Controversies in the management of acute pancreatitis: An update

Table 1 Randomized controlled trials comparing resuscitation with Ringer’s lactate vs normal saline in the initial acute phase of acute pancreatitis

Ref.	RL	NS	SIRS			CRP
Wu et al[15], 2011	19	21	RL	84% at 24 h	P = 0.035	RL	Mean CRP 51 mg/L	P = 0.018
			NS	0% reduction at 24 h		NS	Mean CRP 104 mg/L
de Madaria et al[13], 2018	19	21	RL	Median no of SIRS criteria at 48 h: 01 (0-1)	P = 0.060	RL	Mean CRP at 48 h: 28 mg/L	P = 0.037
			NS	Median no of SIRS criteria at 48 h: 01 (1-2)		NS	Mean CRP at 48 h: 166 mg/L
Choosakul et al[14], 2018	23	24	RL	Reduction in SIRS at 48 h: 26.1%	P = 0.02	No difference in CRP
			NS	Reduction in SIRS at 48 h: 26.1% 4.2%
Karki et al[16], 2022	26	25	RL	SIRS at 24 h: 15.4%	P = 0.025	Median CRP at 72 h: 14.2 mg/L		P < 0.001
			NS	SIRS at 24 h: 44.0%		Median CRP at 72 h: 22.2 mg/L

CRP: C-reactive protein; NS: Normal saline; RL: Ringer’s lactate; SIRS: Systemic inflammatory response syndrome.

Table 2 Recent meta-analyses comparing resuscitation with Ringer’s lactate vs normal saline in patients with acute pancreatitis

Ref.	Inclusion	Conclusion
Zhou et al[17], 2021	4 RCT, 7964 abstracts, 57 full-text documents	Patients resuscitated with RL were less likely to develop moderately severe/severe AP (OR: 0.49; 95%CI: 0.25-0.97), had reduced requirement of ICU admission (OR: 0.33; 95%CI: 0.13-0.81) and had reduced local complications (OR: 0.42; 95%CI: 0.20-0.88)
Aziz et al[18], 2021	4 RCT, 2 cohort studies	Patients resuscitated with RL had a lower rate of ICU admission (RR: 0.43; 95%CI: 0.22-0.84), a lower length of hospital stay (MD: 0.77 d; 95%CI: 1.44-0.09 d) and no difference in overall mortality and SIRS at 24 h
Vedantam et al[19], 2022	6 studies	Patients resuscitated with RL had a decreased need for ICU admission and no statistical difference in the risk of developing SIRS at 24 h (pooled OR: 0.59; 95%CI: 0.22-1.62, P = 0.31)
Chen et al[20], 2022	4 RCT	Patients resuscitated with RL had a reduced incidence of ICU admission (RR: 0.39; 95%CI: 0.18-0.85; P = 0.02), no significant reduction in SIRS at 24 h, 48 h and 72 h and no reduction in risk of mortality, severe disease or local complications

AP: Acute pancreatitis; CI: Confidence interval; ICU: Intensive care unit; MD: Mean difference; OR: Odds ratio; RCT: Randomized controlled trial; RL: Ringer’s lactate; RR: Relative risk; SIRS: Systemic inflammatory response syndrome.

Table 3 Randomized controlled trials comparing aggressive vs restricted fluid resuscitation in the inflammatory phase of acute pancreatitis

Ref.	No. of patients	Disease severity	Aggressive resuscitation	Non-aggressive resuscitation
Mao et al[22], 2009	Aggressive: 36	SAP	Mortality: 94.4%	Mortality: 10.0%
	Non-aggressive: 40		Mechanical ventilation: 30.6%	Mechanical ventilation: 65.0%
Mao et al[23], 2010	Aggressive: 56	SAP	Mortality: 33.9%	Mortality: 15.3%
	Non-aggressive: 59		Sepsis: 78.6%	Sepsis: 57.6%
Wu et al[15], 2011	Aggressive: 19		Reduction in SIRS: 58%	Reduction in SIRS: 42%
	Non-aggressive: 21
Buxbaum et al[24], 2017	Aggressive: 27	Mild AP	Clinical improvement: 70%	Clinical improvement: 42%
	Non-aggressive: 33		SIRS: 7.4%	SIRS: 21.1%
Cuellar-Monterrubeo et al[25], 2020	Aggressive: 43	Mild, moderately severe and severe AP	SIRS at day 7: 13.3%	SIRS at day 7: 13.9%
	Non-aggressive: 45
Li et al[26], 2020	Total number (n = 912)	Hemoconcentration hematocrit > 44% vs < 44%	In hematocrit > 44%: increased NPPV	In hematocrit < 44%: reduced risk of NPPV

AP: Acute pancreatitis; NPPV: Non-invasive positive pressure ventilation; SAP: Severe acute pancreatitis; SIRS: Systemic inflammatory response syndrome.

