Publication

• Title: Immediate versus Postponed Intervention for Infected Necrotizing Pancreatitis
• Acronym: POINTER
• Year: 2021
• Journal published in: The New England Journal of Medicine
• Citation: Boxhoorn L, van Dijk SM, van Grinsven J, et al. Immediate versus postponed intervention for infected necrotizing pancreatitis. N Engl J Med. 2021;385(15):1372-1381.

Context & Rationale

• Background

  • Infected necrotizing pancreatitis is a high-morbidity phase of acute pancreatitis in which invasive intervention (drainage and/or necrosectomy) may be required for sepsis control, but procedural trauma itself can precipitate complications.
  • Minimally invasive “step-up” management (catheter drainage first, with minimally invasive necrosectomy if clinically needed) reduced major complications compared with open necrosectomy and became a dominant paradigm in specialist practice.²
  • Despite agreement to delay debridement until collections are organised (walled-off necrosis), the optimal timing of the first drainage step when infection is suspected remains clinically contested: early drainage for source control versus antibiotics-first to allow maturation and potentially avoid intervention.
  • Contemporary expert guidance endorsed step-up strategies and generally advocated delaying invasive management when feasible, but direct randomised evidence on “immediate” versus “postponed” drainage was limited prior to POINTER.³
• Research Question/Hypothesis

  • In adults with suspected or confirmed infected necrotizing pancreatitis within 35 days of disease onset and with collections amenable to catheter drainage, does immediate catheter drainage (within 24 hours) reduce the total burden of complications (Comprehensive Complication Index) at 6 months compared with a strategy of postponed catheter drainage?
• Why This Matters

  • Timing determines whether patients are exposed to invasive procedures before encapsulation, potentially increasing technical difficulty and the need for repeated interventions.
  • A postponement strategy could allow clinical resolution with antibiotics alone, avoiding drainage and downstream necrosectomy in a meaningful subset.
  • Given substantial resource utilisation (ICU days, procedural burden, and costs), clarifying timing has direct implications for patient outcomes and health-system efficiency.

Design & Methods

• Research Question: In infected necrotizing pancreatitis diagnosed within 35 days and amenable to catheter drainage, is immediate catheter drainage superior to postponed catheter drainage for reducing the 6-month Comprehensive Complication Index?
• Study Type: Multicentre, randomised, open-label, parallel-group superiority trial in 22 participating centres in the Netherlands; central computer randomisation with concealed variable block sizes; stratified by organ failure at randomisation, disease duration (day 0–20 vs day 21–35), and centre volume; pragmatic step-up management with multidisciplinary oversight; protocol and statistical analysis plan prespecified.¹
• Population:
  • Adults (≥18 years) with necrotizing pancreatitis and suspected or confirmed infected necrosis within 35 days after onset, for whom catheter drainage was technically feasible.
  • Confirmed infection: gas in (peri)pancreatic necrotic collections on CT, or positive Gram stain/culture from fine-needle aspiration or drainage.
  • Suspected infection (day 15–35): clinical signs of infection for ≥3 consecutive days without another focus, plus either new-onset organ failure or ≥2/3 rising inflammatory parameters (temperature >38.5°C or <35.5°C; CRP ≥150 mg/L or rising; leukocytes ≥15×10⁹/L or rising).
  • Key exclusions: indication for emergency laparotomy; retroperitoneal intervention already performed; disease duration >35 days; chronic pancreatitis.
• Intervention:
  • Immediate catheter drainage strategy: initiate antibiotics and perform catheter drainage within 24 hours after randomisation.
  • Drainage approach (percutaneous image-guided or endoscopic transluminal) selected by the treating team; additional catheters/upsizing and cross-modality rescue permitted.
  • Step-up escalation: if no clinical improvement within 72 hours (new-onset organ failure or increasing inflammatory markers), perform additional/revised drainage; if still clinically unsuccessful, proceed to minimally invasive necrosectomy (endoscopic transluminal necrosectomy or video-assisted retroperitoneal debridement) preferably after collections became walled-off; open necrosectomy if minimally invasive approaches were not feasible.
• Comparison:
  • Postponed catheter drainage strategy: initiate antibiotics and supportive care, with the intent to postpone catheter drainage until walled-off necrosis (largely/fully encapsulated), but allowing earlier drainage if clinical deterioration or lack of improvement mandated intervention.
  • Same step-up escalation algorithm after any drainage was undertaken.
• Blinding: Open-label for patients and clinicians; outcomes were adjudicated by an independent committee blinded to treatment allocation.
• Statistics: A total of 102 patients were required to detect a 15-point reduction in mean Comprehensive Complication Index (from 40 to 25; SD 27) with 80% power at a two-sided 5% significance level; total sample set at 104 allowing 2% dropout; primary analysis by intention-to-treat (linear regression for the primary endpoint; relative risks and mean differences with 95% confidence intervals for secondary endpoints); no interim efficacy analyses were planned.
• Follow-Up Period: 6 months after randomisation.

