Antioxidant drugs to prevent post-endoscopic retrograde cholangiopancreatography pancreatitis: What does evidence suggest?

Table 1 Main characteristics of the randomized controlled trials included in this study

Ref.	No. of patients (antioxidant/placebo)	Patient characteristics	Antioxidant supplement	Intervention		Study design
				Antioxidant group	Control group
Wollschläger et al[34], 1999	40 (20/20)	Patients undergoing ERCP	Selenite	Selenite, IV, 1 mg bolus/2 × 1 mg infusion, l d before ERCP	Control, no prophylaxis	Randomized, controlled
Budzyńska et al[35], 2001	200 (99/101)	Patients undergoing elective ERCP	Allopurinol	Allopurinol, orally, 200 mg, 15 h and 3 h before ERCP	Placebo, orally, 200 mg, 15 and 3 h before ERCP	Randomized, placebo-controlled
Lavy et al[36], 2004	321 (141/180)	Patients undergoing ERCP	β-carotene	β-carotene, orally, 2 g, 12 h before ERCP	Placebo, orally, 2 g, 12 h before ERCP	Randomized, double-blind, placebo-controlled
Katsinelos et al[37], 2005	249 (124/125)	Patients undergoing diagnostic or therapeutic ERCP	NAC	NAC, IV, 70 mg/kg 2 h before, and 35 mg/kg at 4 h intervals for 24 h after ERCP	Placebo IV, 70 mg/kg 2 h before, and 35 mg/kg at 4 h intervals for 24 h after ERCP	Randomized, double-blind, placebo-controlled
Katsinelos et al[38], 2005	243 (125/118)	Patients undergoing diagnostic or therapeutic ERCP	Allopurinol	Allopurinol, orally, 600 mg, 15 and 3 h before ERCP	Placebo, orally, 600 mg, 15 and 3 h before ERCP	Randomized, double-blind, placebo-controlled
Mosler et al[39], 2005	701 (355/346)	Patients undergoing diagnostic or therapeutic ERCP	Allopurinol	Allopurinol, orally, 4 h (600 mg) and 1 h (300 mg) before ERCP	Placebo, orally, 4 h (600 mg) and 1 h (300 mg) before ERCP	Randomized, double-blind, placebo-controlled
Milewski et al[40], 2006	106 (55/51)	Patients undergoing ERCP	NAC	NAC, two doses of 600 mg orally 24 h and 12 h before ERCP, and 600 mg IV for 2 d after ERCP	Placebo IV, twice a day for 2 d after ERCP	Randomized, placebo-controlled
Kapetanos et al[41], 2007	320 (158/162)	Patients undergoing ERCP	Pentoxifylline	Pentoxifylline, orally, 400 mg, 1 d before ERCP (2 and 10 pm) until the night after ERCP (6 am, 2 and 10 pm)	No intervention	Randomized, controlled
Romagnuolo et al[42], 2008	586 (293/293)	Patients undergoing ERCP	Allopurinol	Allopurinol, orally, 300 mg, 1 h before ERCP	Placebo, orally, 300 mg, 1 h before ERCP	Randomized, double-blind, placebo-controlled
Martinez-Torres et al[43], 2009	170 (85/85)	Patients undergoing ERCP	Allopurinol	Allopurinol, orally, 300 mg, 15 and 3 h before ERCP	Placebo, orally, 300 mg, 15 and 3 h before ERCP	Randomized, placebo-controlled
Abbasinazari et al[44], 2011	74 (29/45)	Patients undergoing ERCP	Allopurinol	Allopurinol, orally, 300 mg, 15 and 3 h before ERCP	Placebo, orally, 300 mg, 15 and 3 h before ERCP	Randomized, double-blind, placebo-controlled
Alavi Nejad et al[45], 2013	100 (50/50)	Patients undergoing ERCP	NAC	NAC, 1200 mg with 150 mL water orally 2 h before ERCP	Placebo, orally 2 h before ERCP	Randomized, double-blind, placebo-controlled

ERCP: Endoscopic retrograde cholangiopancreatography; IV: Intravenously; NAC: N-acetylcysteine.

Table 2 Definition and severity of post-endoscopic retrograde cholangiopancreatography pancreatitis

