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Fisiología Respiratoria, Hipercapnia Permisiva e Injuria Pulmonar

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

Randomized Trial of Oxygen Saturation Targets in Premature Infants - the SUPPORT Trial

Randomized Trial of Early CPAP versus SurfactantStudy Group of the The SUPPORT in Extremely Preterm Infants Eunice Kennedy Shriver NICHD The SUPPORT Trial Neonatal Research Network The SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal or k eon at al R esear ch N et wResearch Network

NEONATAL RESEARCH NETW ORK NICHD

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.

Permissive Hypercapnia: Background - Rationale

· 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

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. Volume Pressure Edema Injury Memb. Flow Coef.

IPPV High Iron Lung High Strapping Low

High Low High

Yes Yes No

Yes Yes No

Yes Yes No

Yes N/A No

Yes N/A No

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

EFFECT OF TIDAL VOLUME ON LUNG COMPLIANCE

3 8 cc/kg Compliance (cc/cmH2O kg) 2 16 cc/kg 1

32 cc/kg

0 0 60 120 Age (min) 180 240

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

EFFECT OF TIMING INFLATION ON LUNG VOLUTRAUMA

6

After Surfactant Before Surfactant

Compliance (cc/cmH2O kg)

4

2

0 0 60 120 180 240

Age (min)

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

.

WHICH VOLUMES CAUSE LUNG INJURY? Volutrauma Zone Overdistention

Time

Volutrauma Zone A B C D

Atelectasis

A High VT B Normal VT, low PEEP high PEEP

© W. Carlo 2003

C Normal VT D Optimal low PEEP ventilation

C C20

8

Volume Above FRC (ml)

Pmax 0.8 Pmax

High inflection point Low inflection point

6 4 2 0 0 5

cmH2O

10

15

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 SpO2 using 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

Methods

CPAP/Limited ventilation

Delivery Room 5 cm H2O Intubation per NRP If intubated, surfactant Intubation/ Considered if: Surfactant FiO2 > 0.5 PaCO2 > 65 mmHg Hemodynamic instability

Surfactant

Standard NRP

Prior to 1 hour

Methods: Extubation Criteria

Within 24 hrs of meeting all criteria CPAP/Limited ventilation

FiO2 < 0.50 and MAP <10 cm PaCO2 < 65 mmHg Vent rate < 20 bpm Hemodynamically Stable

Surfactant

FiO2 < 0.35 and MAP < 8 cm PaCO2 < 50 mmHg Vent rate < 20 bpm Hemodynamically Stable

Ventilator rate < 20 bpm Hemodynamically 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 ventilation 2. clinical shock 3. 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)* 235 125 699 344 748 11 68 Did not meet eligibility criteria Personnel/Equipment not available Eligible but consent not sought Parent unavailable for consent Consent denied by parent or guardian Excluded for other reasons Consented but not randomized

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

346 No BPD Physiologic

219 BPD Physiologic

320 No BPD Physiologic

Results ­ Patient Population

CPAP (N = 663) Birthweight* Gestational age* 24 to 25 6/7ths (%) 26 to 27 6/7ths (%) Race, White/Black/Hispanic (%) Antenatal corticosteroids (%) Multiple births (%)

*Mean ± Standard Deviation

Surfactant (N = 653) 826 + 198 26 + 1 43 57 36 / 42/ 19 96 24

835 + 188 26 + 1 43 57 38 / 38 / 21 97 27

Results ­ Primary Outcome

CPAP Surfactant Adjusted Relative N=663 N=653 Risk (95% CI) Death or BPD (Physiologic) 47.8% 39.2% BPD - Physiologic Death by 36 weeks PMA 14.2% 51.0% 40.6% 17.5% 0.95 (0.85, 1.05) 0.99 (0.87, 1.14) 0.81 (0.63, 1.03)

Results ­ Delivery Room

CPAP (N=663) 23.3% 3.9% 65.7% 34.4% 32.6% 67.1% 2.0% Surfactant (N=653) 25.6% 4.9% 92.9% 93.4% 27.0% 98.9% 4.1% Relative Risk for CPAP vs. Surfactant (95% CI) 0.92 (0.76, 1.11) 0.82 (0.5, 1.34) 0.71 (0.67, 0.75) 0.37 (0.34, 0.42) 1.21 (1.02, 1.43) 0.67 (0.64, 0.71) 0.48 (0.25, 0.91) Adjusted Pvalue 0.38 0.43 <0.001 <0.001 0.02 <0.001 0.02

Variable Apgar at 1 minute <3 Apgar at 5 minutes <3 PPV in the DR Intubated in DR DR intubation for resuscitation Surfactant DR/NICU Epinephrine in DR

Results ­ Other Pre-specified Outcomes

CPAP N=663 Surfactant N=653 Relative Risk or Difference in Means

BPD (O2 use at 36 wks) Death/BPD, 36 wks Severe ROP- survivors Any air leaks (14 days) Mechanical Vent Survivors

(median days)

40.2% 48.7% 13.1% 6.8% 10 55.3% 7.2%

44.3% 54.1% 13.7% 7.4% 13 48.8% 13.2%

0.94 (0.82, 1.06) 0.91 (0.83, 1.01) 0.94 (0.69, 1.28) 0.89 (0.6, 1.32) * 1.14 (1.03, 1.25)* 0.57 (0.41, 0.78)*

Alive and off MV at 7 days Postnatal steroids for BPD * = 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)

