hypercarbia and used initial Nasal CPAP had lowest BPD rates (Columbia) .... N=
653. Relative Risk or. Difference in Means. BPD (O2 use at 36 wks). 40.2%.
Evidence for Efficacy of CPAP
Neonatal Respiratory Distress: Where are we going? Neil Finer Professor of Pediatrics Director UCSD Division of Neonatology
Interhospital Variation of Chronic Lung Disease: Van Marter et al Pediatr 2000;105:1194
Origins of Chronic Lung Disease
Review of number of units demonstrated that the unit which used least ventilation, allowed permissive hypercarbia and used initial Nasal CPAP had lowest BPD rates (Columbia) This unit did not use muscle paralysis Recently reported low BPD rate = 3/81, (4.7%) 50% survival without BPD for infants 500-750 gm Avery et al, Pediatr 1987:79:26
Gregory et al (NEJM 1971;284:1330) demonstrated that CPAP improved oxygenation in infants < 1500 gm with RDS Rhodes et al (Pediatr 1973;52:17) reported increase survival with face mask CPAP CPAP improves FRC and premature infants without adequate FRC are more likely to develop HMD (Upton et al, Arch Dis Child 1991;66:39) The use of CPAP decreases mortality in the presurfactant era ( Ho et al Cochrane LibraryCLIB Issue #3 2002)
Compared early ventilatory practices for VLBW infants at 2 Boston Hospitals (341 infants) with Columbia (100 infants) born from 1991 to 1993 They evaluated use of mechanical ventilation for days 13, and 4-7 CLD ( O2 at 36 weeks) was 4% (Columbia) vs 22%(Boston) No differences in IVH, PVL, NEC, ROP, or mortality (9% vs 10%)
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Interhospital Variation of Chronic Lung Disease: Van Marter et al Pediatr 2000;105:1194 Other practices: Columbia vs Boston Surfactant 10% vs 45% more often in CLD, 23% vs 65% CPAP used primarily at Babies 63% vs 11% Mechanical Ventilation as primary 29% vs 75% Infants with CLD more likely to receive Mechanical Ventilation 77% vs 42% Duration of Mechanical Ventilation 13 days vs 27 days PaCO2 higher at Babies
Mechanical Ventilation and Chronic Lung Disease: Van Marter et al Pediatr 2000;105:1194
Overall Odds Ratio for the development of CLD was related to need for Mechanical Ventilation on day of birth - OR = 13.4 Days 1 - 3 - OR = 9.6 Days 4 -7 -OR = 6.3 Maximum PIP of > 25 cmH2O at birth, or > 20 cmH2O at 1 -3 days increases risk for CLD Message: If you don’’t intubate, the babies do better!!! Oh by the way, this is all retrospective information!!!
CPAP vs Surfactant Mechanical Ventilation and Chronic Lung Disease: Serenius et al Acta Paediatrica. 2004; 93(8):1090
Other studies have reported association between duration of ventilation and BPD/CLD BPD was associated with duration of mechanical ventilation (OR 2.71 per 1-wk increment in duration; 95% CI 1.76-4.18) Other morbidities associated with ventilation Severe IVH or PVL was associated with duration of mechanical ventilation (OR 1.53 per 1-wk increment in duration; 95% CI 1.01-2.33)
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.
Morley et al reported in the COIN Trial of 610 infants between 25 0/7 to 28 6/7 weeks gestation, who were able to breathe at 5 minutes of age and had evidence of respiratory distress.
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COIN Trial Morley et al. NEJM 2008; 358(7):700-708
SUPPORT Trial: Hypothesis
Randomized to intubation and ventilation, OR CPAP at 8 cm H2O; CPAP infants were intubated if they met failure criteria. No requirement for surfactant administration CPAP group had: - no significant reduction in death or oxygen at 36 weeks (the primary outcome), - significantly higher pneumothoraces (9.1% vs. 3.0%), most within the first 2 days
SUPPORT Study Infants from 24 – 27 6/7ths weeks CPAP Arm Delivery Room
Intubation/ Surfactant
•5 cm H20 •Intubation per NRP •If intubated, surfactant •Considered if: •Fi02 > 0.5 •PaCO2 > 65
Surfactant •Standard NRP
•Prior to 1 hour
Hypothesized that early CPAP with a limited ventilator strategy would reduce the incidence of death or survival with BPD at 36 weeks compared to early Surfactant
Methods: Extubation Criteria Within 24 hrs of meeting all criteria CPAP/Limited Ventilation
Surfactant
•Fi02 < 0.50 and MAP < 10 cm •Fi02 < 0.35 and MAP < 8 cm •PaCO2 < 65 •PaCO2 < 50 • Vent rate < 20 bpm •Vent rate < 20 bpm Ventilator rate < 20 bpm •Hemodynamically Stable •Hemodynamically Stable
Hemodynamically Stable
•Hemodynamic instability
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Results –SUPPORT - Primary Outcome
Results – SUPPORT TRial Finer et al NEJM. 2010 May 27; 362(21):1970
Birthweight* Gestational Age*
CPAP (N = 663)
Surfactant (N = 653)
835 +188.2
826 + 198.1
26.2 +1.1
26.2 + 1.1
43 57
43 57
38 / 38 / 21
36 / 42/ 19
97 27
96 24
24 to 25 6/7ths (%) 26 to 27 6/7ths (%) Race, White/Black/Hispanic (%) Antenatal corticosteroids (%) Multiple births (%)
CPAP Surfactant Adjusted Relative N=663 N=653 Risk (95% CI) Death or BPD (Physiologic) BPD - Physiologic
47.8%
51.0%
0.95 (0.85, 1.05)
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)
*Mean +±Standard Deviation
Results – Other Pre-specified Outcomes
Results – Delivery Room
