Discussion
Infected necrosis is a potentially lethal complication of acute pancreatitis, typically requiring invasive intervention. The treatment of infected necrotizing pancreatitis is associated with lengthy hospital stay and high costs. The POINTER trial is the first randomized controlled trial designed to determine the optimal timing of catheter drainage in infected necrotizing pancreatitis: i.e. immediate or postponed, once walled-off necrosis has occurred.
According to current evidence-based international guidelines [
7,
8], suspected or proven infected necrosis in patients with clinical signs of infection is an indication for invasive intervention. There should be a strong reluctance towards intervening in sterile collections [
7,
28]. Currently, intervention is advised when the infected necrosis has become walled-off, which occurs typically 4 weeks after the onset of disease [
29]. This practice of postponing interventions until the stage of walled-off necrosis is based on literature published when open necrosectomy was the standard intervention [
10,
30,
31]. Early necrosectomy is now recognized as having a major impact in the critically ill patient, whereas postponed necrosectomy allows the immune system to recover from the pro-inflammatory response due to pancreatitis.
Since the step-up approach is now considered standard of care, the issue of the optimal timing of catheter drainage has become highly relevant. Current literature reports that 35–64% of patients with infected necrotizing pancreatitis can be treated with catheter drainage alone, without the need for invasive necrosectomy [
3,
5]. Therefore, several expert pancreatologists have stated that they already practice immediate catheter drainage in patients with infected necrosis. In a recent international survey performed in preparation for this study, 55% of expert pancreatologists stated that they typically postpone catheter drainage by using antibiotics, whereas the other 45% proclaimed to drain immediately after diagnosing infected necrosis [
17]. Thus, in practice immediate catheter drainage is already being performed in individual patients, regardless of the effect of antibiotics alone or the degree of encapsulation: (percutaneous) catheter drainage in infected necrosis has been described retrospectively in several cohorts [
32] at a median of 2 weeks (9–15 days) after the onset of disease instead of at 4 weeks (28 days).
Patient outcomes were significantly better in the step-up-approach arm of the PANTER trial compared to the control group (primary open necrosectomy), but mortality (19%) did not differ between the two groups [
3]. The POINTER trial assesses whether early detection of infected necrosis and immediate catheter drainage improve outcomes, to further reduce mortality and morbidity. Earlier intervention may prevent patients from further deterioration while often waiting several weeks before undergoing invasive intervention, and thereby reduce complications and length of hospital stay and improve patient quality of life. In the control group, the effect of antibiotics is awaited while letting the (extra) pancreatic necrotic collections become walled-off. Antibiotic treatment alone may suffice in a small minority of patients [
4], which is another possible benefit for the control group.
Infected necrosis can be diagnosed on imaging (e.g. CECT) by the presence of gas in the (extra) pancreatic necrotic collection, irrespective of the source of the gas (i.e. through gas-forming bacteria or loss of integrity of the gastrointestinal tract). Collections with gas are seen in up to 42% of patients with infected necrosis [
33] and can occur in every phase of the disease [
34,
35]. Infected necrosis can also be confirmed by a positive gram stain or culture gathered with FNA. In a recent study, infected necrosis was confirmed by FNA in 86% (of 28 patients), which was similar to diagnosis based on clinical symptoms (80% of 92 patients) or gas identified on imaging (94% of 88 patients) [
33]. Until recently, FNA was not routinely used in the Netherlands for diagnosing infected necrosis [
17], as its outcome did not influence treatment because invasive intervention was postponed until the stage of walled-off necrosis, even in the case of a positive culture. In the POINTER trial, however, it is pivotal to detect infected necrosis as early as possible so as to perform immediate drainage (group A). Differentiating SIRS from sepsis is, however, very difficult in the first 14 days of the disease. Therefore, in the absence of gas on imaging but with clinical signs of infection in the first 14 days, a positive gram stain or culture after FNA is obligatory prior to randomization. Since the false negative rate of FNA is relatively high [
33], a second FNA is advised in patients with persistent deterioration and a primary negative FNA. Clinical signs alone are sufficient to diagnose (suspected) infected necrotizing pancreatitis after the first 14 days [
3].
After the first 14 days, clinical signs of infected necrosis are much more reliable. In the PANTER trial [
3] it was possible to attain 91% accuracy in the identification of infected necrosis based on clinical criteria. Patients can be randomized in the POINTER trial after the first 14 days, based on the clinical diagnosis of infected necrosis, as was done in the PANTER trial [
3].
