A2b. Risk Stratification of CDH Repair Timing and ECMO Support of CDH. Session Summary. Session Objectives. References

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1 A2b Risk Stratification of CDH Repair Timing and ECMO Support of CDH David Kays, MD Professor of Surgery Johns Hopkins School of Medicine Director of Congenital Diaphragmatic Hernia Program, Director of Extra Corporeal Life Support Program Johns Hopkins All Children s Hospital, St. Petersburg, FL The speaker has signed a disclosure form and indicated he has no significant financial interest or relationship with the companies or the manufacturer(s) of any commercial product and/or service that will be discussed as part of this presentation. Session Summary When should CDH repair be performed? Early? Late? In-between? This talk will define why the answer is different depending upon where an individual CDH patient lies along the CDH severity spectrum. We will also explore how estimating the risk of ECMO can potentially optimize repair timing decisions. Session Objectives At the conclusion of this activity, participants will be able to: describe the risks and benefits of varying approaches to surgical repair timing in CDH; discuss the role of ECMO in improving survival in high severity CDH; explain the relationship between degree of pulmonary hypoplasia and the length of ECMO run in CDH ECMO survivors. References Kays, D. W., Islam, S., Larson, S. D., Perkins, J. M. & Talbert, J. L. (2013). Long-term maturation of congenital diaphragmatic hernia treatment results: Toward development of a severity-specific treatment algorithm. Annals of Surgery, 258(4), , discussion Kays, D. W., Islam, S., Perkins, J. M., Larson, S. D., Taylor, J. A. & Talbert, J. L. (2015). Outcomes in the physiologically most severe congenital diaphragmatic hernia (CDH) patients: Whom should we treat? Journal of Pediatric Surgery, 50(6), Kays, D. W., Islam, S., Richards, D. S., Larson, S. D., Perkins, J. M. & Talbert, J. L. (2014). Extracorporeal life support in patients with congenital diaphragmatic hernia: How long should we treat? Journal of the American College of Surgeons, 218(4), Kays, D. W., Langham, M. R., Ledbetter, D. J. & Talbert, J. L (1999). Detrimental effects of standard medical therapy in congenital diaphragmatic hernia. Annals of Surgery, 230(3), 340-8, discussion Kays, D. W., Talbert, J. L., Islam, S., Larson, S. D., Taylor, J. A. & Perkins, J. (2016). Improved survival in left liver-up congenital diaphragmatic hernia by early repair before extracorporeal membrane oxygenation: optimization of patient selection by multivariate risk modeling. Journal of the American College of Surgeons, 222(4), A2b: Risk Stratification of CDH Repair Timing and ECMO Support of CDH Page 1 of 11

2 Mullassery, D., et al. (2010). Value of liver herniation in prediction of outcome in fetal congenital diaphragmatic hernia: A systematic review and meta-analysis. Ultrasound in Obstetrics & Gynecology: The Official Journal of the International Society of Ultrasound in Obstetrics and Gynecology, 35(5), doi: /uog.7586 Victoria, T., et al. (2012). Use of magnetic resonance imaging in prenatal prognosis of the fetus with isolated left congenital diaphragmatic hernia. Prenatal Diagnosis, 32, A2b: Risk Stratification of CDH Repair Timing and ECMO Support of CDH Page 2 of 11

3 Fundamentals of CDH Care: Part 2 David W. Kays M.D. FACS FAAP Professor of Surgery Johns Hopkins University School of Medicine Director of Congenital Diaphragmatic Hernia Program Director of Extracorporeal Life Support Program Johns Hopkins All Children s Hospital October 18 th 2016 Why should you listen to me? Cared for > 325 CDH Overall Survival (everyone) = 80% Survival of isolated CDH now > 95%. ALL pts d/c breathing on their own. NO patients d/c with tracheostomy CDH is Important (1) CDH is Important (2) CDH Patients are Severity Outliers: CDH affects 1 in every 3000 live births In 2014 in the USA, there were 3,988,076 births with gastroschisis, and fewer than 100 died (*estimate) will develop Wilms tumor, and fewer than 100 died or will die - > 1300 fetuses will have CDH. 650 or more will die from CDH, from termination or during treatment CDH patients suffer from Small lungs and pulmonary hypertension Under developed hearts Are at risk of hypoxic ischemic brain injury Need exacting critical care Advancing the care of CDH babies improves the care of all neonates CDH is a frequently lethal defect Pulmonary Hypoplasia Pulmonary Hypertension Fixed component due to small lungs Reactive component due to CDH physiology time course What is the Current CDH Survival? 54% Survival (2014) (Canadian Population Study) Baylayla et al, J Mat Fetal & Neo Medicine % Survival (2009); CDH Study Group Seetharamaiah et al, J Ped Surgery, 2009 A2b: Risk Stratification of CDH Repair Timing and ECMO Support of CDH Page 3 of 11