Table 4 Meta-analysis on early enteral nutrition vs delayed enteral nutrition/total parenteral nutrition in acute pancreatitis

Ref.	Inclusion	Conclusion
Li et al[35], 2013	6 studies	Early EN vs delayed EN: reduced incidence of all infections (OR: 0.38; 95%CI: 0.21–0.68, P < 0.05); reduced incidence of catheter-related sepsis (OR: 0.26; 95%CI: 0.11–0.58, P < 0.05); reduced pancreatic infection (OR: 0.49; 95%CI: 0.31–0.78, P < 0.05); reduced risk of hyperglycemia (OR: 0.24; 95%CI: 0.11–0.52, P < 0.05); reduced length of hospitalization (mean difference: -2.18; 95%CI: -3.48-(-0.87); P < 0.05); reduced mortality (OR: 0.31; 95%CI: 0.14–0.71, P < 0.05); and no difference in pulmonary complications (P > 0.05)
Feng et al[36], 2017	4 RCTs, 2 retrospective studies	Early EN (within 48 h) vs delayed EN (after 48 h): reduced risk of multiple organ failure (RR: 0.67; 95%CI: 0.46-0.99; P = 0.04); decreased systemic inflammatory response syndrome but not significant (RR: 0.85; 95%CI: 0.71-1.02; P = 0.09); and no significant difference in mortality (RR: 0.78; 95%CI: 0.27-2.24; P = 0.64)
Qi et al[37], 2018	8 studies (727 patients)	Early EN vs late EN and TPN: risk of mortality (OR: 0.56; 95%CI: 0.23-1.34); multiple OF (OR: 0.40; 95%CI: 0.20-0.79); infectious complications: (OR: 0.57; 95%CI: 0.23-1.42); adverse events (OR: 0.45; 95%CI: 0.17-1.21); and pancreatitis-related infections (OR: 0.83; 95%CI: 0.59-1.18)
Zeng et al[38], 2019	17 RCTs	Early EN vs delayed EN: lower mortality (9.21% vs 11.22%) but no statistical significance between the two groups (RR: 0.86; 95%CI: 0.60-1.23; P = 0.42); reduced risk of complications (RR: 0.81; 95%CI: 0.70-0.93; P = 0.002); reduced incidence of infections (RR: 0.68; 95%CI: 0.51-0.91, P = 0.009); and no difference in risk of multi OF (RR: 0.82; 95%CI: 0.59-1.14; P = 0.23)

CI: Confidence interval; EN: Enteral nutrition; OF: Organ failure; OR: Odds ratio; RCT: Randomized controlled trial; RR: Relative risk; TPN: Total parenteral nutrition.

Table 5 Summary of the meta-analysis highlighting the feasibility of nasogastric feeding in acute pancreatitis

Ref.	Inclusion	Conclusion
Zhu et al[40], 2016	4 RCTs	NG vs NJ feed: mortality (RR: 0.71; 95%CI: 0.38-1.32; z = 1.09; P = 0.28); infectious complications (RR: 0.77; 95%CI: 0.45-1.30; z = 0.99; P = 0.32); digestive complications (RR: 1.02; 95%CI: 0.57-1.83; z = 0.08; P = 0.93); achievement of energy balance (RR: 1.00; 95%CI: 0.97-1.03; z = 0.00; P = 1.00)
Dutta et al[41], 2020	5 RCTs	NG vs NJ feed: mortality (RR: 0.65; 95%CI: 0.36-1.17; no difference in the rate of OF, procedure-related complications, the requirement of surgical intervention and the requirement of PN

CI: Confidence interval; NG: Nasogastric; NJ: Nasojejunal; OF: Organ failure; PN: Parenteral nutrition; RCT: Randomized controlled trial; RR: Relative risk.