Key Results

This trial was not stopped early. 104 patients underwent randomisation (55 immediate drainage; 49 postponed drainage).

• The primary endpoint was neutral: mean Comprehensive Complication Index 57 vs 58 (mean difference −1; 95% CI −12 to 10; P=0.90).
• A postponed strategy avoided drainage entirely in 19/49 patients (39%); 17/19 survived without any intervention for infected necrosis.
• Immediate drainage increased procedural intensity without shortening ICU/hospital stay: necrosectomy 51% vs 22% (RR 2.27; 95% CI 1.27 to 4.06) and mean total interventions 4.4 vs 2.6 (mean difference 1.8; 95% CI 0.6 to 3.0).
• Selected subgroup estimates for the primary outcome did not demonstrate a consistent advantage for immediate drainage (e.g., organ failure at randomisation: CCI 81 vs 87; mean difference −6; 95% CI −26 to 17; disease duration ≤20 days: CCI 67 vs 62; mean difference 5; 95% CI −12 to 20).

Internal Validity

• Randomisation and allocation: Central computer-based randomisation with concealed variable block sizes; stratified by key prognostic factors (organ failure at randomisation; disease duration; centre volume), supporting allocation concealment and balance.
• Baseline comparability: Groups were broadly similar (mean age 58 vs 60 years; male sex 69% vs 63%; median APACHE II 11 vs 12; organ failure at randomisation 24% vs 16%; CT severity index median 7 vs 7; necrosis >30% in 35% vs 33%).
• Blinding and bias risk: Open-label delivery introduces risk of performance bias (especially for discretionary co-interventions), but outcomes were adjudicated by a committee blinded to allocation and many endpoints were objective.
• Protocol adherence / crossover: 51/55 (93%) in the immediate group received drainage within 24 hours; 4/55 (7%) were delayed (mean 4±2 days). In the postponed group, 1/49 (2%) received drainage within 24 hours (clinical deterioration). Two postponed patients already had walled-off necrosis at diagnosis.
• Separation of the variable of interest (timing and exposure): Time from randomisation to first drainage was 1±1 days (immediate) versus 13±15 days (postponed). Time from disease onset to first drainage was mean 24 days (median 24; IQR 20–30) versus mean 34 days (median 29; IQR 24–40); mean difference −10 days (95% CI −19 to −5).
• Strategy separation beyond timing (avoidance of procedures): Drainage occurred in 55/55 (100%) versus 30/49 (61%); necrosectomy in 28/55 (51%) versus 11/49 (22%); mean total interventions 4.4 (3.6–5.3) versus 2.6 (1.8–3.6).
• Timing appropriateness and technical state of collections: At the time of first drainage, (peri)pancreatic necrosis was largely or fully encapsulated in 60% (immediate) versus 70% (postponed), reflecting earlier intervention before full maturation in the immediate strategy.
• Outcome assessment and definitions: Primary endpoint (Comprehensive Complication Index) incorporates severity-weighted complications (Clavien–Dindo grades), enhancing sensitivity to total morbidity; however, components that depend on management decisions (e.g., antibiotic escalation, procedural thresholds) may still be indirectly influenced by open-label care.
• Statistical rigour: Target sample size was achieved (n=104); precision limits for mortality and several complications remained wide (e.g., death RR 1.25; 95% CI 0.42 to 3.68), limiting certainty about moderate survival differences.

Conclusion on Internal Validity: Overall, internal validity appears moderate: randomisation and follow-up were robust with clear strategy separation, but open-label care and a morbidity-weighted composite endpoint introduce plausible performance-related influences, and the small sample leaves wide confidence intervals for key clinical outcomes (notably mortality).