Patients are randomized to undergo either immediate (< 24 h) or postponed (in walled-off necrosis) catheter drainage of infected collections. Both the surgical and the endoscopic step-up approach are allowed, depending on the location of the necrotic collection(s), the extent of encapsulation and the preference of the treating physician. It is known that both approaches are effective and safe and that not all (peri) pancreatic collections are approachable using a single technique [
6,
9].
The CCI [
20,
21] is the primary endpoint of the trial. Patients with infected necrotizing pancreatitis often have a long disease course with multiple complications, and therefore the CCI score is considered a representative tool to take into account all these complications. The individual complications (e.g. organ failure and mortality), number of (repeat) interventions, hospital and ICU lengths of stay, QALYs and direct and indirect costs are also analyzed as secondary end points.
Patients are stratified based on organ failure at baseline, since it is known that patients with organ failure have poorer outcomes, as compared to patients with no organ failure. Patients are also stratified on disease duration (cutoff 20 days) since this is obviously related to the onset of walled-off necrosis. Finally, patients are stratified on expected high versus low volumes of patient inclusion.
In conclusion, the POINTER trial is a multicenter randomized controlled trial that investigates whether immediate catheter drainage reduces the CCI in patients with infected necrotizing pancreatitis, as compared to postponed catheter drainage.
Acknowledgements
Steering/adjudication committee
MG Besselink, MD PhD, dept. of surgery, Amsterdam UMC, University of Amsterdam (chair); HC van Santvoort, MD PhD, dept. of surgery, St. Antonius Hospital Nieuwegein and University Medical Center Utrecht; J van Grinsven, MD PhD, dept. of surgery, Amsterdam UMC, University of Amsterdam and St. Antonius Hospital Nieuwegein; SM van Dijk, MD, dept. of surgery, Amsterdam UMC, University of Amsterdam and St. Antonius Hospital Nieuwegein; MA Boermeester, MD PhD, dept. surgery, Amsterdam UMC, University of Amsterdam; TL Bollen, MD PhD, dept. of radiology, St. Antonius Hospital Nieuwegein; MJ Bruno, MD PhD, dept. of gastroenterology and hepatology, Erasmus MC University Medical Center Rotterdam; MG Dijkgraaf, PhD, clinical research unit, Amsterdam UMC, University of Amsterdam; KP van Lienden, MD PhD, dept. of radiology, Amsterdam UMC, University of Amsterdam; P Fockens, MD, PhD, dept. of gastroenterology and hepatology, Amsterdam UMC, University of Amsterdam.
Data safety monitoring committee
JPH Drenth, MD PhD, dept. of gastroenterology and hepatology, Radboud University Medical Center Nijmegen (chair); DJ Gouma, MD PhD, dept. of surgery, Amsterdam UMC, University of Amsterdam; LPS Stassen, MD PhD, dept. of surgery, Maastricht University Medical Center; J Stoker, MD PhD, dept. of radiology, Amsterdam UMC, University of Amsterdam; S van Dieren, MD PhD, epidemiologist, Amsterdam UMC, University of Amsterdam.
Acute pancreatitis expert panel
MA Boermeester, MD PhD, dept. of surgery, Amsterdam UMC, University of Amsterdam; TL Bollen, MD PhD, dept. of radiology, St Antonius Hospital Nieuwegein; MJ Bruno, MD PhD, dept. of gastroenterology and hepatology, Erasmus MC University Medical Center Rotterdam; VC Cappendijk, MD PhD, dept. of radiology, Jeroen Bosch Hospital ‘s-Hertogenbosch; CH Dejong, MD PhD, dept. of surgery, Maastricht University Medical Center; CH van Eijck, MD PhD, dept. of surgery, Erasmus MC University Medical Center Rotterdam; P Fockens, MD PhD, dept. of gastroenterology and hepatology, Amsterdam UMC, University of Amsterdam; H van Goor, MD PhD, dept. of surgery, Radboud University Medical Center Nijmegen; MG Besselink, MD PhD, dept. of surgery, Amsterdam UMC, University of Amsterdam; JW Haveman, MD PhD, dept. of surgery, University Medical Center Groningen, University of Groningen; HS Hofker, MD PhD, dept. of surgery, University Medical Center Groningen, University of Groningen; JS Laméris, MD PhD, dept. of radiology, Amsterdam UMC, University of Amsterdam; KP van Lienden, MD PhD, dept. of radiology, Amsterdam UMC, University of Amsterdam; VB Nieuwenhuijs, MD PhD, dept. of surgery, Isala Clinics Zwolle; JW Poley, MD PhD, dept. of gastroenterology and hepatology, Erasmus MC University Medical Center Rotterdam.
