Wally A. Carlo, M.D.University of Alabama at Birmingham

Fisiología Respiratoria, Hipercapnia Permisiva e

Injuria Pulmonar

Randomized Trial of Oxygen Saturation Targets in Premature

Infants - the SUPPORT Trial

The SUPPORT Study Group of the Eunice Kennedy Shriver NICHD

Neonatal Research Network

eon at a l R esear ch N et w or kN EON ATAL RESEARCH N ETW ORKNICHD

The SUPPORT Study Group of the Eunice Kennedy Shriver NICHD

Neonatal Research Network

Randomized Trial of Early CPAP versus Surfactant in Extremely Preterm

InfantsThe SUPPORT Trial

Background• Surfactant treatment at less than 2 hours of life

significantly decreases death, air leak, and death or bronchopulmonary dysplasia (BPD) in preterm infants - but not BPD alone

• However, no surfactant studies had a comparison group who received early CPAP

• Retrospective cohort studies demonstrated that the early use of CPAP in very preterm infants with respiratory distress may decrease mechanical ventilation without increased morbidity and without surfactant

BACKGROUND –CONSENSUS CONFERENCE

• To minimize side effects, blood gas targets do not have to be in the “normal” ranges

• Assisted ventilation may lead to adverse consequences

• Gas trapping (dynamic hyperinflation) and alveolar overdistention may lead to lung damage and should be limited

ACCP Conference. Chest 104:1833, 1993.

• Maintenance of normocapnia in some patients with severe respiratory failure necessitates high ventilatory support

• Compensated respiratory acidosis is generally well tolerated and may reduce lung injury

• Clinical studies show trend or significant benefits of a limited ventilation strategy with permissive hypercapnia

Permissive Hypercapnia:Background - Rationale

LUNG INJURY DURING ASSISTED VENTILATION

1. Chest wall restriction limits pressure-induced lung injury (Hernandez, et al., 1988)

2. Overexpansion of the thorax with negative pressures causes lung injury (Dreyfus, et al., 1988)

VOLUME vs PRESSURE IN LUNG INJURY

Pulm. Epith. Hyaline Lymph Filtr.VolumePressure Edema Injury Memb. Flow Coef.

IPPV High High Yes Yes Yes Yes YesIron Lung High Low Yes Yes Yes N/A N/AStrapping Low High No No No No No

Dreyfus et al, 1988; Bshouty et al, 1988; Hernandez et al, 1989; Corbridge et al, 1990; Carlton et al, 1990

EFFECT OF TIDAL VOLUMEON LUNG COMPLIANCE

Bjorklund et al., 39:326A, 1996.

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32 cc/kg

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EFFECT OF TIMING INFLATION ON LUNG VOLUTRAUMA

Ingirmarsson et al. Pediatr Res 41:255A, 1997.

Before SurfactantAfter Surfactant

B Normal VT, high PEEP

WHICH VOLUMES CAUSE LUNG INJURY?

A High VTlow PEEP

D Optimal ventilation

A BTime

Volutrauma Zone

C

Volutrauma Zone Atelectasis

Overdistention

DC Normal VT

low PEEP© W. Carlo 2003

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PERMISSIVE HYPERCAPNIA: BACKGROUND

• Why worry about PaCO2?

• Is it not volutrauma that causes lung injury?

PREVENTION OF VOLUTRAUMA

•Low tidal volume

Decreased CO2 elimination

Hypercapnia

High ventilator rate (inefficient)

Permissive hypercapnia

Hypothesis

Early CPAP with a limited ventilator strategy would reduce the incidence of death or survival with BPD at 36 weeks compared to early surfactant

Method – Patients

• Inborn infants of 240/7 to 276/7 weeks gestation for whom a decision had been made to provide full resuscitation were eligible

• Antenatal Parental consent was obtained• Enrollment from February 2005 to February 2009• Randomization was stratified by center and by

gestational age (24 and 25 weeks; 26 and 27 weeks)

Factorial Design

Infants also randomized to 2 ranges of SpO2using purpose-built blinded oximeters

CPAP Intervention

• In the delivery room, CPAP at 5 cm H2O was provided until NICU admission using a T-piece resuscitator, a neonatal ventilator, or an equivalent methodology