Ref.	Definition of post-ERCP pancreatitis	Severity of post-ERCP pancreatitis
Wollschläger et al[34], 1999	Abdominal pain attributed to pancreatitis, in association with a serum lipase or amylase level ≥ 2 times the upper limit of normal	NA
Budzyńska et al[35], 2001	Abdominal pain attributed to pancreatitis, together with a need for an unplanned hospitalization or an extension of a planned hospitalization by at least 2 d, and a serum amylase level ≥ 3 times the upper limit of normal at 24 h after ERCP	Mild: symptoms lasting up to 3 d and pancreas normal on the CT scan. Moderate: requiring specific therapeutic measures for 4-10 d, Balthazar’s grade B/C on CT. Severe: local or systemic complications for more than 10 d, Balthazar’s grade D/F on CT, or death
Lavy et al[36], 2004	Abdominal pain attributed to pancreatitis, in association with an amylase level ≥ 3 times the upper limit of normal	Mild: requiring 2-3 d of hospitalization. Moderate: requiring 4-10 d of hospitalization. Severe: requiring 10 d of hospitalization or requiring surgical intervention or leading to death
Katsinelos et al[37], 2005	Abdominal pain attributed to pancreatitis, together with a need for an unplanned hospitalization or an extension of a planned hospitalization by at least 2 d, and a serum amylase level ≥ 3 times the upper limit of normal at 24 h after ERCP	Mild: symptoms persisting for 3 d and a normal appearance of the pancreas by US and/or CT. Moderate: requirement for specific therapeutic measures for 4-10 d (Balthazar’s grade B/C on CT). Severe: local or systemic complications for more than 10 d after ERCP (Balthazar’s grade D/F) or death
Katsinelos et al[38], 2005	Abdominal pain attributed to pancreatitis, together with a need for an unplanned hospitalization or an extension of a planned hospitalization by at least 2 d, and a serum amylase level ≥ 3 times above the upper limit of normal at 24 h after ERCP	Mild: symptoms persisting for 3 d and a normal appearance of the pancreas by US and/or CT. Moderate: requirement for specific therapeutic measures for 4-10 d (Balthazar’s grade B/C on CT). Severe: local or systemic complications for more than 10 d after ERCP (Balthazar’s grade D/F) or death
Mosler et al[39], 2005	New-onset or increased abdominal pain lasting for more than 24 h, causing the unplanned admission of an outpatient for more than one night or prolonging a planned admission of an inpatient, and associated with a serum amylase level ≥ 3 times the normal level, at approximately 18 h (the next morning) after ERCP	Mild: hospitalization lasting 2-3 d. Moderate: hospitalization lasting 4-10 d. Severe: hospitalization prolonged for more than 10 d or any of the following: hemorrhagic pancreatitis, pancreatic necrosis, pancreatic pseudocyst, or the need for percutaneous drainage or surgery
Milewski et al[40], 2006	Clinical features consistent with acute pancreatitis beginning after ERCP and lasting for at least 24 h, associated with a serum amylase level > 5 times the normal level	NA
Kapetanos et al[41], 2007	Abdominal pain attributed to pancreatitis, together with a need for an unplanned hospitalization or an extension of a planned hospitalization by at least 2 d, and a serum amylase level ≥ 3 times the upper limit of normal at 24 h after ERCP	Mild: clinical pancreatitis and serum amylase at least three times higher than normal at more than 24 h after ERCP, requiring admission or prolongation of planned admission for 2-3 d. Moderate: required hospitalization for 4-10 d. Severe: required hospitalization for more than 10 d, an intervention (percutaneous drainage or surgery), or diagnosis of a pseudocyst
Romagnuolo et al[42], 2008	Abdominal pain attributed to pancreatitis requiring medical attention, in association with a serum lipase or amylase level > 2 times the upper limit of normal	NA
Martinez-Torres et al[43], 2009	Serum amylase level above 600 IU/L or ≥ 3 times the normal value, and sharp pain irradiating to the back and nausea or vomiting	Mild: two or fewer signs from Ranson’s criteria. Moderate: three to six signs. Severe: more than six signs. The criteria were as follows. At admission: age, > 55 yr; WBC count, > 16000/mL; serum glucose level, > 11.1 mmol/L; SLDH/ALT, > 350 IU/L; AST level, > 250 IU/L. During initial 48 h: hematocrits, decrease of more than 0.10; BUN level, increase of more than 5 mg/dL; calcium, < 2 mmol/L; PaO2, < 60 mmHg; base deficit, > 4 mmol/L; fluid sequestration, > 6 L
Abbasinazari et al[44], 2011	NA	Mild: amylase concentration at least three times the upper limit of normal at more than 24 h after ERCP, requiring admission for 2-3 d. Moderate: admission for 4-10 d. Severe: admission for more than 10 d
Alavi Nejad et al[45], 2013	Serum amylase level > 275 U/mL or serum lipase level > 1000 U/mL with the presence of abdominal pain	The severity of pancreatitis based on the number of hospitalized days following ERCP. Mild: < 4 d. Moderate: 4-10 d. Severe: > 10 d

CT: Computed tomography; US: Ultrasound; ERCP: Endoscopic retrograde cholangiopancreatography; NA: Not available; AST: Aspartate aminotransferase; BUN: Blood urea nitrogen; SLDH/ALT: Serum lactate dehydrogenate to alanine aminotransferase ratio; WBC: White blood cell.

Table 3 Outcome data of the randomized controlled trials included in this study

Ref.	Antioxidant group					Control group
	No. of patients (n)	No. of PEP cases (n)	PEP stratified according toseverity			No. of patients (n)	No. of PEP cases (n)	PEP stratified according to severity
			Mild	Moderate	Severe			Mild	Moderate	Severe
Wollschläger et al[34], 1999	20	2	NA	NA	NA	20	3	NA	NA	NA
Budzyńska et al[35], 2001	99	12	9	2	1	101	8	5	3	0
Lavy et al[36], 2004	141	14	10	4	0	180	17	9	4	4
Katsinelos et al[37], 2005	124	15	8	7	0	125	12	7	5	0
Katsinelos et al[38], 2005	125	4	4	0	0	118	21	8	11	2
Mosler et al[39], 2005	355	46	28	16	2	346	42	24	16	2
Milewski et al[40], 2006	55	4	NA	NA	NA	51	6	NA	NA	NA
Kapetanos et al[41], 2007	158	9	6	1	2	162	5	4	0	1
Romagnuolo et al[42], 2008	293	16	8	6	2	293	12	4	6	2
Martinez-Torres et al[43], 2009	85	2	2	0	0	85	8	8	0	0
Abbasinazari et al[44], 2011	29	3	2	1	0	45	5	3	2	0
Alavi Nejad et al[45], 2013	50	5	NA	NA	NA	50	14	NA	NA	NA
Total	1534	132				1576	153

ERCP: Endoscopic retrograde cholangiopancreatography; PEP: Post-ERCP pancreatitis; NA: Not available.