Protocol violations due to incorrect orders or switching envelopes occurred in both groups (see Fig. 2). Among 304 patients assigned to DPC, 6 (2%) received PC instead, leaving 298 patients who actually received DPC. Of the 303 assigned to PC, 9 (2.9%) patients received DPC instead, leaving 294 in the PC group. In addition, 4 (1.3%) and 5 (1.7%) patients were later lost to follow-up, resulting in 300 and 298 patients in the DPC and PC groups, respectively, for the modified ITT analysis. The PP analysis considered only the 294 and 289 patients for these corresponding groups who received the treatment as per randomization. An AT approach moved 6 DPC patients to PC, and 9 PC patients to DPC, resulting in 303 and 295 patients included in DPC and PC groups, respectively.
Of 598 patients, 52 patients had superficial SSIs with a rate of 8.7% (95% CI 6.7, 11.2). Of these, SSI was mostly diagnosed within 7 to 10 days (88%). In the DPC group with SSI, 5 patients had the appearance of purulent drainage (2 Pseudomonas aeruginosa, 1 negative culture, 2 with no cultures); all of them had their closure delayed further.
A modified ITT analysis indicated lower SSI rates in the PC than DPC group, that is, 7.3% (4.4, 10.3) versus 10% (6.6, 13.3), a RD of −2.7%(−7.1%, 1.9%) (see Table 2), but this did not reach statistical significance. A sensitivity analysis of best (no infection) and worst (infection) case scenarios yielded estimated RDs of −2.6% (−7.1%, 1.8%) and −2.2% (−7.1%, 2.5%). Results of PP, AT, and IV analyses were similar, with RDs of −1.9 (−6.5%, 2.6%), −1.1% (−5.6%, 3.4%), and −2.8% (−7.6%, 1.9%), respectively. The adjusted IV analysis yielded a RD of −3.6% (−8.3%, 1.1%). Analyses for all approaches were repeated after imputation (see supplement Table 1, http://links.lww.com/SLA/B308). Results of imputed and unimputed data were very similar for all approaches except for the adjusted IV regression, where imputed data showed a lower effect of PC versus DPV than unimputed data [ie, −2.6% (−7.3%, 2.1%) vs −3.6% (−8.3%, 1.1%)]. Combining these RCT data with previous meta-analysis data2 yielded a RD of −1.7% (−14.2%, 10.8%).
LOS and Recovery Times
The ITT analysis indicated the mean LOS was not different, that is, 4.4 days (4.1, 4.6) and 4.3 days (4.0, 4.6) in the DPC and PC groups, respectively (see Table 3). DPC patients returned to normal activities/work at 3.8 days (3.4, 4.3) and 9.0 days (7.5, 10.1), compared with 3.6 days (3.2, 4.1) and 7.7 days (6.2, 9.1) days in the PC patients. Analyses using other approaches (with and without imputation) were again very similar (see Supplement Table 2 and Table 3, http://links.lww.com/SLA/B308).
Postoperative Pain and QoL
The ITT approach indicated the mean postoperative pain scores were not different, that is, 61 (59, 63) and 62 (59, 64) for DPC and PC groups at day 1, and 29 (27, 31) for both groups at day 3. The MD was 0.3 (−2.5, 3.0), which was nonsignificant.
The QoL scores for PC and DPC groups were quite low at day 3, that is, 0.54 (0.52, 0.56) and 0.53 (0.51, 0.55), respectively (see Table 3). The scores at day 30 for these corresponding groups increased to 0.79 (0.77, 0.81) and 0.78 (0.77, 0.80), respectively. The overall MD was 0.02 (−0.01, 0.04), which was nonsignificant. Results of other approaches (with and without imputation) were again very similar (see supplement Tables 4 and Table 5, http://links.lww.com/SLA/B308).
Costs of Treatment
Our results indicated similar LOS between groups. Direct medical costs were estimated, comprised mainly of the cost of dressings (189 Baht/time, 2 times/d) and re-suture (472 Baht).17 As a result, median total direct medical costs were, respectively, 3033 (2733, 3333) and 1200 (900, 1500) for DPC and PC groups, a median difference of 1833 (−1884, −1781) Baht in favor of PC. Other direct nonmedical costs including informal care and transportation and indirect costs of income lost were not significantly different. However, total costs accounting for both direct and indirect costs were significantly higher for DPC than PC, with a median difference of −2083 Baht (−2756, −1410).
This RCT compared superficial SSI rates between PC and DPC. Our primary results, based on an ITT approach, demonstrated that the superficial SSI rate was 2.7% lower in PC than DPC, although this was not significant. Although LOS, recovery time, postoperative pain, and QoL were not significantly different, total costs were about 2083 Baht (∼60 US$) lower in the PC than DPC groups. Although this may appear small ($60 USD and 56 Euros), this represents about 1 week's wages in Thailand.