• Intubation only for infants who required intubation for resuscitation based on standard NRP indications, not performed for the surfactant administration

• Intubated infants given surfactant

CPAP/Limited ventilation

Surfactant

Delivery Room 5 cm H2OIntubation per NRPIf intubated, surfactant

Standard NRP

Intubation/Surfactant

Considered if:FiO2 > 0.5PaCO2 > 65 mmHgHemodynamic instability

Prior to 1 hour

Methods

Methods: Extubation CriteriaWithin 24 hrs of meeting all criteria

CPAP/Limited ventilation

Surfactant

FiO2 < 0.50 and MAP <10 cmPaCO2 < 65 mmHgVent rate < 20 bpmHemodynamically Stable

FiO2 < 0.35 and MAP < 8 cmPaCO2 < 50 mmHgVent rate < 20 bpmHemodynamically Stable

Ventilator rate < 20 bpmHemodynamically stableVentilator rate < 20 bpmHemodynamically stable

Methods – Duration of Intervention• The criteria for both arms were in effect for the

first 14 days of life, following which the infant was treated as per NICU standard practice.

• For both arms, intubation could be performed at any time for the occurrence of repetitive:1. apnea requiring bag and mask ventilation2. clinical shock3. sepsis, and/or 4. the need for surgery

Methods – BPD Definitions

• For the primary outcome, BPD was defined using the physiologic definition:- receipt > 30% oxygen at 36 weeks - need for positive pressure support - if FiO2 < 30%, oxygen withdrawal performed

• Pre-specified secondary outcomes included the evaluation of BPD defined by the receipt of oxygen at 36 weeks.

Methods – Sample Size Estimate

• Baseline rate of BPD/Death of 50%• Absolute risk difference of 10%• Increased by 1.12 to allow for multiples

randomized to same treatment• Increased by 1.17 to adjust for attrition• Increased further to minimize Type I error using

a conservative 2% level of significance• Final sample size was 1310 infants

Methods – Data Analysis• The primary and categorical outcomes were analyzed

using Poisson regression implementation in a Generalized Estimating Equation (GEE) model to obtain adjusted relative risk and 95% CI

• Continuous outcomes were analyzed using mixed effects linear models to produce adjusted means and standard errors

• Adjustment was performed for pre-specified stratification (center and GA) and for familial clustering as multiple births were randomized to the same treatment arms

3546 Infants were assessed for eligibility (3127 pregnancies)*

1316 Underwent randomization

663 Were assigned CPAP 653 Were assigned Surfactant

94 Died before discharge

569 Survived to discharge, transfer one year of life

114 Died before discharge

539 Survived to discharge, transfer or one year of life

223 BPD Physiologic

219 BPD Physiologic

235 Did not meet eligibility criteria125 Personnel/Equipment not available699 Eligible but consent not sought 344 Parent unavailable for consent748 Consent denied by parent or guardian11 Excluded for other reasons68 Consented but not randomized

346 No BPDPhysiologic

320 No BPD Physiologic

Results – Patient Population

CPAP(N = 663)

Surfactant(N = 653)

Birthweight* 835 + 188 826 + 198Gestational age* 26 + 1 26 + 1

24 to 25 6/7ths (%) 43 4326 to 27 6/7ths (%) 57 57

Race, White/Black/Hispanic (%) 38 / 38 / 21 36 / 42/ 19Antenatal corticosteroids (%) 97 96Multiple births (%) 27 24

*Mean ± Standard Deviation

Results – Primary Outcome

CPAPN=663

SurfactantN=653

Adjusted Relative Risk (95% CI)

Death or BPD (Physiologic) 47.8% 51.0% 0.95 (0.85, 1.05)

BPD - Physiologic 39.2% 40.6% 0.99 (0.87, 1.14)

Death by 36 weeks PMA 14.2% 17.5% 0.81 (0.63, 1.03)

Results – Delivery Room

VariableCPAP

(N=663)Surfactant

(N=653)

