Post on 11-Dec-2018
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.
0
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0 60 120 180 240
Age (min)
32 cc/kg
16 cc/kg
8 cc/kg
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(cc/
cmH
2O k
g)
Com
plia
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(cc/
cmH
2O k
g)
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0 60 120 180 240
Age (min)
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
0
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0 5 10 15
C
C20
Pmax
0.8 Pmax
cmH2O
Vol
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ve F
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(ml)
Highinflection pointLow inflection point
20
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