4 CDH is a Spectrum CDH is a Spectrum Can define by Herniated Viscera Left: Liver down (least severe) Right: more severe (on average) Left: Liver Up (most severe) Can define by Lung Size: Lung to head ratio (LHR). 3-D Lung volumes LHR > 1.4 less severe LHR more severe LHR < 1.0 most severe CDH is a Spectrum Defining CDH Severity by Physiology Survival by Physiologic variables at birth and soon after Can define by physiology at birth and soon after Apgar scores at 1 and 5 minutes Birth weight CDH Study Group predicted survival (birth weight and 5 minute Apgar) Nicutools.org Blood gas values at 1 hour of life (ph, PCO2, PO2) CDH Severity by Anatomic Grading Data from n= 240 CDH Left Liver Down Right Left Liver Up And what about Left Liver-Up CDH? N=97 N=42 N=101 Birthweight / / / 683 Apgar / / / 2.2 Apgar / / / 2.2 ECMO 11% 55% 69% CDH SG Predicted Survival 74% 62% 53% - Most severe anatomic subset - Worst pulmonary hypoplasia - 45% Survival 2010 Meta-analysis survival - 45% Survival 2012 Top CDH Children s Hospital Publication Mullassery D, et al, Ultrasound Obstet Gynecol. 2010;35: Victoria T, et al. Prenat. Diagn.; 2012;32: A2b: Risk Stratification of CDH Repair Timing and ECMO Support of CDH Page 4 of 11

5 Fundamentals of CDH Care CDH Treatment Fundamental #2 23 Years of CDH care and Research (320 CDH patients) 5 major lessons learned -Lungs (ventilation must be lung protective. Really) -Repair (required) -ECMO (not just yes or no, but how well it s done) -Risk stratification to define care -Believe (2) Repair the Hernia (CDH) (n=268) CDH Survival to Discharge 0 Repaired Not Repaired Why wouldn t a CDH be repaired? Severe Associated Anomalies: (10%) -Chromosomal -Cardiac (single ventricle anatomy) -CNS Repair was delayed: never got repaired -Repair was delayed for stabilization or resolution of P. HTN Ended up on ECMO unrepaired ECMO course went poorly (complications) -These patients are potentially recoverable Timing of Repair ECMO: Role in CDH Centers with highest reported survival use ECMO ECMO use averages 25 50% of patient N = 268 Evaluated Surgical repair timing related to ECMO Results stratified by anatomic severity Evaluated Surgical repair timing related to ECMO Results stratified by anatomic severity Annals of Surgery, 2013 Kays, Islam, Larson, Perkins, Talbert A2b: Risk Stratification of CDH Repair Timing and ECMO Support of CDH Page 5 of 11

6 Repair first vs ECMO first, all patient requiring ECMO Survival and Risk of ECMO Related to Repair Timing Left liver down CDH (less severe): 99% Survival (96/97) (11% ECMO) Repair in first 48 hours does not improve survival but increases need for ECMO in LLD CDH Annals of Surgery, 2013 Kays, Islam, Larson, Perkins, Talbert Conclusion: Delay repair beyond 48 hrs in Left liver down CDH Annals of Surgery, 2013 Kays, Islam, Larson, Perkins, Talbert Survival and Risk of ECMO Related to Repair Timing Left Liver-Up CDH (Severe): Spectrum of CDH related to Optimal Timing of Repair CDH Spectrum of Severity (Left) Repaired before ECMO 17/18 Survived (94%) Arrived ECMO Unrepaired 16/25 Survived (64%) Repair before ECMO (first hours) Improves survival in LLU (severe) CDH Repair in first 48hours does not significantly increase need for ECMO in LLU CDH Conclusion: early repair of LLU CDH improves survival in LLU CDH patients that require ECMO Left Liver Up Survival 76/101 (75%) Small Bowel Colon Small Bowel Colon Stomach Spleen Reactive Pulmonary Hypertension (resolves with time) Benefit from Delay of Repair (to decrease risk of ECMO) Small Bowel Colon Stomach Spleen +Liver Benefit from Early Repair (to assure repair!) Small Bowel Colon Stomach Spleen +Liver Fixed Pulmonary Hypertension (resolves with lung growth) Kays, 2016 Comparison of Severity Indices Left Liver-Up CDH Early repair before ECMO vs Delay & arrive to ECMO unrepaired ECMO 1 st n=20 Early Repair Before P=(Mann Whit) ECMO n=22 Survived 13 (65%) 21 (96%) Apgar Apgar CDH SG Surv st LHR LHR o/e ph PO PCO Surv Eq ECMO risk ECMO risk P Surv w/o ECMO hr AUC= hr AUC= hr AUC= 0.83 LHR o/e AUC= 0.80 A2b: Risk Stratification of CDH Repair Timing and ECMO Support of CDH Page 6 of 11

