Research Topics for Perforated Peptic Ulcer Disease
High-Priority Research Gaps Identified from Current Evidence
1. Optimal Time Window for Non-Operative Management Conversion to Surgery
Research Question: In hemodynamically stable patients with sealed perforated peptic ulcer on contrast study, what is the optimal time threshold (6,12, or 24 hours) for converting from non-operative management to surgical intervention to minimize mortality?
Rationale: Current guidelines show that every hour of surgical delay increases mortality by 2.4%, yet non-operative management requires a 12-hour observation period before declaring failure 1. This creates a critical knowledge gap—the 2.4% hourly mortality increase conflicts with the recommended 12-hour NOM trial period 1. The Croft trial used 12 hours as the cutoff, but this was arbitrary and not evidence-based 1, 2. A prospective randomized trial comparing 6-hour versus 12-hour decision points for NOM failure would directly address this mortality-critical timing paradox.
Study Design: Multicenter RCT with mortality as primary outcome, comparing early (6-hour) versus standard (12-hour) conversion thresholds in patients meeting strict NOM criteria 1, 3.
2. Age-Stratified Surgical Timing in Elderly Patients (70-80 Years)
Research Question: In patients aged 70-80 years with perforated peptic ulcer, does immediate surgery (within 2 hours) versus rapid resuscitation followed by surgery (within 6 hours) reduce 30-day mortality?
Rationale: Guidelines explicitly warn against NOM in patients >70 years due to paradoxically higher mortality if NOM fails 1. However, the evidence also shows that elderly patients have worse outcomes with delayed surgery 1. The critical gap is whether elderly patients benefit from ultra-early surgery (bypassing extensive resuscitation) or whether they need optimized resuscitation first. Current data from Buck et al. shows 2.4% mortality increase per hour, but this wasn't stratified by age 1. The Croft trial showed elderly patients were "less likely to respond to conservative treatment" but didn't examine optimal surgical timing in this population 1, 2.
Study Design: Prospective cohort study with propensity score matching, comparing mortality and morbidity between immediate surgery (<2 hours) versus optimized resuscitation then surgery (2-6 hours) in patients 70-80 years old 4, 5.
3. Predictive Model for Non-Operative Management Success Using Dynamic Biomarkers
Research Question: Can a validated scoring system incorporating serial lactate measurements, heart rate trends, and pneumoperitoneum size at 0,6, and 12 hours predict NOM failure with >90% sensitivity in patients with sealed perforations?
Rationale: Current NOM selection criteria are static (initial presentation only), yet NOM fails in 28-46% of selected patients 1, 3. Songne et al. identified heart rate >94 bpm, pneumoperitoneum size, and meteorism as failure predictors, but these were measured at baseline only 1. No study has examined whether serial measurements of these parameters during the NOM trial can predict failure earlier than 12 hours. Given that mortality increases 2.4% per hour of delay, a predictive model using 6-hour serial measurements could identify failing NOM patients 6 hours earlier, potentially saving lives 1.
Study Design: Prospective multicenter validation study of a novel dynamic scoring system, with external validation cohort, measuring sensitivity/specificity for predicting NOM failure 3, 4.
4. Comparative Effectiveness of Laparoscopic versus Open Surgery in Delayed Presentation (>24 Hours)
Research Question: In patients presenting >24 hours after perforation with established peritonitis, does laparoscopic repair versus open repair reduce 30-day mortality and major complications (Clavien-Dindo III-V)?
Rationale: Delayed presentation (>24 hours) is a major mortality risk factor, with Surapaneni showing zero mortality if operated within 24 hours versus significant mortality beyond 48 hours 1. However, all existing laparoscopic studies (including the 2024 barbed suture study) excluded or didn't stratify by time to presentation 6. The critical gap is whether laparoscopic surgery maintains its advantages in the high-risk delayed presentation subgroup, or whether open surgery is superior when dealing with established feculent peritonitis. Current guidelines recommend surgery "as soon as possible" in delayed cases but don't specify approach 1.
Study Design: Multicenter RCT or high-quality propensity-matched cohort comparing laparoscopic versus open repair specifically in patients presenting >24 hours after symptom onset, with mortality as primary outcome 4, 6, 5.
5. Optimal Resuscitation Endpoint Beyond Lactate Normalization
Research Question: In septic patients with perforated peptic ulcer, does resuscitation targeting lactate clearance >20% per hour versus absolute lactate normalization (<2 mmol/L) before surgery reduce postoperative mortality and organ failure?
Rationale: Guidelines recommend lactate normalization as a resuscitation target, but this is extrapolated from sepsis literature, not PPU-specific data 1, 7. The critical gap is that complete lactate normalization may delay surgery excessively in some patients, while the 2.4% hourly mortality increase from surgical delay continues. No study has examined whether lactate clearance rate (a dynamic measure) is a better endpoint than absolute normalization (a static target) in the PPU population specifically 7, 8. The WSES guidelines emphasize "rapid resuscitation within 1 hour" but don't define what constitutes adequate resuscitation if lactate hasn't normalized by 1 hour 1, 7.
Study Design: Prospective RCT comparing lactate clearance-guided versus lactate normalization-guided resuscitation protocols, with time to surgery and 30-day mortality as co-primary outcomes 7, 5, 9.
6. Role of Contrast-Enhanced CT in Predicting Surgical Complexity and Mortality
Research Question: Does preoperative contrast-enhanced CT severity scoring (quantifying peritoneal fluid volume, pneumoperitoneum extent, and perforation size) predict need for definitive surgery versus simple closure and 30-day mortality?
Rationale: Current guidelines recommend water-soluble contrast study only to confirm sealed perforation for NOM candidates 1, 3. However, studies show that perforation size >1 cm² and extensive pneumoperitoneum predict worse outcomes, yet these are typically assessed intraoperatively 4, 5. The gap is that preoperative imaging severity scoring could guide surgical planning (simple closure versus definitive surgery) and inform consent discussions about mortality risk. The 2007 study by Kocer et al. showed definitive surgery had higher mortality than simple closure, but patient selection for definitive surgery wasn't standardized 5, 9.
Study Design: Prospective multicenter cohort developing and validating a CT-based severity score, correlating with intraoperative findings, surgical approach, and mortality 4, 5.
Methodological Considerations for All Proposed Studies
Critical Design Elements:
- Primary outcome must be mortality (not surrogate endpoints like hospital stay), as this is the most clinically meaningful outcome in PPU 4, 5, 9
- Stratification by age (<70 vs ≥70 years) is mandatory given the strong age-mortality relationship 1, 2
- Time-to-surgery must be precisely documented (not just "early" vs "late") given the 2.4% per-hour mortality increase 1
- Standardized resuscitation protocols following Surviving Sepsis Campaign targets (MAP ≥65 mmHg, UOP ≥0.5 mL/kg/h, lactate normalization) 1, 7
Common Pitfalls to Avoid:
- Selection bias in NOM studies: Patients selected for NOM are inherently lower-risk, making comparison with surgical cohorts invalid without propensity matching 3, 2
- Immortal time bias: Time spent attempting NOM must be accounted for when comparing mortality rates 1, 3
- Heterogeneous surgical techniques: Studies must standardize whether simple closure, omental patch, or definitive surgery is performed, as this affects mortality 5, 9