Post on 23-Dec-2015
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?