External Validity

• Population representativeness: Adults with early infected necrotizing pancreatitis in whom catheter drainage was technically feasible and emergency laparotomy was not indicated; patients with very late disease (>35 days), chronic pancreatitis, prior retroperitoneal intervention, or immediate surgical indications were excluded.
• Illness severity spectrum: Although many patients were seriously ill (baseline organ failure 24% and 16%), the trial design required a window for randomisation; patients requiring immediate operative management were not represented.
• Setting and expertise: Conducted in a high-resource national network with specialist multidisciplinary experience, and access to both percutaneous and advanced endoscopic drainage and minimally invasive necrosectomy; transferability may be reduced where endoscopic or surgical minimally invasive expertise is limited.
• Applicability across systems: The core question (antibiotics-first watchful waiting versus routine early drainage) is widely applicable, but procedure types, thresholds for escalation, and support infrastructure may vary and influence reproducibility of procedural burden and outcomes.

Conclusion on External Validity: Overall, external validity is moderate: findings are highly relevant to specialist centres managing infected necrotizing pancreatitis with step-up pathways, but may not directly generalise to patients requiring emergent operative management or to settings without access to minimally invasive drainage/necrosectomy expertise.

Strengths & Limitations

• Strengths: Pragmatic randomised comparison of two clinically realistic strategies; central concealed randomisation with stratification; high protocol adherence; blinded outcome adjudication; clinically meaningful resource-use outcomes; demonstrates procedural avoidance is achievable without excess morbidity in a substantial subgroup.
• Limitations: Open-label care; modest sample size with wide confidence intervals for mortality; heterogeneity in drainage modality and escalation decisions (although pragmatic); suspected infection criteria can misclassify sterile necrosis, potentially diluting any benefit of immediate drainage; the strategy comparison includes “avoidance” as well as “delay,” which complicates attribution to timing alone.

Interpretation & Why It Matters

• Clinical implication

  In clinically stable patients with infected necrotizing pancreatitis early in the disease course, an antibiotics-first strategy that postpones catheter drainage does not worsen the overall complication burden (CCI 57 vs 58) or mortality (13% vs 10%) and can avoid any intervention in 39% of patients.
• Mechanistic insight

  Earlier drainage occurred before full encapsulation more often (60% vs 70% largely/fully encapsulated) and was associated with greater downstream procedural escalation (necrosectomy 51% vs 22%), consistent with “intervention begets intervention” in non-organised necrosis.
• Practice framing

  POINTER supports reframing “early source control” in infected necrosis as primarily medical (antibiotics plus vigilant monitoring) unless deterioration mandates drainage, rather than defaulting to routine immediate catheter drainage for all suspected cases.

Controversies & Subsequent Evidence

• Strategy versus timing: The control strategy permitted clinical resolution without any drainage (39%), so POINTER tests a combined “postpone-and-select” approach (antibiotics-first with intervention only if needed) rather than a pure timing shift among patients destined to be drained; this is clinically meaningful but changes causal interpretation.
• Endpoint selection and open-label care: The Comprehensive Complication Index is sensitive to total morbidity and may detect differences missed by mortality alone, but it can incorporate management-dependent events; although adjudication was blinded, open-label co-intervention thresholds can still influence complication incidence and grading.
• Infection ascertainment: A substantial proportion were enrolled on suspected infection (clinical criteria), creating potential inclusion of sterile necrosis; this would bias towards null differences in benefit from immediate drainage (if early source control only helps true infection).
• Precision limits for survival: Mortality estimates were imprecise (RR 1.25; 95% CI 0.42 to 3.68), so POINTER robustly excludes large mortality benefit but cannot exclude smaller clinically relevant differences.
• Relationship to technique trials: Prior and subsequent trials comparing minimally invasive strategies (e.g., percutaneous-first step-up versus open surgery; endoscopic versus surgical approaches) inform “how” to intervene, whereas POINTER specifically informs “when” to initiate the drainage step within a step-up framework.²

Summary

• POINTER randomised 104 patients with suspected/confirmed infected necrotizing pancreatitis (≤35 days) to immediate drainage within 24 hours versus postponed drainage (antibiotics-first, delay until walled-off or clinically mandated).
• The primary outcome was neutral: mean Comprehensive Complication Index at 6 months was 57 vs 58 (mean difference −1; 95% CI −12 to 10; P=0.90).
• Postponement avoided invasive intervention entirely in 19/49 patients (39%), with 17/19 surviving without any procedure for infected necrosis.
• Immediate drainage increased procedural burden: necrosectomy 51% vs 22% (RR 2.27; 95% CI 1.27 to 4.06) and mean total interventions 4.4 vs 2.6 (mean difference 1.8; 95% CI 0.6 to 3.0).
• Mortality and major complications were similar, but estimates for mortality remained imprecise (13% vs 10%; RR 1.25; 95% CI 0.42 to 3.68).