Causes of Death ­ 24-25 wk Strata

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

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: Subjects: Multicenter RCT 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 group pH< 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 value N=307 N=303 BPD 28d/death 54% 65% 0.63 0.46 - 0.88 <0.05 BPD 36w/death 34% 39% 0.80 0.58 - 1.12 NS Pneumothorax 9% 3% <0.001 Days on ventilator 3 4 <0.001 Pneumothorax 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 21 1 8 Surfactant 22 7 6 p Value NS NS NS

BPD/death (%) Pneumothorax (%) IVH 3-4 (%)

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 PMA

Outcome Death or CLD (ALL) Death (ALL) Death or major morbidity

Soll et al PAS Vancouver 2010

PS N=209 36% 7% 39%

NCPAP N=223 30% 4% 34%

RR (95%CI) (vs PS) 0.83 (0.64, 1.09) 0.57 (0.25, 1.27) 0.88 (0.68, 1.12)

Early CPAP vs Surfactant in Very Low Birth Weight Infants

Results

GA Birth Weight Oxygen at 36 wks (%) Death (%) Pneumothorax (%) IVH (3-4 (%) Mechanical Vent (%) Surfactant (%)

CPAP (n=131)

30 wks 1196 (1162-1229) gm 7 8 3 5 30 28

Surfactant (n=125)

30 wks 1197 (1163-1230) gm 10 10 6 6 52 46

p-value

NS NS NS NS NS NS <0.001 <0.01

J. Tapia. PAS 2010

· 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%

RCT of CPAP vs. Ventilation (Rojas Trial)

Rojas et al ­ Pediatrics 2009;123:137-42

Results - Demographic Variables

Minimal Vent (N=109) Birth weight (gm) 742 ± 130 Gestational age (wk) 25 ± 2 Antenatal steroid (%) 74 Surfactant (%) 98 Male (%) 48 Race (%) B/W/O 46/39/15 Randomization age (hr) 6.5 ± 3.0 Routine Vent (N=111) 728 ± 135 25 ± 2 75 96 56 48/43/9 7.1 ± 2.8 p value NS NS NS NS NS NS NS

Carlo et al. J Pediatr 41:370, 2002

SAVE Trial

Results - Primary Outcome Measures

Minimal Ventilation (N=109) Mortality or BPD (%) 63 Mortality (%) 23 BPD (%) 52 Routine Ventilation RR (N=111) 68 0.93 22 1.06 60 0.88 CI (0.77-1.12) (0.65-1.74) (0.67-1.14)

Carlo et al. J Pediatr 41:370, 2002

SAVE Trial

Results - Secondary Analyses

Minimal Routine Ventilation Ventilation RR Ventilation at 36 wk (%) BPD or death in 501-750 gm (%) *p<0.05 1 68 16 86 CI NNT 7 6

0.09 (0.01-0.67)* 0.79 (0.65-0.96)*

Carlo et al. J Pediatr 41:370, 2002

SAVE Trial

Results - Long-term Follow-up

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

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 ARR Carlo (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 624/1568 (40%) RR 0.88 Control 689/1538 (45%) 95% CI 0.81; 0.96

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

Study or sub-category COIN NEJM CURPAPS Peds SUPPORT NEJM VON 2010 Total (95%, CI) CPAP n/N 104/307 5/103 323/663 68/223 Surfactant n/N 118/303 5/105 353/653 138/425 OR (fixed) 95% CL OR (fixed) 95% CL 0.80 (0.58, 1.12) 1.02 (0.29, 3.64) 0.81 (0.65, 1.00) 0.91 (0.64, 1.29) 0.83 (0.71, 0.97)

39%/1296 41%/1486

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 10 Favours treatment Favours control

Finer 2010.

Early CPAP vs Early Surfactant ­ ELBW Infants Death at 36 Weeks

Study OR (fixed) or sub-category 95% CL COIN NEJM CURPAPS Peds SUPPORT NEJM VON 2010 Total (95%, CI) CPAP n/N 95% CL 20/307 18/303 11/103 9/105 94/663 114/653 9/223 30/425 10%/1296 12%/1486 Surfactant n/N 1.10 (0.67, 2.13) 1.28 (0.51, 3.22) 0.78 (0.68, 1.06) 0.66 (0.26, 1.19) 0.82 (0.64, 1.04) OR (fixed)

Total events: 134 (CPAP), 171 (Surfactant) Test for heterogeneity: ChF=2.78, df=3 (P=0.43), F=0% 0.1 0.2 0.5 Test for overall effect: Z=1.64 (P=0.10)

Finer 2010.

2 5 10 Favours treatment Favours control

1

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

Study OR (fixed) or sub-category 95% CL COIN NEJM CURPAPS Peds SUPPORT NEJM VON 2010 Total (95%, CI) CPAP n/N 95% CL 51/207 62/198 22/72 18/73 144/378 165/373 68/223 138/425 32%/880 36%/1069 Surfactant n/N 0.72 (0.46, 1.11) 1.34 (0.65, 2.79) 0.78 (0.58, 1.41) 0.91 (0.64, 1.29) 0.83 (0.69, 1.01) OR (fixed)

Total events: 285 (CPAP), 383 (Surfactant) Test for heterogeneity: ChF=2.59, df=3 (P=0.46), F=0% Test for 2010. effect: Z=1.86 (P=0.06) Finer overall

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 support 2. If intubated (FiO2 > 50%,PCO2 >65, pH < 7.20, others): give surfactant 3. 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

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