Principal Investigator: DR NAOMI KEBBA, MBChB (MAK), MMED SURGERY (MAK)

1. POSTOPERATIVE COMPARISON OF CHEST CLOSURE WITH OR WITHOUT A DRAIN FOLLOWING PATENT DUCTUS ARTERIOSUS LIGATION IN UGANDAN CHILDREN: A NON-BLINDED RANDOMISED CONTROLLED CLINICAL TRIAL. Principal Investigator: DR NAOMI KEBBA, MBChB (MAK), MMED SURGERY (MAK) College of Health Sciences, Makerere University, P.O Box 7072, KAMPALA, UGANDA Co-Investigators: MR MWAMBU TOM, MBchB (MAK), MMED SURGERY (MAK), FCS MR. OKETCHO MICHAEL, MBchB (MAK), MMED SURGERY (MAK), FCS. DR EKWARO A. OBUKU, MBchB (MAK), MSc Clinical Trials, (LSHTM)

2. INTRODUCTION • Patent DuctusArteriosus (PDA) is the most common lesion operated at the Uganda Heart Institute, accounting for 54% of procedures in 2010. • The Standard Of Care is routine insertion of a chest drain post-operatively. • This potentially exposes the patient to post-operative complications including:* • increased post-operative pain • poor chest excursions with low SpO2 • increased incidence of surgical site infections. • Frequently the drainage is not significant (<4ml/hr for children above 6yrs and <2mls/hr below 6yrs): • Pleura can effectively reabsorb fluid of up to 500ml • Previous retrospective studies have shown no added risk e.g. increased mortality, to the patients if routine use of the chest tube is avoided *Brandt et al. Clin Intensive Care. 1994;5 (3):123-129. Bailey et al. J AccidEmerg Med. 2000;17 (2):111-114., Gilsanz et al. CHEST. 1978;74 (2):167-9. Heffner et al. CHEST . 1995;108 (4):1053-58.

3. PROBLEM STATEMENT/ JUSTIFICATION Problem statement • Standard of care for PDA predisposes the patients to more post operative complications. • It may increase the costs of surgery Justification • There is controversy over chest tube use in the expert community (equipoise)* • In Low and Middle Income Countries where chest drainage facilities and skills for chest tube removal in children are limited, chest closure without a drain may be of advantage: • Avert potential post-operative complications • Avert potential additional costs of surgery. • * CTSNet.

4. OBJECTIVES General objective • To compare the post-operative outcomes of chest closure with or without a drain following Patent Ductus Arteriosus ligation. Specific objectives • To compare the post-operative complications in those with or without a chest drain following PDA ligation. • To compare length of ICU stay in those with chest tubes or those without chest tubes.

5. RESEARCH QUESTION Research Question • Does closure of the PDA without a chest drain reduce post-operative complications? Study Hypothesis • Null: There is no difference in the development of post-operative complications between children who receive a chest tube and those who do not receive a chest tube after PDA ligation surgery. • Alternate: There is a difference in the development of post-operative complications between children who receive a chest tube and those who do not receive a chest tube after PDA ligation surgery.

6. METHODOLOGY Setting: • Uganda Heart Institute • Mulago National Referral & Teaching Hospital • Kampala city (capital of Uganda) • Surgery paid for by donors: HWAN SUNG, GIFT OF LIFE etc Design: • Randomized Controlled Trial Sample size estimation: • 86 children would detect a 21.9% difference in complications assuming: • 28.1% complications with DRAIN • 6.2% complications with-OUT DRAIN • 5% level of significance; • 95% Confidence Interval; Analysis: • Two analyses • One interim analysis • Stopping rule: Fixed Nominal • One final analysis

7. Table 1: Fixed nominal rule to maintain overall type I error = 0.05 * *Pocock SJ. Clinical Trials: A Practical Approach. Chichester: Wiley; 1984

8. RECRUITMENT • April 12- April 13, original sample size 86 patients (Pocock formula*), number achieved 44. • Consecutive sampling- patients consecutively recruited from booking ledger by order of date for surgery. • Randomisation • 44 patients randomised to DRAIN (22) and NO DRAIN (22). • Block randomization; varying size (4 or 6) • Allocation concealment: opaque envelopes issued consecutively • Randomized after PDA ligation. • Non-blinded • *Pocock, S.J. Clinical Trials A Practical Approach (1983): John Wiley and Sons Ltd.

