Abstract: We included eight RCTs with 311 participants in this review. After exclusion of five participants, we included 306 participants in one or more outcomes. Five trials (240 participants) investigated the three main treatments: open necrosectomy (121 participants), minimally invasive step-up approach (80 participants), and peritoneal lavage (39 participants) and were included in the network meta-analysis. Three trials (66 participants) investigated the variations in the main treatments: early open necrosectomy (25 participants), delayed open necrosectomy (11 participants), video-assisted minimally invasive step-up approach (12 participants), endoscopic minimally invasive step-up approach (10 participants), minimally invasive step-up approach (planned surgery) (four participants), and minimally invasive step-up approach (continued percutaneous drainage) (four participants). The trials included infected or sterile necrotising pancreatitis of varied aetiology. All the trials were at unclear or high risk of bias and the overall quality of evidence was low or very low for all the outcomes. Overall, short-term mortality was 30% and serious adverse events rate was 139 serious adverse events per 100 participants. The differences in short-term mortality and proportion of people with serious adverse events were imprecise in all the comparisons. The number of serious adverse events and adverse events were fewer in the minimally invasive step-up approach compared to open necrosectomy (serious adverse events: rate ratio 0.41, 95% CI 0.25 to 0.68; 88 participants; 1 study; adverse events: rate ratio 0.41, 95% CI 0.25 to 0.68; 88 participants; 1 study). The proportion of people with organ failure and the mean costs were lower in the minimally invasive step-up approach compared to open necrosectomy (organ failure: OR 0.20, 95% CI 0.07 to 0.60; 88 participants; 1 study; mean difference in costs: USD -11,922; P value < 0.05; 88 participants; 1 studies). There were more adverse events with video-assisted minimally invasive step-up approach group compared to endoscopic-assisted minimally invasive step-up approach group (rate ratio 11.70, 95% CI 1.52 to 89.87; 22 participants; 1 study), but the number of interventions per participant was less with video-assisted minimally invasive step-up approach group compared to endoscopic minimally invasive step-up approach group (difference in medians: 2 procedures; P value < 0.05; 20 participants; 1 study). The differences in any of the other comparisons for number of serious adverse events, proportion of people with organ failure, number of adverse events, length of hospital stay, and intensive therapy unit stay were either imprecise or were not consistent. None of the trials reported long-term mortality, infected pancreatic necrosis (trials that included participants with sterile necrosis), health-related quality of life at any time frame, proportion of people with adverse events, requirement for additional invasive intervention, time to return to normal activity, and time to return to work. Low to very low quality evidence suggested that the minimally invasive step-up approach resulted in fewer adverse events, serious adverse events, less organ failure, and lower costs compared to open necrosectomy. Very low quality evidence suggested that the endoscopic minimally invasive step-up approach resulted in fewer adverse events than the video-assisted minimally invasive step-up approach but increased the number of procedures required for treatment. There is currently no evidence to suggest that early open necrosectomy is superior or inferior to peritoneal lavage or delayed open necrosectomy. However, the CIs were wide and significant benefits or harms of different treatments cannot be ruled out. The TENSION trial currently underway in Netherlands is assessing the optimal way to perform the minimally invasive step-up approach (endoscopic drainage followed by endoscopic necrosectomy if necessary versus percutaneous drainage followed by video-assisted necrosectomy if necessary) and is assessing important clinical outcomes of interest for this review. Implications for further research on this topic will be determined after the results of this RCT are available.

Plain-language summary: Eight trials including 311 participants met the inclusion criteria for the review, of whom 306 participants were included in various comparisons. The treatments compared in five trials included necrosectomy, peritoneal lavage, and the step-up approach. Three other trials compared variations in timing of necrosectomy and methods of step-up approach. The participants in the trials had infected or sterile pancreatic necrosis resulting from varying causes. Overall, the short-term death rate (mortality over a short time) was 30% and serious adverse events (side effects or complications) rate was 139 per 100 participants. The differences in short-term mortality and percentage of people with serious adverse events were imprecise in all the comparisons. The number of serious adverse events and adverse events were fewer in the minimally invasive step-up approach compared to open necrosectomy. The complications resulting from the disease and treatment included heart failure (heart does not pump enough blood around the body at the correct pressure), lung failure (lungs do not remove waste products from the blood), kidney failure (kidneys do not remove waste products from the blood), and blood poisoning (micro-organisms and their poisons are in the blood). The percentage of people with organ failure and the average costs were lower in the minimally invasive step-up approach compared to open necrosectomy. The number of adverse events were more with the video-assisted minimally invasive step-up approach compared to the endoscopic-assisted minimally invasive step-up approach but the total numbers of procedures performed were less with the video-assisted minimally invasive step-up approach compared to the endoscopic minimally invasive step-up approach. The differences in any of the other comparisons for number of serious adverse events, percentage of people with organ failure, number of adverse events, length of hospital stay, and intensive therapy unit stay were either imprecise or were not consistent. None of the trials reported long-term mortality, infected pancreatic necrosis (in trials that included participants with sterile necrosis), health-related quality of life (which measures physical, mental, emotional, and social functioning), percentage of people with adverse events, requirement for additional invasive intervention, time to return to normal activity, and time to return to work. The overall quality of evidence was low or very low for all the measurement because the trials were at high risk of bias (e.g. prejudice of people who conducted the trial and trial participants who prefer one treatment over another) and were small trials. As a result, further studies are required on this topic.