Further Reading

Other Trials

• 2010 van Santvoort HC, Besselink MG, Bakker OJ, et al. A step-up approach or open necrosectomy for necrotizing pancreatitis. N Engl J Med. 2010;362(16):1491-1502.
• 2012 Bakker OJ, van Santvoort HC, van Brunschot S, et al. Endoscopic transgastric vs surgical necrosectomy for infected necrotizing pancreatitis. JAMA. 2012;307(10):1053-1061.
• 2019 van Grinsven J, van Dijk SM, Dijkgraaf MGW, et al. Postponed or immediate drainage of infected necrotizing pancreatitis (POINTER trial): study protocol for a randomised controlled trial. Trials. 2019;20(1):239.

Systematic Review & Meta Analysis

• 2021 Ricci C, Pagano N, Ingaldi C, et al. Treatment for infected pancreatic necrosis should be delayed, possibly avoiding an open surgical approach: a systematic review and network meta-analysis. Ann Surg. 2021;273:251-257.
• 2022 Gao L, et al. The clinical outcome of early versus delayed minimally invasive intervention for infected pancreatic necrosis: a systematic review and meta-analysis. J Gastroenterol. 2022;57:397-406.
• 2022 Zhu Y, et al. Early intervention in infected necrotizing pancreatitis: a systematic review and meta-analysis. Dig Surg. 2022;39:224-231.
• 2023 Niu B, et al. Comparison of early and late intervention for necrotizing pancreatitis: a systematic review and meta-analysis. J Dig Dis. 2023;24(5):321-331.

Observational Studies

• 2011 Zerem E, et al. Step-up approach to infected necrotising pancreatitis: a 20-year experience of percutaneous drainage in a single centre. Dig Liver Dis. 2011;43(2):133-138.
• 2022 Chen J, et al. Early versus delayed intervention for necrotizing acute pancreatitis with persistent organ failure. Hepatobiliary Pancreat Dis Int. 2022;21(2):162-168.
• 2023 Timmerhuis HC, et al. Over-and Misuse of Antibiotics and the Clinical Consequence in Necrotizing Pancreatitis: an observational multicentre study. Ann Surg. 2023;278(4):Not reported.

Guidelines

• 2020 Baron TH, DiMaio CJ, Wang AY, Morgan KA. American Gastroenterological Association clinical practice update: management of pancreatic necrosis. Gastroenterology. 2020;158(1):67-75.e1.

Notes

• Further Reading is selective and constrained to references with DOI landing pages available from the trial’s protocol/manuscript materials; additional high-quality trials, systematic reviews, and guidelines exist but were not included here because DOI-verified details were not present in the provided documents.

Overall Takeaway

POINTER is a landmark timing trial within infected necrotizing pancreatitis because it directly tested an antibiotics-first postponed drainage strategy against routine immediate drainage in a contemporary step-up setting. It demonstrated that postponement can safely avoid invasive intervention in a large minority of patients (39%) while maintaining similar overall morbidity (CCI 57 vs 58) and mortality (13% vs 10%), and it showed that routine immediate drainage increases procedural escalation (necrosectomy 51% vs 22%) without improving patient-centred outcomes.

Bibliography

• 1. van Grinsven J, van Dijk SM, Dijkgraaf MGW, et al. Postponed or immediate drainage of infected necrotizing pancreatitis (POINTER trial): study protocol for a randomised controlled trial. Trials. 2019;20(1):239. Link
• 2. van Santvoort HC, Besselink MG, Bakker OJ, et al. A step-up approach or open necrosectomy for necrotizing pancreatitis. N Engl J Med. 2010;362(16):1491-1502. Link
• 3. Baron TH, DiMaio CJ, Wang AY, Morgan KA. American Gastroenterological Association clinical practice update: management of pancreatic necrosis. Gastroenterology. 2020;158(1):67-75.e1. Link