RELAP trial
Planned versus on demand relaparotomy in secondary peritonitis
(Dutch multicenter RCT)
Background and objectives
Abdominal sepsis (secondary peritonitis) is associated with a high mortality rate (20-60%, mean 30%), long hospital stay, and a considerable long-term morbidity. In the Netherlands, about 3000 patients with secondary peritonitis are treated yearly. Surgery is the mainstay of the treatment of abdominal sepsis. Although already in 1990 the European Society of Infectious Diseases advocated the need of a randomized trial comparing the efficicacy of current treatment strategies, such a study has yet to be performed. Therefore, the discussion is still ongoing whether a more aggressive surgical strategy (planned relaparotomy) is to be preferred or introduces more harmful side-effects than a more conservative strategy (relaparotomy on demand). On clinical and pathophysiological grounds a reduction in mortality and disease-related morbidity can be expected of the on demand strategy compared to planned relaparotomies: (1) reduction of the number of operations per patient reduces the risk of surgery-related complications; (2) increased activation of inflammatory reactions after relaparotomy may contribute to persisting organ dysfunction and development of multiple organ failure; (3) an adequate and timely selection of patients with residual infection is possible with modern CT imaging techniques; (4) an on demand strategy offers the opportunity of percutaneous (minimal invasive), CT-guided drainage of abscesses. Whether a relaparotomy on demand strategy indeed improves clinical outcome of patients with abdominal sepsis, needs to be investigated in a randomized clinical trial.
Research questions
Does relaparotomy on demand in comparison with planned relaparotomy in patients with secondary peritonitis reduce the risk of 180-day poor outcome (death or readmission/surgical intervention for morbidity)? Other study questions: comparison of incidence/prevalence of (intermediate)long-term morbidity, quality of life, and 'quality-adjusted life years' (QALYs) until 1 year follow-up, and medical and indirect costs between the two treatment strategies.
Study design
A randomized, multicenter, clinical trial in 234 patients with secondary peritonitis. Randomization: block randomization after the index laparotomy with stratification for severity of disease (APACHE II score at study entry: 11-20 or >20) and participating hospital. Follow-up period for the primary endpoint is 6 months. For the secondary endpoints, a follow-up period of 1 year is chosen.
Study population
Patients with an APACHE II score > 10 and peritonitis caused by perforation or infection of an abdominal organ or ischemia/necrosis of (part of) the digestive tract or by postoperative complications (e.g. anastomotic leakage, non-localized abscesses) undergoing emergency laparotomy.
Intervention
Group 1: planned relaparotomy for inspection, drainage and peritoneal lavage every 36-48 hours after the index laparotomy until negative findings at the last relaparotomy. Group 2: relaparotomy after the index laparotomy only in case of deterioration or lack of progression (based on predefined clinical and radiodiagnostic criteria).
Outcome measures
Primary: death (all-cause mortality) or readmission/surgical intervention for morbidity (according to documented definitions) within 6 months after admission. Secondary: medium-term morbidity, days of mechanical ventilation, duration of ICU- and hospital stay, days outside the hospital in 1 year, quality of life, cost-utility analysis. Tertiairy: economic evaluation of medical and indirect costs (cost-effectiveness analysis).
Power/data-analysis
Based on the combined primary endpoint to detect (a) an absolute reduction in mortality of 10% and (b) an absolute reduction in readmission or surgical intervention for morbidity in survivors of 10%: reduction in poor outcome from 44% to 28%. Sample size needed including 5% drop-outs (after inclusion) is 117 (111+6) patients in each arm (power 0.80, a=0.05). Data-analysis: intention-to-treat comparison of both arms with respect to primary outcome. Additional analysis for secondary and tertiairy endpoints.
Economic evaluation
Cost-effectiveness analysis of medical and indirect medical costs associated with each of the two treatment strategies is performed primarily with respect to the primary endpoint of 180 days and secondarily with respect to QALYs at medium-term follow-up (1 year). Volume data on resource use will be based on the hospital information system, combined with prospective data collection in CRFs and patient questionnaires. A simulation model will be developed which (1) evaluates the sensitivity of the endpoints as well as the cost parameters and (2) is extrapolated to the Dutch target population.
This study was funded by
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