Four approaches were applied to test the robustness of the results, that is, modified ITT with/without noninferiority test, PP, AT, and a counterfactual method. The ITT analysis is seen as the least biased because it preserves the original random allocation as recommended in the Consolidated Standards of Reporting Trials guideline.27 However, the ITT estimate may be biased if there is protocol violation and loss to follow-up as in our study. The estimated RD was −2.7%, which may be biased away from the null because protocol violations were higher in the PC than in the DPC groups, that is, 4.6% versus 3.3%. The PP and AT analyses may be more relevant than the ITT analysis in assessing the actual effects of interventions received. The PP analysis considers only patients who were randomly allocated and complied with their allocation, whereas the AT analysis considers actual intervention received, regardless of randomization.28 The PP analysis is prone to selection bias because the randomization is broken due to nonadherence, whereas the AT approach deals with data as if it was observational. Therefore, both approaches are potentially biased if the pattern of protocol violation and confounders are different between the 2 groups. The IV regression is applied to estimate what the intervention effect would have been (ie, counterfactual effects) if patients who were randomly assigned to PC actually received DPC, or vice versa.29,30 The IV regression itself can adjust for observed and unobserved confounders. As a result, the RD between PC versus DPC groups was −2.8%, which was about 0.1% higher than the ITT estimate. Surprisingly, the IV regression with adjustment for covariates yielded a higher effect of PC than the IV regression without adjustment, with a RD of −3.6%. Missing data for some covariates used in the adjusted model might have played a role in this discrepancy, given the RDs of the 2 IV models were closer to each other after applying multiple imputations to fill in missing data. Analyses for all approaches using complete/unimputed and imputed data showed similar directions of intervention effect in with favor of PC, although none reached statistical significance for superiority.
Our results confirm findings of the previous systematic review and meta-analysis,2 which demonstrated similarly lower superficial SSI in PC than in DPC groups, that is, 23% (12%, 33%) versus 26% (10%, 42%), respectively. However, the estimated incidence from this meta-analysis was much higher than our RCT, which might be explained by the fact that a few included studies did not prescribe antibiotic prophylaxis and thus had superficial SSI rates as high as 37%31 and 57%.19 Our study was planned to show superiority; however, it could also be interpreted as a noninferiority trial. Recommendations are that a noninferiority margin should be set to not exceed 25% of the standard effect.23,32,33 An estimate of 20% (ie, 10% of SSI in DPC) would give a noninferiority margin of 2%, and therefore our observed RD of −2.7% (upper end of CI 1.9%) would have met this noninferiority test (Z = −2.02, SE = 0.023, P = 0.021).
Our results are contrary to the RCT by Duttaroy et al,9 which demonstrated much higher superficial SSI in PC than DPC (ie, 45.2% vs 2.7%). This might be because they considered not only ruptured or gangrenous appendicitis but also peptic and typhoid perforations. In addition, the incision was midline, whereas ours was a right lower-quadrant incision, which is shorter and hence less prone to infection. Five per cent of patients in that study died, reflecting the greater severity of patients.
We did not find a difference in LOS between PC and DPC, which was in contrast to the previous systematic review and meta-analysis2 that found longer LOS in DPC than PC. This might be explained by the fact that patients in both groups were routinely prescribed preoperative intravenous antibiotics, and these were continued until body temperature <37.8°C for 24 to 48 hours after operation, hence prolonging LOS in the PC group.
In all, 476 (78%) patients had intra-abdominal fluid cultures; 105 (22%) were positive with hospital-acquired organisms including 47% P aeruginosa, 45% Escherichia coli (ESBL), 8% multidrug-resistant E coli, and 1% Acinetobacter bauminii. Among 52 superficial SSIs, 26 (50%) had wound cultures after opening the wound, and 2/3 were gram-negative positive bacteria. Of these, 5 (29%) were resistant strains (ie, 2 P aeruginosa, 2 multidrug-resistant E coli, and 1 ESBL); resistant organisms could have been seeded during wound care or have developed during hospitalization.34
Our study cannot inform the use of other types of appendectomy (eg, laparoscopic). Laparoscopic appendectomy can significantly reduce the rate of superficial SSI in complicated appendicitis as compared with open procedure,35 but this option is not always available, sometimes due to technical reasons and sometimes due to cost constraints. Our study also cannot inform the use of other types of DPC (eg, subcutaneous drain36,37 and wound wicks38) in which re-suturing is not required, thus potentially reducing the cost difference. Our findings may also be generalizable to other operations that require laparotomy and where DPC might be considered, but this would need to be specifically addressed.
Our study also indicated that DPC costs were about 2083 Baht higher than PC, without a benefit over PC in terms of efficacy and QoL. Therefore, PC was more cost-effective that DPC. Given a mid-year population in Thailand 2015 of 65,729,098 (http://stat.dopa.go.th/stat/statnew/upstat_age_disp.php), an estimated rate of appendectomy of 14/10,000/yr1 would result in 92,020 appendectomies/yr in Thailand. The prevalence of complicated appendicitis from our study was 18.2%,39 indicating 16,748 cases of complicated appendicitis across the country. Using PC routinely instead of DPC in all patients would save about 34,886,084 Baht country-wide.
To the best of our knowledge, our study is the largest RCT to date to assess the efficacy of DPC and PC in adult complicated appendicitis. Patients were randomized to receive DPC or PC to balance unknown and known risk factors (eg, BMI, diabetes, ASA classification, operative time, and degree of contamination, etc)40–43 of superficial SSI. After adjusting for wound management (ie, PC vs DPC), we found that diabetes, operative duration, visible feculent contamination, and ruptured appendicitis were risk factors for SSI, but BMI was not (data not shown). Although some protocol violations occurred, we applied modified ITT, PP, AT, and counterfactual IV regression to deal with these, and results were all similar and consistent. In addition, multiple imputation was applied to fill in missing data, and results were again consistent with un-imputed data. Although we could not blind the outcome assessors who monitored occurrence of superficial SSI, we tried to reduce any ascertainment bias by using standard protocols for diagnosing superficial SSI.
Primary wound closure is not different to DPC in adults with complicated appendicitis (ie, gangrenous and ruptured) with respect to SSI or LOS, although there are lower costs.
We would like to thank all involving persons that provide us kindly, intentionally help in many ways with moral support. These included every assistant in all collaborating centers and at our DMU, Section for Clinical Epidemiology and Biostatistics, Faculty of Medicine, Ramathibodi Hospital.
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appendicitis; delayed primary closure; surgical site infection; wound closure; wound infection
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