1. Evidence Based Medicine and Level 1 Outcomes Research in Pediatric Surgery George W. Holcomb, III, M.D., MBA Children’s Mercy Hospital Kansas City, Missouri Center for Prospective Clinical Trials www.centerforprospectiveclinicaltrials.com

2. The Right People Good to Great

3. Integration of best research evidence with clinical expertise and patient values Treating patients based on data, not “feeling” (gestalt), or one’s own experience Evidence Based Medicine

4. Levels of Evidence Question A clinical surgeon publishes a retrospective review of 350 patients over 20 years undergoing an endorectal pull- through (Soave procedure) for Hirschsprung’s Disease. This is felt to be a seminal paper on this disease in infants and children. What is the level of evidence for this paper? Level 1(A) Level 2(B) Level 3(C) Level 4(D) Level 5(E)

5. 5 – Expert opinion, or applied principles from physiology, basic science, or other conditions 4 – Case series or poor quality case control and cohort studies 3 – Case control studies 2 – Review of case control or cohort studies with agreement or poor quality randomized trial 1 – Prospective, randomized controlled trials Levels Of Evidence

6. Levels of Evidence 5.Expert opinion, or applied principles from physiology, basic science, or other conditions Example: Leave patient intubated and paralyzed for 3-5 days following an esophageal resection to take tension off esophageal anastomosis No data – no study to show intubated/paralyzed patient has less esophageal tension Transverse incision is used for abdominal exploration in baby b/c better exposure No data to support this practice

7. Levels of Evidence 4.Case series or poor quality case control and cohort studies Example: 1)Paper reviewing results from one approach to a disease Large retrospective review of Soave operation for Hirschsprung’s Disease

8. Levels of Evidence 3.Case control studies Example: 1)Paper showing different management strategies/operative technique for one disease process Single center (or multicenter) retrospective review of Duhamel vs Soave operation for Hirschsprung’s Disease

9. Levels of Evidence 2.Review of case control or cohort (followed “long- term”) studies with agreement or a poorly performed prospective randomized trial Example: 1)Review of two or three large series describing one management strategy (Soave procedure) compared to two or three large series describing another management strategy (Duhamel procedure)

10. Levels of Evidence 1.Prospective randomized trials

11. Children’s Mercy Hospital Focus on common conditions which are “controversial”: Pyloric stenosis Perforated appendicitis Pectus excavatum Fundoplication for reflux Empyema Non-palpable intra-abdominal testis

12. Complicated cases (relatively rare) best suited for multi-institutional trials: But, need good infrastructure at each institution Choledochal cyst Esophageal atresia Pulmonary lobectomy Pull-through for high imperforate anus

13. Remember There is a lot more to an MIS operation than just technique Postoperative care is also important and open for study (antibiotics?, pain management?, etc.)

14. Open vs Lap Pyloromyotomy Lap vs Open – 2003 - controversial around the world and in our hospital Different feeding regimens used in our hospital (2 hours, 4 hours, 6 hours) Different postoperative pain management strategies utilized Differences between staff made it difficult for residents, NPs, floor nurses Benefits: single protocol for feeding, pain management, discharge used in study still used currently (6 years later) No level 1 data

15. Outcomes Results Outcomes OPEN (n = 100) OPEN (n = 100) LAP (n = 100) LAP (n = 100) P value OR time (mins) 19:28 +/- 0.60 19:34 +/- 0.78 Emesis (#) 2.61 +/- 0.27 1.84 +/- 0.23 Full Feeds (hrs) 21:01 +/- 2.16 19:30 +/- 1.46 LOS (hrs) 33:10 +/- 1.63 29:38 +/- 1.69 Tylenol (doses) 2.23 +/- 0.18 1.59 +/- 0.16 (Mean +/- S.E.) ( Mean +/- S.E.) 0.93 0.05 0.43 0.12 0.01 Ann Surg 244:363-370, 2006

16. Cosmetic Outcome Results Cosmetic Outcome Open Open Lap Lap

17. 2. Thoracoscopy vs Fibrinolysis for Empyema

18. Fibrinolysis had been shown to be better than chest tube drainage alone in several retrospective studies Primary thoracoscopic debridement had been shown to better that tube drainage alone in several retrospective studies At the initiation of this study, there were no comparative data between primary thoracoscopic debridement and fibrinolysis as initial treatment for empyema in children Treatment Of Empyema