Variable Apgar at 1 minute /= 1200 g with established RDS may reduce short term oxygen requirements – Not powered for important clinical effects. One current multicenter study and one single center study currently recruiting (http://clinicaltrials.gov/ct2/show/NCT01116921?term=LMA +and+surfactant&rank=2 , http://clinicaltrials.gov/ct2/show?term=LMA+and+surfact ant&rank=3)
Surfactant by Tracheal Catheter Gopel et al, Lancet. 2011 Nov 5; 378(9803):1627
36 (33%) infants in the Catheter group were mechanically ventilated compared with 82 (73%) in the standard treatment group (number needed to treat 3, 95% CI 2-4, p 14 days (J Pead Child Health, 2011;47:340) 15 of 20 required Ventilatory support and 6 received iNO, only 3 deaths of 20 who left DR
Conclusions of the Individual Patient Data Meta Analyses
Routine use of iNO for treatment of respiratory failure in preterm infants cannot be recommended
No particular subgroup of infants who benefited more or less from iNO therapy could be identified from individual–level data about entry characteristics
Use of a higher iNO starting dose may be associated with improved outcome, based on trial-level information
Further studies of longer duration starting at 3 d – 1 week are underway in view of the NO-CLD results
Intractable Severe Neonatal Lung Diseases
Surfactant deficiencies Lymphangiectasia Severe PIE from lung hypoplasia, CDHernia and baro/volutrauma Alveolar Capillary Dysplasia These will need your Magic – Stem cells, Transplant, Extracorporeal Lung Support – Grazit et al, J Thorac Cardiovasc Surg. 2011 Jun; 141(6):e48-50.
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Have we altered CLD in the Preterm Infant? What is is the evidence for Change
Are we lowering CLD? Payne et al Pediatr 2010;125:437
Payne et al Pediatr 2010;125:437
4065 very low birth weight infants from 8 NICUS were treated in ReLI NICUs in VON collaborative evaluated at 3 times,1998, 2001, and 2006. Over this interval, the ReLI group decreased delivery room intubation (70% vs 52%; P < .001), conventional ventilation (75% vs 62%; P < .001), and postnatal steroids for BPD (35% vs 10%; P < .001).
There was increased use of nasal continuous positive airway pressure (57% vs 78%; P < .001). BPD-free survival remained unchanged (68% vs 66%;), and the BPD rate increased (25% vs 29%; P = .017), Survival to discharge increased (90% vs 93%; P < .001), and nosocomial infections decreased (18% vs 15%; P = .045). Similar results from Europe (Groenendaal et al, Acta Paed 2012;99:354)
ELBW CLD Rates by Birth Weight - CPQCC
Very Preterm Infants 2012: Future Markedly decreased need for intubation especially if > 25 weeks –and for those that require increased support apart from CPAP and non-invasive ventilation – surfactant will be available without intubation For Infants 24 – 25 weeks – Probably 30-50% will still need intubation for ventilation support for premature lung, apnea, sepsis, and will receive surfactant However another 25-30% will receive Surf - hopefully without need for intubation
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Very Preterm Infants 2012: Future
Caffeine will be given within 1-3 hours of birth We will use higher SpO2 range and see more ROP CLD as defined by Oxygen requirement at 36 weeks may decrease to as low as 40% EXCEPT for 22- 23 week infants. Few infants will be ventilator dependent These immature infants will have increased survival from present levels – 30% to about 50-60% but with 60-80% CLD and other morbidities – Some will need Magic!
Columbia Experience
Columbia Experience
Ammari et al, J Pediatr 2005;147:341
Ammari et al, J Pediatr 2005;147:341 Gestation DR al Age Intubati on 23-25 wks 31% N = 87 26-28 wks 5% N = 106 29-31 wks 0% N = 54
DR CPAP
Birth Weight
DR DR CPAP Intubation
72 Hours CPAP Failure
CPAP Success
27%
73%
40%
33%
CPAP Success
69%
72 hours CPAP Failure 38%
31%
< 699 gm N = 79
18%
71%
17%
78%
700-999 gm 11% N = 90
89%
95% 100%
7%
93%
1000-1250 gm N = 92
99%
8%
92%
1%
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Nasal CPAP and Early Surfactant for < 30 wk Infants: Verder et al, Pediatr 1999;103(2).
11 Neonatal Units in Denmark from April 1995 to Jan 1997 Previous study (NEJM 1994;331:1051) showed benefit for early CPAP ( not DR) followed by intub + Surf + extubation 60 infants < 30 wks, + RDS, a/APO2 was .35-.22 on CPAP > 6 cmH2O Treated with early CPAP and given Surfactant Randomized to - early Curosurf vs later when a/APO2 < .21.15 Infants intubated for Curosurf 2.5ml/kg in 2 doses, then extubated, usually within 10 minutes!!!
MAPPiNO objectives
to determine whether iNO in preterm infants receiving assisted ventilation improves survival without morbidity
Verder et al, Pediatr 1999;103(2). Results: 33 infants -BW=950gm vs 27 infants –BW = 935, Gest=27 vs 28, Nasal CPAP started at median of 17 min Randomization at 4.3 hours Early Rx rec’ ’d Surfactant at 5.2 hrs vs 9.9 hrs for late group Only 4 infants could not be extubated after Surfactant instillation MVent/Death = 21% vs 63%, p=0.0013 by logistic regression Death = 9% for Early Rx vs 26% for late Rx
Inclusion criteria for studies Study design: randomized controlled trials Participants:
to determine whether the effects of iNO differ according to the risk profile of the patient
preterm infants (