7 Best Predictive Equations Combine Anatomic and Physiologic Stratifiers Sorted by DOB Sorted by Prob Surv w/o ECMO At risk <=0.37 Improved chance of survival for 7, Converted 4 from delayed repair to early. (# needed to Rx=60) Probability of ECMO=Exp(a+b+c)/(1+Exp(a+b+c)) A=40.18 B= 4.919*ph1 C= *LHR o/e D= *PO2 Prob Survive w/o ECMO=Exp(a+b+c)/(1+Exp(a+b+c)) A= B=0.0587*LHR o/e C= 5.151*pH 1 D=2.584*log(n)PO2 So What about ECMO? Survival vs Time on ECMO Does it help? Reports show poor survival in CDH patients on ECMO more than 14 days Should we limit length of support? J American College of Surgeons, 2014 Kays, Islam, Larson, Perkins, Talbert Association of risk factors with duration 1st Run ECMO 2 nd Run ECMO A2b: Risk Stratification of CDH Repair Timing and ECMO Support of CDH Page 7 of 11

8 Lessons of CDH Care 1: Don t injure the lungs 2: Repair the CDH 3: Use ECMO inclusively 4: Risk Stratify Repair timing 5: Believe Are Some CDH Patients just Too severe to Treat? What are the outcomes in the worst CDH Patients? Background More severely affected CDH patients may be terminated, or may have treatment limited at birth due to concerns about viability and outcome. J Pediatr Surg Jun;50(6):893 7 Kays DW, Islam S, Perkins JM, Larson SD, Taylor JA, Talbert JL 6.64 / >130 / 15 Methods Retrospective review of 268 consecutive CDH patients treated from September, 1992 January 1, (10%) Excluded due to highly severe/lethal associated anomalies -previously published. -uni-ventricular hearts, severe chromosomes, CNS, 240 patients, incl other anomalies and prematures 172 inborn CDH, treated aggressively for survival, that make up this study Individual Severity Variables Correlated to Mortality Variable P Level Test # Survived % Apgar 5 <.0001 < % CDH SG Pred Surv <.0001 <25% % PCO2 & ph <.0001 >100 & < % ECMO (time to).456 < 6 hr % Defining the worst 10%. Single and multivariable models A2b: Risk Stratification of CDH Repair Timing and ECMO Support of CDH Page 8 of 11

9 GA BW Ap 1 Ap 5 Pred Side ph 1 PCO2 PO2 ECMO Surv d/c m Respd/c % Left 6.59 > No No * * Left 6.75 > Yes Yes cc NC Stepwise variable elimination algorithm Apgar-1 CDH SG Predicted Survival BW Apgar-5 1 hours Right 6.67 > Yes No * * Left 6.64 > Yes Yes cc NC Left Yes No * * Left 6.76 > Yes Yes cc NC Left Yes No * * Left 6.8 > No No * * Left 6.88 > Yes Yes cc NC Left 6.95 > Yes No * * Left No No * * Left Yes Yes cc NC Left 6.85 > Yes No * * Left 6.93 > Yes Yes cc NC Left Yes No * * Right 6.93 > Yes Yes cc NC Right 6.88 > Yes Yes cc NC. GA BW Ap 1 Ap 5 Pred Side ph 1 PCO2 PO2 ECMO Surv d/c m Respd/c % Left 6.59 > No No * * Left 6.75 > Yes Yes cc NC Right 6.67 > Yes No * * Left 6.64 > Yes Yes cc NC Left Yes No * * Left 6.76 > Yes Yes cc NC Left Yes No * * Left 6.8 > No No * * Left 6.88 > Yes Yes cc NC Left 6.95 > Yes No * * Left No No * * Left Yes Yes cc NC Left 6.85 > Yes No * * Left 6.93 > Yes Yes cc NC Left Yes No * * Right 6.93 > Yes Yes cc NC Right 6.88 > Yes Yes cc NC GA BW Ap 1 Ap 5 Pred Side ph 1 PCO2 PO2 ECMO Surv d/c m Respd/c % Left 6.59 > No No * * Left 6.75 > Yes Yes cc NC Right 6.67 > Yes No * * Left 6.64 > Yes Yes cc NC Left Yes No * * Left 6.76 > Yes Yes cc NC Left Yes No * * Left 6.8 > No No * * Left 6.88 > Yes Yes cc NC Left 6.95 > Yes No * * Left No No * * Left Yes Yes cc NC Left 6.85 > Yes No * * Left 6.93 > Yes Yes cc NC Left Yes No * * Right 6.93 > Yes Yes cc NC Right 6.88 > Yes Yes cc NC Most Severe 10%: (N=172) Survival 8/17 = 47%. 3 prematures, not ECMO eligible, all died GA BW Ap 1 Ap 5 Pred % Side ph 1 PCO2 PO2 ECMO Surv d/c m Respd/c Survivals Summarized Left 6.75 > Yes Yes cc NC Right 6.67 > Yes No * * Left 6.64 > Yes Yes cc NC Left Yes No * * Left 6.76 > Yes Yes cc NC Left Yes No * * Left 6.88 > Yes Yes cc NC Left 6.95 > Yes No * * Inborn All % Inborn ECMO eligible % Inborn Worst 10% all % Left Yes Yes cc NC Left 6.85 > Yes No * * Left 6.93 > Yes Yes cc NC Left Yes No * * Right 6.93 > Yes Yes cc NC Right 6.88 > Yes Yes cc NC Left No Yes * * Left 6.8 > Yes Yes cc NC Inborn Worst 10% ECMO eligible % 10% Most Severe ECMO Eligible patients (N=164 ) Survival 10/16 (63%) A2b: Risk Stratification of CDH Repair Timing and ECMO Support of CDH Page 9 of 11