Table 6 Guidelines on the use of antibiotics in acute pancreatitis

Societies	Prophylactic antibiotics	Indications of therapeutic antibiotics	Probiotics
ACG, 2013[50]	Not recommended	Extrapancreatic infections. Cholangitis, catheter-acquired infections, bacteremia, urinary tract infection, pneumonia. Infected pancreatic necrosis	Not recommended
IAP/APA, 2013[46]	Not recommended	Infected pancreatic necrosis	No recommendations
Japanese guidelines, 2021[51]	Not recommended	Not addressed	No recommendations
AGA, 2018[11]	Not recommended	Not addressed	No recommendations
ESGE, 2018[52]	Not recommended	Infected pancreatic necrosis	Not recommended
World Society of Emergency Surgery, 2019[53]	Not recommended	Infected pancreatic necrosis	No recommendations

ACG: American College of Gastroenterology; AGA: Androgenetic Alopecia; APA: American Pancreatic Association; ESGE: European Society of Gastrointestinal Endoscopy; IAP: International Association of Pancreatology.

Table 7 Important randomized controlled trials on analgesics in acute pancreatitis

Ref.	Country	Comparison drugs	Study design	Patients, n	Rescue agent	Primary outcome	Results	Conclusion
Blamey et al[74], 1984	United Kingdom	IM buprenorphine vs IM pethidine	RCT, blinding not mentioned	32	Pethidine	Pain relief at 24 h	No significant difference in pain relief at 24 h and no significant difference in pain-free period	No superiority established
Ebbehøj et al[75], 1985	Denmark	Indomethacin suppository vs placebo	Placebo-controlled, double-blind RCT	30	Opiate not specified	Pain relief using VAS; Pain-free days	Indomethacin provided better pain control, a lesser number of painful days and lesser need for rescue analgesia	Indomethacin suppository favored over placebo
Jakobs et al[76], 2000	Germany	IV buprenorphine vs IV procaine	Open-label RCT	39	Procaine group–pethidine; buprenorphine group–pethidine	Pain relief: VAS ever 8 hr for 3 d; rescue demand	Buprenorphine provided better pain relief on days 1 and 2 with lesser need for rescue analgesia; comparable side effects, complications, mortality	Buprenorphine favored
Stevens et al[77], 2002	United States	Transdermal fentanyl IM pethidine vs placebo and IM pethidine	Double-blind placebo-controlled RCT	32	IM pethidine	Pain relief: Self-reported 0-5 scale; self-reported satisfaction 1-5 at discharge	Fentanyl provided no significant difference in pain relief at 24 h but better pain relief at 36 h and a shortened hospital stay	Fentanyl favored
Kahl et al[78], 2004	Germany	Infusion procaine vs IV pentazocine	Open RCT	101	IM pethidine	Pain relief based on VAS and rescue analgesia	Pentazocine provided better pain relief until day 3 and required fewer rescue doses	Pentazocine favored
Peiró et al[79], 2008	Spain	IV metamizole vs SC morphine	Open RCT	16	Pethidine	Pain relief based on VAS and time to pain relief	Metamizole showed better pain relief at 24 h and faster pain relief, which was nonsignificant	A favorable trend towards metamizole but a small sample size
Wilms et al[80], 2009	Germany	IV procaine vs IV placebo	Double-blind placebo-controlled RCT	42	Buprenorphine	Pain relief and need for rescue analgesia over 3 d	Failed to show better pain relief as compared to placebo, and the need for rescue analgesia was similar in both groups	Procaine is not superior to placebo
Layer et al[81], 2011	Germany	IV procaine vs IV placebo	Double-blind placebo-controlled RCT	44	Metamizole or buprenorphine	Pain relief at 3 d; rescue analgesia; proportion achieving > 67% drop in VAS	Procaine showed higher analgesic superiority with greater pain relief at 72 h, lesser need for rescue analgesia and more patients achieving VAS drop > 67%	Procaine favored over placebo
Sadowski et al[82], 2015	Switzerland	Epidural analgesia vs PCA	Open RCT	35	Not applicable	Safety and efficacy of EA; pancreatic perfusion on CT; pain relief VAS	EA was safe, provided faster pain relief and increased pancreatic perfusion	EA favored over PCA
Gülen et al[83], 2016	Turkey	Tramadol vs paracetamol + dexketoprofen	Single-blind RCT	90	Morphine	Pain relief at 30 min	No significant drop in VAS at 30 min for both agents and a similar need for rescue analgesia for both groups	No superior analgesia
Mahapatra et al[84], 2019	India	IV pentazocine vs IV diclofenac	Double blind RCT	50	Fentanyl PCA	Pain relief; pain-free period; rescue analgesia	Higher rescue analgesia needed with diclofenac; longer pain-free period and lower need for PCA with pentazocine	Pentazocine favored
Kumar et al[85], 2019	India	IV diclofenac vs IV tramadol	Double-blind RCT	41	IV morphine	Pain relief VAS over 7 d; painful days; rescue demand; time for significant VAS drop	No significant difference among both groups except time to a significant drop in VAS was quicker with diclofenac	No superior agent
Chen et al[86], 2022	China	Hydromorphone PCA vs IM pethidine	Open-label RCT	77	IM dezocine	Change in VAS score over 72 h; rescue analgesia; organ failures; local complications; ICU admission LOH; mortality	No significant difference in VAS score deduction was noted with PCA as compared to pethidine, but a higher dose of hydromorphone needed for similar pain relief; need for rescue analgesia similar	No superior agent