Relative Risk for CPAP vs. Surfactant

(95% CI)Adjusted P-

valueApgar at 1 minute <3 23.3% 25.6% 0.92 (0.76, 1.11) 0.38

Apgar at 5 minutes <3 3.9% 4.9% 0.82 (0.5, 1.34) 0.43

PPV in the DR 65.7% 92.9% 0.71 (0.67, 0.75) <0.001

Intubated in DR 34.4% 93.4% 0.37 (0.34, 0.42) <0.001

DR intubation for resuscitation

32.6% 27.0% 1.21 (1.02, 1.43) 0.02

Surfactant DR/NICU 67.1% 98.9% 0.67 (0.64, 0.71) <0.001

Epinephrine in DR 2.0% 4.1% 0.48 (0.25, 0.91) 0.02

Results – Other Pre-specified Outcomes

CPAPN=663

SurfactantN=653

Relative Risk or Difference in Means

BPD (O2 use at 36 wks) 40.2% 44.3% 0.94 (0.82, 1.06)Death/BPD, 36 wks 48.7% 54.1% 0.91 (0.83, 1.01)Severe ROP- survivors 13.1% 13.7% 0.94 (0.69, 1.28)Any air leaks (14 days) 6.8% 7.4% 0.89 (0.6, 1.32)Mechanical Vent Survivors(median days)

10 13 *

Alive and off MV at 7 days 55.3% 48.8% 1.14 (1.03, 1.25)*Postnatal steroids for BPD 7.2% 13.2% 0.57 (0.41, 0.78)*

* = p<0.05

SUPPORT – Other Results

No differences in the incidence of:• PDA, PDA requiring surgery • NEC, medical or surgical• Severe IVH/PVL

• In the 24 to 25 weeks strata CPAP infants had a lower mortality than Surfactant infants:

CPAP 23.9% vs Surfactant 32.1%Relative Risk difference 0.74 (0.57, 0.98)

Contributory Cause of DeathCPAP(N=68)

Surfactant(N=90)

Respiratory distress syndrome 13/68 (19.1) 31/90 (34.4)Bronchopulmonary dysplasia 10/68 (14.7) 7/90 (7.8)Infection 14/68 (20.6) 15/90 (16.7)Necrotizing enterocolitis 10/68 (14.7) 16/90 (17.8)Central nervous center insult 11/68 (16.2) 5/90 (5.6)Immaturity 3/68 (4.4) 5/90 (5.6)Other 7/68 (10.3) 11/90 (12.2)

Causes of Death – 24-25 wk Strata

SUMMARY• There was no significant difference for primary

outcome of death or BPD• More CPAP infants were alive and off mechanical

ventilation by day 7 (p=0.011) • CPAP infants received less postnatal steroids for

BPD (p<0.001) and required fewer vent days (p=0.03)

• CPAP Infants 24 to 25 6/7 weeks had a significantly lower mortality rate while hospitalized (p<.01)

• CPAP infants did not have increased morbidities

CONCLUSIONS

• Early CPAP with a limited ventilator strategy for the extremely low birth weight infant is associated with decreased exposure to intubation and mechanical ventilation, decreased death in the most immature infants, without any increase in measured morbidities

• All surviving infants will be followed to 18-22 months for a complete neurodevelopmental assessment

What about other major trials of early CPAP/permissive hypercapnia?

RCT of CPAP vs. Ventilation (COIN Trial): Methods

Design: Multicenter RCTSubjects: 25 0/7 to 28 6/7 week infants, breathing at 5

min.

Intervention: CPAP at 8 cmH2O vs. intubation/surfactant

Intubation criteria for CPAP grouppH< 7.25 PaCO2 > 60 mmHg; FiO2 > 0.60; and/or apnea

Morley et al. NEJM 358; 700, 2008

RCT of CPAP vs. Ventilation (COIN Trial)

610 subjects, 960 ± 215 gm, 94% got ANS

CPAP Intubation RR CI p valueN=307 N=303

BPD 28d/death 54% 65% 0.63 0.46 - 0.88 <0.05BPD 36w/death 34% 39% 0.80 0.58 - 1.12 NSPneumothorax 9% 3% <0.001Days on ventilator 3 4 <0.001Pneumothorax rate increased in the CPAP group (3 to 9%, p<0.003)Mortality, days of ventilatory support, days of O2, hospital stay, IVH ¾, PVL, NEC, PDA ligation, ROP, home O2 and steroid treatment did not differ between the groups