10 Discharge and Respiratory Outcomes Average time to discharge for survivors of worst 10%: 3.3 months ( ) No patients required tracheostomies or home ventilation. Discharged home on nasal cannula oxygen What is Survival Potential in CDH? : N=240 w/o lethal associated anomalies CDH Left Liver-Down Right Left Liver-Up n=97 n=42 n=101 Gestational Age / / /- 2.8 Birthweight / / /- 683 Apgar / / /- 2.2 Apgar / / /- 2.2 CDH SG Predicted Survival 74% 62% 53% Newborn from earlier slides ph Survival Achieved: 99% 92% 75% P<0.001 P<0.001 P<0.001 Risk Stratification (90%?) All discharged breathing spontaneously, on no support greater than nasal cannula oxygen. No surgical airways. No home vents. Ann Surg Oct;258(4):638 44; discussion Kays DW, Islam S, Larson SD, Perkins J, Talbert JL. CDH Treatment Fundamentals (1) Do not injure the lungs with ventilation (2) Repair the Hernia (CDH) (3) Inclusive Use of ECMO for as long as necessary (4) Risk stratify treatment (surgical repair timing) (5) Believe the baby with CDH can survive Overall Results All Bochdalek CDH patients September 1, 1992 December consecutive patients 79% Survival Overall (234 survived) 266 without lethal associated anomalies 88% survival in patients w/o lethal associated anomalies (233 survived) (Last 100 Cases: Survival > 90%) (6) Refer the Mom to the best centers CDH Quantity of Survival Care of lungs Putting a face with the numbers L Liver Up CDH Diagnosed prenatally at 14 weeks LHR 0.69 At birth, on VA ECMO w/in 4 hours Repaired on ECMO at 3 days 2 ECMO runs lasting 29 days Quality of Survival Care of brain A2b: Risk Stratification of CDH Repair Timing and ECMO Support of CDH Page 10 of 11

11 NP Focused Protocols Neuro-protective Brain monitoring NIRS Biomarkers of brain injury Correlation with Outcomes Much more work to do: Passionate people and families Improved Risk Stratification to refine repair timing decisions Development of more specific protocols: Neuro protection Expanded education Expanded collaborations Defining Neurologic outcomes MRI findings at discharge Robust neurodevelopmental f/u Feeding and growth outcomes balanced with pulmonary function Reported by risk stratification Critical Evaluation of ECMO type Effect of prematurity Long term Pulmonary HTN outcomes more Thank You: Johns Hopkins All Children s Hospital Johns Hopkins School of Medicine University of Florida Research and Program Coordinator Joy Perkins, RN, RRT Partners and Mentors Paul Colombani, MD Jonathan Ellen, MD Saleem Islam, MD Nicole Chandler, MD David Burchfield, MD Max R Langham, MD Jen T. Wung, MD Paul Danielson, MD James L. Talbert, MD Shawn Larson, MD Janice Taylor, MD Mike Weiss, MD Charles Stolar, MD Johns Hopkins All Children s Hospital Pediatric Surgery Fellows Dan Neal, Statistician A2b: Risk Stratification of CDH Repair Timing and ECMO Support of CDH Page 11 of 11