The Golden Hour Debates Giving High-risk Neonates the Best Possible Start Michael S. Dunn, MD, FRCPC Sunnybrook Health Sciences Centre Toronto, Ontario, CANADA Neil N. Finer, MD UCSD San Diego, CA

Prophylactic Surfactant or CPAP for ELBW Neonates Resolved that: Initial respiratory management of ELBW neonates should include intubation and prophylactic surfactant Pro – Michael Dunn Con – Neil Finer

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Prophylactic Surfactant or CPAP for ELBW Neonates Resolved that: Initial respiratory management of ELBW neonates should include intubation and prophylactic surfactant Pro – Michael Dunn Con – Neil Finer

Outline RDS and surfactant The arguments for prophylactic surfactant Guidelines and “Best Practices” CPAP instead of prophylactic surfactant When should we use prophylactic surfactant in 2011?

What do we Know? RDS is the leading cause of mortality and morbidity in preterm infants Surfactant deficiency is the major cause of RDS The risk of RDS and related complications increases with decreasing gestational age Surfactant replacement therapy is highly effective in reducing mortality and RDS related morbidity

Timing of Surfactant Treatment Prophylactic Treatment shortly after birth of a selected group of infants regardless of individual presentation Delayed Selective Treatment of infants only after a period of observation reveals evidence of “significant” RDS

RESPONSE TO SURFACTANT TREATMENT: PHYSIOLOGY

SURFACTANT THERAPY: EVIDENCE FROM TRIALS EFFECT ON NEONATAL MORTALITY Decreased Risk Increased COMPARISONS Number of Studies 0.2 0.5 1.0 2.0 4.0 DELIVERY ROOM SURFACTANT v. NO SURFACTANT SYNTHETIC SURFACTANT 7 NATURAL SURFACTANT 8 SURFACTANT TREATMENT v. NO SURFACTANT SYNTHETIC SURFACTANT 5 NATURAL SURFACTANT 12 0.2 0.5 1.0 2.0 4.0 Soll, 1997 Typical Relative Risk and 95% CI

SURFACTANT THERAPY: EVIDENCE FROM TRIALS EFFECT ON PNEUMOTHORAX Decreased Risk Increased COMPARISONS Number of Studies 0.2 0.5 1.0 2.0 4.0 DELIVERY ROOM SURFACTANT v. NO SURFACTANT SYNTHETIC SURFACTANT 6 NATURAL SURFACTANT 8 SURFACTANT TREATMENT v. NO SURFACTANT SYNTHETIC SURFACTANT 5 NATURAL SURFACTANT 12 0.2 0.5 1.0 2.0 4.0 Soll, 1997 Typical Relative Risk and 95% CI

SURFACTANT THERAPY: EVIDENCE FROM TRIALS EFFECT ON BPD OR DEATH Decreased Risk Increased COMPARISONS Number of Studies 0.2 0.5 1.0 2.0 4.0 DELIVERY ROOM SURFACTANT v. NO SURFACTANT SYNTHETIC SURFACTANT 4 NATURAL SURFACTANT 7 SURFACTANT TREATMENT v. NO SURFACTANT SYNTHETIC SURFACTANT 4 NATURAL SURFACTANT 10 0.2 0.5 1.0 2.0 4.0 Soll, 1997 Typical Relative Risk and 95% CI

What about Timing? Is it better to provide surfactant to infants at high risk of RDS shortly after delivery rather that wait until they exhibit signs of significant disease?

Prophylactic Surfactant Therapy Potential Advantages Facilitation of initial lung aeration and reabsorption of lung liquid Decreased baro/volutrauma Improved distribution of administered surfactant

Prophylactic Surfactant Advantages Facilitation of initial lung aeration and reabsorption of lung liquid

Prophylactic Surfactant Advantages Decreased baro/volutrauma

Prophylactic Surfactant Advantages Improved distribution of administered surfactant

Prophylactic Surfactant Therapy Potential Disadvantages Increased cost Increased exposure Destabilization at critical time Necessitates endotracheal intubation Adverse physiologic effects of laryngoscopy Trauma to upper airway Risk of barotrauma/volutrauma Inadvertent hyperventilation

Prophylactic vs Selective Surfactant EFFECT ON NEONATAL MORTALITY Decreased Risk Increased STUDY 0.2 0.5 1.0 2.0 4.0 Kendig 1991 Dunn 1991 Egberts 1993 Kattwinkel 1993 Walti 1995 Bevilacqua 1996 Bevilacqua 1997 TYPICAL ESTIMATE 0.2 0.5 1.0 2.0 4.0 Soll 2001 Relative Risk and 95% CI

