moss TJM, Polglase, Bold G, Beaumont, C Ikegami M & AH Jobe AJRCCM 2008

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).

*

Time (min)

***

Bubble CPAPConstant Pressure CPAP

7.5

7.4

7.3

7.2

7.1

7.0

pH

0 30 60 90 120 150

Time (min)

0 30 60 90 120 150

PaC

O2 (

mm

Hg

)

100

80

60

40

20

0

* * **

Pillow J, Hillman N, Moss TJM, Polglase, Bold G, Beaumont, C Ikegami M & AH Jobe AJRCCM 2008

Bubble CPAP enhanced ventilation

*

Bubble CPAPConstant Pressure CPAPP

aO

2 (

mm

Hg

)400

300

200

100

0

Time (min)

0 30 60 90 120 150

Pillow J, Hillman N, Moss TJM, Polglase, Bold G, Beaumont, C Ikegami M & AH Jobe AJRCCM 2008

Bubble CPAP improved oxygenation

A

% O

2 e

xtr

acti

on

10

8

6

4

2

0Bubble

12 L/minConstantPressure

p=0.041

Bubble8 L/min

p=0.045

Pillow J, Hillman N, Moss TJM, Polglase, Bold G, Beaumont, C Ikegami M & AH Jobe AJRCCM 2008

Bubble CPAP enhanced O2 extraction

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.

*Younquist et al Respiratory case 2013

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 from3-7).

• 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).*

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?