9. ELIGIBILITY Inclusion criteria: • All children with a confirmed diagnosis of PDA • Age 12 years and below • Proxy consent by parent or guardian • Assent by children > 8 years Exclusion criteria: • Broncho spasms pre-operatively. • Concurrent other chest surgery with PDA ligation. • Damage to thoracic duct or ductus arteriosus noticed during surgery.

10. Table 2: Socio demographic and pre-operative baseline characteristics of enrolled children *All data in median and interquartile ranges except if starred, where frequency and proportion (%) was used.

11. Socio demographic and pre-operative baseline characteristics of enrolled children

12. Table 3: Intraoperative characteristics for the drain and no drain groups. • *All data in median and interquartile ranges except if starred, where frequency and proportion (%) was used.

13. Intraoperative characteristics for the drain and no drain groups.

14. Table 4: logistic regression analysis of postoperative outcomes of surgery • (*)-Zero values in cells did not permit generation of Odds Ratios. Fisher’s exact test was employed for hypothesis testing, since expected values <5, by Cochran’s rules;(#)- used in computing the “revised” combined endpoint; (α) ­– P-value cut-off for one interim analysis (after 50% recruitment) and one final analysis (after 100% recruitment) is 0.029 using the Fixed Nominal Rule (see table 1 above)

15. LIMITATIONS AND ETHICAL CONSIDERATIONS LIMITATIONS • Selection bias. • Very slow recruitment. • Could not blind. • small numbers-need to complete recruitment. ETHICAL CONSIDERATIONS • Study approved by MAK- SOMREC • Informed consent by gaurdians, assent for ≥ 8years. • All data confidential • PI trained in GCP guidelines

16. DISCUSSION • From our data, the safety of not routinely using the chest tube is evident, 95.5% did not retain significant fluid. One patient (4.5%) underwent uneventful tube insertion. • In one study, though done for different chest surgeries, 90.5% of the patients did wellwithout chest tube insertion, 9.3% underwent an uneventful postoperative chest tube insertion or thoracentesis *. *Aru G.M. et al. Ann Thorac Surg.1999; 68 (4): 1376-8.

17. CHILD RECEIVED CHEST TUBE POST OPERATIVELY

18. POST OPERATIVE PERIOD UNDERWATER SEAL BOTTLE WITH ONLY 28ML OF FLUID AT 24HRS FULL APPEARANCE OF UNDERWATER SEAL BOTTLE

19. PLEURAL SEPARATION AT 48 HOURS, “F”-distance between pleurae

20. DISCUSSION • The need for higher oxygen levels in the drain arm -more pain and splinting of the diaphragm =compromised respiration • ICU stay was not affected by presence or absence of the tube. • Both groups routinely spend 24 hours in ICU

21. CONCLUSION • The evidence suggests that avoiding routine use of a chest drain after uncomplicated PDA surgery is safe and does not put the child at risk of more complications. • Children who routinely receive a chest drain were prone to complications as a result of the tube itself which included increased pain, higher oxygen demand and drainage site infection. • Routine chest tube use may not be necessary in uncomplicated surgery. Final analysis of full data to confirm this direction.

22. ACKNOWLEDGEMENT Sponsor • This work is supported by the Fogarty International Center, the National Heart Lung and Blood Institute, and the Common Fund of the National Institutes of Health under Award Number R24TW008861.

23. ACKNOWLEDGEMENT Cardiothoracic surgeons at Uganda Heart Institute • MR MWAMBU TOM, MBchB (MAK), MMED SURGERY (MAK), FCS • MR. OKETCHO MICHAEL, MBchB (MAK), MMED SURGERY (MAK), FCS. Trial advisor and supervisor • DR EKWARO A. OBUKU, MBchB (MAK), MSc Clinical Trials, (LSHTM) Support team • Dr Magala (Registrar cardiothoracic surgery), nurses- John, Ben, Senga, Eva, Muraa