Morley et al. NEJM 358; 700, 2008

RCT of CPAP vs. Ventilation (CURCPAP Trial)

CPAP Surfactant p ValueBPD/death (%) 21 22 NSPneumothorax (%)

1 7 NS

IVH 3-4 (%) 8 6 NS

Sandri et al. Pediatrics 125;31402, 2010

RCT of CPAP vs. Ventilation (VON Trial )648 infants 26 to 29 weeks

Clinical Status at 36 weeks PMAOutcome PS

N=209NCPAP N=223

RR (95%CI)(vs PS)

Death or CLD (ALL) 36% 30% 0.83 (0.64, 1.09)

Death (ALL) 7% 4% 0.57 (0.25, 1.27)

Death or major morbidity 39% 34% 0.88 (0.68, 1.12)

Soll et al PAS Vancouver 2010

Early CPAP vs Surfactant in Very Low Birth Weight Infants

ResultsCPAP

(n=131)Surfactant

(n=125) p-valueGA 30 wks 30 wks NS

Birth Weight 1196 (1162-1229) gm 1197 (1163-1230) gm NS

Oxygen at 36 wks (%) 7 10 NS

Death (%) 8 10 NS

Pneumothorax (%) 3 6 NS

IVH (3-4 (%) 5 6 NS

Mechanical Vent (%) 30 52 <0.001

Surfactant (%) 28 46 <0.01

J. Tapia. PAS 2010

RCT of CPAP vs. Ventilation (Rojas Trial)

• 279 infants from 27 to 31 wks• Compared CPAP to intubation/surfactant and

extubation within 1 hr of birth• CPAP group had lower BPD/death rates 54 vs

63% (NS)• Air leaks higher in CPAP – 9% vs 2%

Rojas et al – Pediatrics 2009;123:137-42

Results - Demographic Variables

Minimal Vent Routine Vent p value(N=109) (N=111)

Birth weight (gm) 742 ± 130 728 ± 135 NSGestational age (wk) 25 ± 2 25 ± 2 NSAntenatal steroid (%) 74 75 NSSurfactant (%) 98 96 NSMale (%) 48 56 NSRace (%) B/W/O 46/39/15 48/43/9 NSRandomization age (hr) 6.5 ± 3.0 7.1 ± 2.8 NS

Carlo et al. J Pediatr 41:370, 2002

Results - Primary Outcome Measures

Minimal RoutineVentilation Ventilation RR CI(N=109) (N=111)

Mortality or BPD (%) 63 68 0.93 (0.77-1.12)Mortality (%) 23 22 1.06 (0.65-1.74)BPD (%) 52 60 0.88 (0.67-1.14)

SAVE Trial

Carlo et al. J Pediatr 41:370, 2002

Results - Secondary AnalysesMinimal Routine

Ventilation Ventilation RR CI NNTVentilation at

36 wk (%) 1 16 0.09 (0.01-0.67)* 7BPD or death in

501-750 gm (%) 68 86 0.79 (0.65-0.96)* 6

*p<0.05

SAVE Trial

Carlo et al. J Pediatr 41:370, 2002

Minimal RoutineVentilation Ventilation RR CI

Death or NDI (%) 64 68 0.9 (0.8-1.2)NDI (%) 51 55 0.9 (0.7-1.3)CP (%) 11 20 0.55 (0.2-1.2)

SAVE Trial

Results - Long-term Follow-up

Carlo et al. J Pediatr 41:370, 2002

Summary of Major Trials of Early CPAP and/or Permissive Hypercapnia

BPD/Death CPAP/PHC

Experimental Control ARRCarlo (2002) 63% 68% 5%Morley (2008) 34% 39% 5% Rojas (2009) 54% 63% 9%Soll (2010) 30% 36% 6%Finer (2010) 48% 51% 3%Neocosur/Tapia (2010) 15% 19% 4%CURPAP/Sandri (2010) 21% 22% 1%