AF Schaapherder, MD PhD, dept. of surgery, Leids University Medical Center; R Timmer, MD PhD, dept. of gastroenterology and hepatology, St Antonius Hospital Nieuwegein; HC van Santvoort, MD PhD, dept. of surgery, St Antonius Hospital Nieuwegein and University Medical Center Utrecht.
Key staff at coordinating centers
MG Besselink, MD PhD, dept. of surgery, Amsterdam UMC, University of Amsterdam (principal investigator); HC van Santvoort, MD PhD, dept. of surgery, St. Antonius Hospital Nieuwegein and University Medical Center Utrecht (co-principal investigator); J van Grinsven, MD PhD, dept. of surgery, Amsterdam UMC, University of Amsterdam and St. Antonius Hospital Nieuwegein (study coordinator); SM van Dijk, MD, dept. of surgery, Amsterdam UMC, University of Amsterdam and St. Antonius Hospital Nieuwegein (study coordinator).
Clinical centers and principal investigators (all in the Netherlands)
1. Amsterdam UMC, University of Amsterdam, PO 22660, 1100 DD Amsterdam; MG Besselink, dept. of surgery.
2. Albert Schweitzer Hospital, PO 444, 3300 AK Dordrecht; W van de Vrie, dept. of gastroenterology and hepatology.
3. Amphia Hospital Breda, PO 90158, 4800 RK Breda; T Seerden, dept. of gastroenterology and hepatology.
4. Catharina Hospital, PO 1350, 5623 EJ Eindhoven; EJ Schoon, dept. of gastroenterology and hepatology.
5. Erasmus MC University Medical Center, PO 2040, 3000 CA Rotterdam; MJ Bruno, dept. of gastroenterology and hepatology.
6. Gelre Hospital, PO 9014, 7300 DS Apeldoorn; P van Duijvendijk, dept. of surgery.
7. Hospital Gelderse Vallei, PO 9025, 6710 HN Ede; BJ Witteman, dept. of gastroenterology and hepatology.
8. Isala Clinics, PO 10400, 8000 GK Zwolle; AC Poen, dept. of gastroenterology and hepatology.
9. Jeroen Bosch Hospital, PO 90153, 5200 ME 's-Hertogenbosch; DJ Lips, dept. of surgery.
10. Spaarne Gasthuis, PO 417, 2000 AK Haarlem; RW van der Hulst, dept. of gastroenterology and hepatology.
11. Leids University Medical Center, PO 9600, 2300 RC Leiden; AF Schaapherder, dept. of surgery.
12. Maasstad Hospital Rotterdam, PO 9100, 3007 AC Rotterdam; M Hadithi, dept. of gastroenterology and hepatology.
13. Maastricht University Medical Center, PO 5800, 6202 AZ Maastricht; CH Dejong, dept. of surgery.
14. Maxima Medical Center, PO 7777, 5500 MB Veldhoven; JW Straathof, dept. of gastroenterology and hepatology.
15. Meander Medical Center, PO 1502, 3800 BM, Amersfoort; MP Schwartz, dept. of gastroenterology and hepatology.
16. Medical Center Leeuwarden, PO 888, 8901 BR Leeuwarden; ER Manusama, dept. of surgery.
17. Medisch Spectrum Twente, PO 50000, 7500 KA Enschede; NG Venneman, MD PhD, dept. of gastroenterology and hepatology.
18. OLVG Amsterdam, PO 95500, 1090 HM Amsterdam; JM Jansen, dept. of gastroenterology and hepatology.
19. Radboud University Nijmegen Medical Center, PO 9101, 6500 HB Nijmegen; H van Goor, dept. of surgery.
20. Reinier de Graaf Gasthuis, PO 5011, 2600 GA Delft; R Quispel, dept. of gastroenterology and hepatology.
21. Rijnstate Hospital, PO 9555, 6800 TA Arnhem; BMW Spanier, dept. of gastroenterology and hepatology.
22. St Antonius Hospital, PO 2500, 3430 EM Nieuwegein; D Boerma, dept. of surgery.
23. University Medical Center Groningen, PO 30001, 9700 RB Groningen; JW Haveman, dept. of surgery.
24. University Medical Center Utrecht, PO 85500, 3508 GA Utrecht; IQ Molenaar, dept. of surgery.
25. Amsterdam UMC, Vrije Universiteit van Amsterdam, PO 7057, 1007 MB Amsterdam; DL van der Peet, dept. of surgery.
Independent physician
PJ Tanis, MD PhD, dept. of surgery, Amsterdam UMC, University of Amsterdam.