19. Inclusion Criteria Study Population Inclusion Criteria Under 18 years of age  Septation or loculation seen on ultrasound or computed tomography  Greater than 10,000 white blood cells identified on pleural tap Criteria Exclusion Criteria Immunodeficiency process Secondary condition that would limit discharge

20. Using our own institution’s retrospective data on length of hospitalization after intervention between thoracoscopic debridement and fibrinolysis with an alpha 0.05 and power of 0.8 Sample size of 36 with 18 in each arm Sample Size

21. Empyema Study Protocol Fibrinolysis 12 Fr tube placed by IR or surgery in procedure room 4mg tPA in 40ml NS given into tube on insertion and each day for 3 doses Thoracoscopy Thoracoscopic debridement with chest tube left behind on – 20 cm H20 suction APSA, 2008 J Pediatr Surg 44:106-111, 2008

22. Length of hospitalization after intervention (tPA or thoracoscopic debridement) until discharge criteria met (chest tube removed, afebrile & oral analgesics) Empyema Study Protocol Empyema Study Protocol Primary Outcome Measure APSA, 2008 J Pediatr Surg 44:106-111, 2008

23. Days of Tmax > 38  CDays of tube drainage Doses of analgesia Days of oxygen requirement Hospital charges after intervention Procedure charges Empyema Study Protocol Empyema Study Protocol Secondary Outcome Measure APSA, 2008 J Pediatr Surg 44:106-111, 2008

24. Patient Variables at Consultation WBC 20.819.70.71 Weight (kg) 24.620.70.52 Age (Years) 4.8 5.20.77 Days of Symptoms 9.010.60.32 VATStPA P value O2 support (L/min) 0.81 0.790.96 Study Results ER/PCP visits 2.9 2.70.69 J Pediatr Surg 44:106-111, 2008

25. Outcomes 16.6% failure rate for fibrinolysis VATStPA P value PO Fever (Days) 3.1 3.80.46 O2 tx (Days) 2.25 2.330.89 LOS (Days) 6.89 6.830.96 Patient Charges $11,660$7,5750.01 Analgesic doses22.321.40.90 Study Results J Pediatr Surg 44:106-111, 2008

26. London Prospective Trial VATS v Fibrinolysis w/Urokinase No difference in LOS (6 v 6 days) No difference in 6 month CXR VATS more expensive ($11.3K v $9.1K) 16 % failure rate for fibrinolysis Am J Respir Crit Care Med 174:221-227, 2006

27. There appears to be no therapeutic or recovery advantages to thoracoscopic debridement compared to fibrinolysis as the primary treatment for empyema Thoracoscopy results in significantly higher patient charges CONCLUSIONS J Pediatr Surg 44:106-111, 2008

28. 3. Complete esophageal mobilization vs minimal mobilization during laparoscopic fundoplication

29. Prospective Randomized Trial Primary Outcome Measure Transmigration of fundoplication wrap  2 centers participating  Powered at 360 patients (12%vs 5%)  All patients get upper GI study at 1 yr  Study closed at interim analysis (177 pts)  Presentation at APSA, 2010

30. Epidural vs PCA for pain control after MIS pectus repair (Nuss procedure) Sample size of 110 Patients (now at 109) APSA, 2011 PRCT’s Now Enrolling

31. PRCTs Now Enrolling Burn study – SSD vs collagenase One stage vs 2 stage laparoscopic orchiopexy for intra- abdominal testis Standardized feeding protocol vs ad lib feedings following laparoscopic pyloromyotomy Esophago-crural sutures vs no sutures at laparoscopic fundoplication (both groups receive minimal esophageal dissection) SSULS appendectomy vs 3 port lap appendectomy SSULS cholecystectomy vs 4 port lap cholecystectomy Irrigation/suction vs suction alone in patients with perforated appendicitis

32. Why Do This? Manage patient according to evidence: Evidence based medicine allows us to treat patients on objective data rather than our own opinions which are fraught with anecdotal experience and may not represent the best care for the patient

33. QUESTIONS www.centerforprospectiveclinicaltrials.com