Prophylactic vs Selective Surfactant EFFECT ON PNEUMOTHORAX Decreased Risk Increased STUDY 0.2 0.5 1.0 2.0 4.0 Kendig 1991 Dunn 1991 Egberts 1993 Kattwinkel 1993 Walti 1995 Bevilacqua 1996 TYPICAL ESTIMATE 0.2 0.5 1.0 2.0 4.0 Soll 2001 Relative Risk and 95% CI

Reviewers' Conclusions Prophylactic surfactant administration to infants judged to be at risk of developing respiratory distress syndrome (infants less than 30-32 weeks gestation), compared to selective use of surfactant in infants with established RDS, has been demonstrated to improve clinical outcome. Infants who receive prophylactic surfactant have a decreased risk of pneumothorax, a decreased risk of pulmonary interstitial emphysema and a decreased risk of mortality. However, it remains unclear exactly which criteria should be used to judge "at risk" infants who would require prophylactic surfactant administration.

Surfactant-replacement therapy for respiratory distress in the preterm and term neonate. Engle WA; American Academy of Pediatrics Committee on Fetus and Newborn. Pediatrics. 2008 Feb;121(2):419-32. Surfactant should be given to infants with respiratory distress syndrome as soon as possible after intubation irrespective of exposure to antenatal steroids or gestational age. Prophylactic surfactant replacement should be considered for extremely preterm infants at high risk of respiratory distress syndrome, especially infants who have not been exposed to antenatal steroids.

PBP 4 Administer surfactant as soon as possible after birth for eligible infants Develop guidelines and criteria for your unit for prophylactic surfactant administration Ensure that surfactant is available in the delivery room or in a location close to the delivery room When the delivery of an infant who is eligible for prophylactic surfactant is expected, start warming the surfactant before the infant is born Do not wait for X-ray confirmation of endotracheal tube positioning before giving surfactant. Use the depth of endotracheal tube insertion, by palpation (Jain 2004) of the endotracheal tube, and symmetry of breath sounds to confirm that the tube is in the appropriate tracheal location Do not wait to complete umbilical catheter placement and obtain radiographs before giving surfactant Develop local guidelines for ‘rescue’ surfactant in infants who do not qualify for prophylactic surfactant Educate staff about the importance of early administration of surfactant

“New” Evidence CPAP instead of prophylactic surfactant Is there evidence to support a change to the guidelines? Should we be using CPAP as our first line approach to the initial respiratory management of preterm babies?

Avery et al, Pediatrics 1987 Comparison of death and CLD (oxygen at 28 days) in babies 700-1500g

Early Nasal CPAP What is the Evidence? Inter-institutional benchmarking studies Avery 1987 Van Marter 2000 Vanpee 2007 Descriptive, cohort or before/after studies Jacobsen 1993 Kamper 1993 Gittermann 1997 Lindner 1999 DeKlerk 2001 Narendran 2003 Ammari 2005 Lopez Maestro 2006

NASAL CPAP and OUTCOME OF PRETERM INFANTS Comparison of clinical outcome before (n=57) and after (n=59) introduction of nasal continuous positive airway pressure De Klerk AM and De Klerk RK. J Paediatr Child Health 2001

Intriguing, but level of evidence is low…..

The CPAP vs Intubation RCTs CPAP or Intubation (COIN) Trial Surfactant, Positive Pressure, Oxygenation Randomized Trial (SUPPORT) VON Delivery Room Management Trial

Clinical Trials nCPAP versus DR Intubation Study Patients N Death / BPD CPAP ETT Other Findings with CPAP COIN 25-28 wk Vigorous 610 .80 (.58-1.12) 59 % Inc. air leak Inc. mort (NS) 25-26 wk 75% of intubated babies given surf SUPPORT 24-27 wk 1316 .91 (.83-1.01) 83% Dec. mort 24-25 wk Air leak similar DRM 26-29 wk Liveborn 648 .83 (.64-1.09) 52% Dec. mort (NS)

Conclusions COIN SUPPORT VON DRM In infants born at 25 to 28 weeks’ gestation, early nasal CPAP did not significantly reduce the rate of death or BPD, as compared with intubation. Even though the CPAP group had more incidences of pneumothorax, fewer infants received oxygen at 28 days, and they had fewer days of ventilation. SUPPORT The results of this study support consideration of CPAP as an alternative to intubation and surfactant in preterm infants. VON DRM Preterm neonates in this trial who were initially managed with either nCPAP or prophylactic surfactant with rapid extubation to nCPAP had similar clinical outcomes to those treated with prophylactic surfactant followed by a period of mechanical ventilation. An approach that utilizes early nCPAP leads to a reduction in the number of infants who are intubated and given surfactant.

