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.cmhclinicaltrials.com

2. The Right People

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. Flawed Prospective Studies Are Usually Better Than Retrospective Data Collections

12. p - Value Commonly accepted p-value is 0.05 5/100 (1/20) chance that if a difference is found b/w variables, there really is no difference b/w the variables If p=0.01 there is a 1/100 chance that if a difference is found b/w variables, there really is no difference P=0.07 7/100 – still pretty significant, but readers will think there really is no significance b/c >0.05 (depends on what variable one is looking at)

13. How To Set Up a Study Alpha –Usually 0.05 is used; establishes level of significance of study  Value is used to determine # of patients needed  Retrospective fundoplication review: 12% vs 5% 360 patients needed to show a significant difference αIf α was 0.1, need fewer patients αIf α was 0.01, need more patients (because significance is greater) α  Set the α low to avoid a Type I error

14. How To Set Up a Study Power – commonly accepted is 0.8 20% chance that the study will fail to detect a difference when there really is one or 80% chance that the study will detect a difference when one does exist Underpowering a study risks a Type II error

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

16. 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.)

17. Landscape of Pediatric Surgery Young field, most practicing surgeons are 2-3 generations removed from the founders of the field Very few training centers, the opinions of a few affect the masses Wide variety of rare cases make acquisition of objective treatment data difficult

18. 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

19. 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

20. Conclusions Operative approach for pyloromyotomy has no significant influence on operating time or length of recovery Laparoscopic pyloromyotomy results in significantly less post-operative discomfort Fewer episodes of emesis and doses of Tylenol Laparoscopic pyloromyotomy results in obvious cosmetic benefits ASA, 2006

21. 2. Thoracoscopy vs Fibrinolysis for Empyema

22. Fibrinolysis had been shown to be better than chest tube drainage alone Primary thoracoscopic debridement had been shown to better than 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

23. 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

24. 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 J Pediatr Surg 44:106-111, 2008

25. 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 J Pediatr Surg 44:106-111, 2008

26. 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 J Pediatr Surg 44:106-111, 2008

27. 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

28. 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

29. 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

30. 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

31. PRCTs Now Enrolling Burn study – SSD vs collagenase (100/150) – Stopped early at interim analysis One stage vs 2 stage laparoscopic orchiopexy for intra-abdominal testis (28/30) Standardized feeding protocol vs ad lib feedings following laparoscopic pyloromyotomy (100/150) Esophago-crural sutures vs no sutures at laparoscopic fundoplication (both groups receive minimal esophageal dissection), APSA 2010 Irrigation/suction vs suction alone in patients with perforated appendicitis American Surgical 2012? Use of US vs landmark guided CVL placement (with Stanford) (40/80) IR drainage of appendiceal abscess with vs w/o instillation of fibrinolytic agent (tPA) (39/62) SSULS cholecystectomy vs 4 port lap cholecystectomy, APSA 2012? SSULS splenectomy vs 4 port lap splenectomy (6/30)

32. Summary Evidence based decision making will continue to have a stronger presence in medical training Patient management will continue to become more influenced by evidence over opinion Hurdles to performing prospective trials in surgery and medicine are mostly surmountable

33. QUESTIONS www.cmhclinicaltrials.com