Summary of Major Trials of Early CPAP and/or Permissive Hypercapnia

Preliminary meta-analysis SUPPORT, COIN, VON, Neocosur,

CURPAP and Rojas

BPD/Death

CPAP/PHC Control

624/1568 (40%) 689/1538 (45%)

RR 0.88 95% CI 0.81; 0.96

Early CPAP vs Early Surfactant –ELBW Infants Death or BPD at 36 Weeks

Study CPAP Surfactant OR (fixed) OR (fixed)or sub-category n/N n/N 95% CL 95% CLCOIN NEJM 104/307 118/303 0.80 (0.58, 1.12)CURPAPS Peds 5/103 5/105 1.02 (0.29, 3.64)SUPPORT NEJM 323/663 353/653 0.81 (0.65, 1.00)VON 2010 68/223 138/425 0.91 (0.64, 1.29)

Total (95%, CI) 39%/1296 41%/1486 0.83 (0.71, 0.97)Total events: 500 (CPAP), 614 (Control)Test for heterogeneity: ChF=0.48, df=3 (P=0.92), F=0%Test for overall effect: Z=2.28 (P=0.02)

0.1 0.2 0.5 1 2 5 10Favours treatment Favours controlFiner 2010.

Study CPAP Surfactant OR (fixed)OR (fixed)or sub-category n/N n/N95% CL 95% CLCOIN NEJM 20/307 18/303 1.10 (0.67, 2.13)CURPAPS Peds 11/103 9/105 1.28 (0.51, 3.22)SUPPORT NEJM 94/663 114/653 0.78 (0.68, 1.06)VON 2010 9/223 30/425 0.66 (0.26, 1.19)

Total (95%, CI) 10%/1296 12%/1486 0.82 (0.64, 1.04)Total events: 134 (CPAP), 171 (Surfactant)Test for heterogeneity: ChF=2.78, df=3 (P=0.43), F=0%Test for overall effect: Z=1.64 (P=0.10) 0.1 0.2 0.5 1 2 5 10

Favours treatment Favours control

Early CPAP vs Early Surfactant –ELBW Infants Death at 36 Weeks

Finer 2010.

Study CPAP Surfactant OR (fixed)OR (fixed)or sub-category n/N n/N95% CL 95% CLCOIN NEJM 51/207 62/198 0.72 (0.46, 1.11)CURPAPS Peds 22/72 18/73 1.34 (0.65, 2.79)SUPPORT NEJM 144/378 165/373 0.78 (0.58, 1.41)VON 2010 68/223 138/425 0.91 (0.64, 1.29)

Total (95%, CI) 32%/880 36%/1069 0.83 (0.69, 1.01)Total events: 285 (CPAP), 383 (Surfactant)Test for heterogeneity: ChF=2.59, df=3 (P=0.46), F=0%Test for overall effect: Z=1.86 (P=0.06)

Early CPAP vs Early Surfactant – ELBW > 27 weeks – Death or BPD at 36 Weeks

Finer 2010.

So What Should I Do In My Daily Practice?

Suggestions for ELBW/ELGAN Infants 1. Use CPAP instead of intubation and surfactant

as the mode of initial support2. If intubated (FiO2 > 50%,PCO2 >65, pH < 7.20,

others): give surfactant3. Attempt to wean the ventilator if PCO2 < 55-65,

pH > 7.20, FiO2 < 50%

Thanks to the many parents, infants, and NICU staff

Special Thanks to the Research Coordinators of the NRN

Study Funded by the NICHD and NHLBI

NICHD Neonatal Research Network Centers (2005-2009)

• Brown University• Case Western Reserve Univ• Duke University• Emory University• Indiana University• RTI International• Stanford University• Tufts Medical Center • University of Alabama –

Birmingham

• University of California – San Diego• University of Cincinnati• University of Iowa • University of Miami• University of New Mexico• University of Rochester • University of Texas, Southwestern –

Dallas• University of Texas – Houston• University of Utah• Wake Forest University• Wayne State University• Yale University