So we can do whatever we want! WooHoo!

But…… Are there any circumstances in which surfactant prophylaxis is likely to be the preferred approach?

Reviewers' Conclusions Prophylactic surfactant administration to infants judged to be at risk of developing respiratory distress syndrome (infants less than 30-32 weeks gestation), compared to selective use of surfactant in infants with established RDS, has been demonstrated to improve clinical outcome. Infants who receive prophylactic surfactant have a decreased risk of pneumothorax, a decreased risk of pulmonary interstitial emphysema and a decreased risk of mortality. However, it remains unclear exactly which criteria should be used to judge "at risk" infants who would require prophylactic surfactant administration.

Questions What about the highest-risk babies? If an elective nCPAP approach is taken, might some infants be disadvantaged by a delay in delivery of surfactant? How do we decide who might benefit from intubation and prophylactic surfactant versus a trial of CPAP?

Let’s look at the smallest, most immature babies…..

Surfactant Treatment and Endotracheal Intubation by Gestation Age 23 24 25 26 27 28 29 30 31 32 33 Gestational Age (weeks)

Initial Stabilization Columbia 23-25 weeks GA 87 Initial Stabilization 27 60 Intubation CPAP 33 27 Failure Success Ammari et al. J Pediatr 2005

Outcome at 36 weeks percent Dead or oxygen Died Oxygen 25/26 27/28

PULMONARY AIR LEAK P=0.001

Clinical Trials nCPAP versus DR Intubation Study Patients N Death / BPD CPAP ETT Other Findings with CPAP COIN 25-28 wk Vigorous 610 .80 (.58-1.12) 59 % Inc. air leak Inc. mort (NS) 25-26 wk 75% of intubated babies given surf SUPPORT 24-27 wk 1316 .91 (.83-1.01) 83% Dec. mort 24-25 wk Air leak similar DRM 26-29 wk Liveborn 648 .83 (.64-1.09) 52% Dec. mort (NS)

The Surfactant Positive Airway Pressure And Pulse Oximetry Trial In ELBW Infants (SUPPORT) - NICHD RR (95% CI) 0.74 (0.57, 0.98) P = 0.03 percent P < 0.0005 Finer. NEJM 2010 48

So, what are the arguments? Surfactant administration as soon after birth as is feasible and safe provides the best opportunity to evenly expand and stabilize the surfactant deficient lung This can be achieved by intubation and administration of prophylactic surfactant shortly after birth Most preterm infants born at less than 26 weeks’ require intubation at some point in their clinical course anyway

Conclusions Although often successful in allowing preterm neonates to avoid intubation, initial management with nCPAP will result in a delay in the administration of surfactant to many surfactant deficient infants This delay can result in an increased risk of air leak and other complications of prematurity Intubation with surfactant prophylaxis should remain the preferred approach to the initial respiratory management of the highest-risk preterm neonates (ie. those born at less than 26 weeks’ gestation)

CPAP and Surfactant Should very preterm infants be treated with elective intubation, surfactant and a period of ongoing MV or stabilized on nCPAP with later selective surfactant? Should very preterm infants be treated with elective intubation, surfactant and rapid extubation to nCPAP or stablilized on nCPAP with later selective surfactant? If an infant is initially stabilized on nCPAP, what criteria should be used for selective surfactant treatment?

Clinical Trials ISX versus nCPAP Study Patients N Death / BPD MV Other Findings Rojas et al 27-31 wk RDS 279 .86 (.70-1.05) .69 (.49-.97) No diff in MV, BPD in lower GA group. Very high BPD rate CURPAP 25-28 wk Vigorous 208 1.03 (.61-1.72) .95 (.64-1.41) Dec. air leak with nCPAP (NS). Very low BPD rate DRM 26-29 wk Liveborn 648 .94 (.70-1.25) 1.14 (.97-1.35) ISX similar to CPAP Air leak similar ?Conclusion:

Angela Kribs MD Cologne, Germany Combining the Art of Gentle Resuscitation and Surfactant Administration Angela Kribs MD Cologne, Germany

Respiratory management of RDS (n=155) % They observed an increase of the use of CPAP as primary respiratory support over time from 65 on 95% and at the same time a decrease of mechanical ventilation as primary respiratory support and also during the course of RDS in the first 72 hrs of live.

Outcome of preterm infants < 1000 g and < 27 weeks % With the use of the new method we could reach a survival rate of 80% of all live born infants for infants with a GA 23 to 25 weeks and of 90 % for infants of 26 weeks. Survival without neonatal complications increased with increasing GA. Gestational Ages