CT: Computed tomography; EA: Epidural analgesia; ICU: Intensive care unit; IM: Intramuscular; IV: Intraveneous; LOH: Loss of heterozygosity; PCA: Patient-controlled analgesia; RCT: Randomized controlled trial; SC: Synovial chondromatosis; VAS: Visual analog scale.

Table 8 Indications of drainage of collection in acute pancreatitis

Clinical suspicion or documented infected pancreatic collection

Presence of gas in the fluid collection on imaging

Systemic signs of infections

Increasing leucocytes and worsening clinical condition

Persistent or new onset organ failure

Pressure symptoms

Gastric outlet obstruction

Intestinal obstruction

Biliary obstruction

Persistent symptoms (e.g., pain, persistent unwellness)

Disconnected pancreatic duct (i.e. full transection of the pancreatic duct) with ongoing symptoms

Table 9 Timing of first catheter drainage and outcome in various studies of acute pancreatitis

Ref.	Number of days after the onset of the disease when PCD was performed, mean (range)	Patients, n	IPN, %	Mortality, %
Infected necrotic collection
Freeny et al[112], 1998	9 (1-48)	34	100	12
Navalho et al[110], 2006	18	30	100	17
Mortelé et al[113], 2009	12 (2-33)	13	100	17
Baril et al[114], 2000	24 (18-30)a	7	100	0
Bala et al[115], 2009	26 (18-88)	8	100	13
Baudin et al[116], 2012	19.8 ± 15.7	48	100	29
Tong et al[101], 2012	PCD only = 30.74 ± 5.67; PCD + surgery = 27.80 ± 6.00	34	100	0 and 7
Pascual et al[117], 2013	28 ± 17	13	100	23
Wroński et al[102], 2013	PCD only = 33 (27-46); surgery = 35 (8-116)	18	100	0 and 17
Wang et al[118], 2016	11.7 ± 8.1	59	100	18.6
Infected or sterile necrotic collection
Lee et al[103], 2007	10 (1-58)a	23	12	4
Bruennler et al[119], 2008	3.5 (median 7)	80	65	23
van Santvoort et al[99], 2010	30 (11-71)a	43	91	19
Kumar et al[104], 2014	36.4 ± 7	12	67	8
Bellam et al[120], 2019	Median: 20 d	51	33.3	29.4
Gupta et al[121], 2020	Median: 22 d (range: 3–267 d)	146	47.9	20.5
Lu et al[105], 2020	15.26 ± 7.08	43	86	13.9
	50.86 ± 19.58	55	56.3	10.9
Sterile necrotic collection
Walser et al[122], 2006	NR	22	0	9.1

^aSome patients underwent endoscopic transluminal drainage.

IPN: Infectious pancreatic necrosis; NR: Not reported; PCD: Percutaneous catheter drainage.

Table 10 Outcome on endoscopic drainage of a pancreatic collection with various types of stents

Ref.	Collection	n	Success
Lee et al[124], 2014	WON and pseudocyst	PS = 25; FCMS = 25	PS: 90%; FCMS: 87%
Mukai et al[125], 2015	WON	PS = 27; BFMS = 43	PS: 90.6%; FCMS: 97.7%
Siddiqui et al[126], 2017	WON	PS = 106 FCMS = 121; LAMS = 86	PS: 81%; FCMS: 95%; LAMS: 90%
Bapaye et al[127], 2016	WON	PS = 61; BFMS = 72	PS: 73.7%; BFMS: 94.0%
Bang et al[123], 2019	WON	PS = 29; LAMS = 31	PS: 96.6%; LAMS: 93.5%
Muktesh et al[128], 2022	WON 108	PS = 45; BFMS = 53	PS: 81.8%; BFMS: 96.2%

BFMS: Biflanged metal stent; FCMS: Fully covered self-expandable metal stent; LAMS: Lumen-apposing metal stent; PS: Plastic stent; WON: Walled-off necrosis.