Randomized controlled trial: neostigmine for intra-abdominal hypertension in acute pancreatitis

Wenhua He, Peng Chen, Yupeng Lei, Liang Xia, Pi Liu, Yong Zhu, Hao Zeng, Yao Wu, Huajing Ke, Xin Huang, Wenhao Cai, Xin Sun, Wei Huang, Robert Sutton, Yin Zhu, Nonghua Lu, Wenhua He, Peng Chen, Yupeng Lei, Liang Xia, Pi Liu, Yong Zhu, Hao Zeng, Yao Wu, Huajing Ke, Xin Huang, Wenhao Cai, Xin Sun, Wei Huang, Robert Sutton, Yin Zhu, Nonghua Lu

Abstract

Background: Intra-abdominal hypertension (IAH) in acute pancreatitis (AP) is associated with deterioration in organ function. This trial aimed to assess the efficacy of neostigmine for IAH in patients with AP.

Methods: In this single-center, randomized trial, consenting patients with IAH within 2 weeks of AP onset received conventional treatment for 24 h. Patients with sustained intra-abdominal pressure (IAP) ≥ 12 mmHg were randomized to receive intramuscular neostigmine (1 mg every 12 h increased to every 8 h or every 6 h, depending on response) or continue conventional treatment for 7 days. The primary outcome was the percent change of IAP at 24 h after randomization.

Results: A total of 80 patients were recruited to neostigmine (n = 40) or conventional treatment (n = 40). There was no significant difference in baseline parameters. The rate of decrease in IAP was significantly faster in the neostigmine group compared to the conventional group by 24 h (median with 25th-75th percentile: -18.7% [- 28.4 to - 4.7%] vs. - 5.4% [- 18.0% to 0], P = 0.017). This effect was more pronounced in patients with baseline IAP ≥ 15 mmHg (P = 0.018). Per-protocol analysis confirmed these results (P = 0.03). Stool volume was consistently higher in the neostigmine group during the 7-day observational period (all P < 0.05). Other secondary outcomes were not significantly different between neostigmine and conventional treatment groups.

Conclusion: Neostigmine reduced IAP and promoted defecation in patients with AP and IAH. These results warrant a larger, placebo-controlled, double-blind phase III trial. Trial registration Clinical Trial No: NCT02543658 (registered August /27, 2015).

Keywords: Acute compartment syndrome; Acute pancreatitis; Intra-abdominal hypertension; Neostigmine.

Conflict of interest statement

Robert Sutton has received research support and/or funding from Calcimedica, Cypralis, GlaxoSmithKline, MSD/Merck, and Novartis, has been a consultant for AbbVie, Calcimedica, Cypralis, Eagle Pharmaceuticals, Novartis, and Takeda (all funds to the University of Liverpool), and is collaborating in the IMI2 TransBioLine project with multiple public and private institutions including Janssen, Lilly, MSD/Merck, Novartis, Pfizer, Roche, and Sanofi-Aventis. The other authors declare no conflicts of interest.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Study flowchart. AP, acute pancreatitis; IAH, intra-abdominal hypertension
Fig. 2
Fig. 2
Intention-to-treat plots of increased stool volumes (mL/24 h minus baseline 24 h stool volume before randomization). *P < 0.05, **P < 0.01, ***P < 0.001)

References

    1. Mederos MA, Reber HA, Girgis MD. Acute pancreatitis: a review. JAMA. 2021;325:382–390. doi: 10.1001/jama.2020.20317.
    1. Guo Q, Li A, Xia Q, et al. The role of organ failure and infection in necrotizing pancreatitis: a prospective study. Ann Surg. 2014;259:1201–1207. doi: 10.1097/SLA.0000000000000264.
    1. Schepers NJ, Bakker OJ, Besselink MG, et al. Impact of characteristics of organ failure and infected necrosis on mortality in necrotising pancreatitis. Gut. 2019;68:1044–1051. doi: 10.1136/gutjnl-2017-314657.
    1. Garg PK, Singh VP. Organ failure due to systemic injury in acute pancreatitis. Gastroenterology. 2019;156:2008–2023. doi: 10.1053/j.gastro.2018.12.041.
    1. Shi N, Liu T, de la Iglesia-Garcia D, et al. Duration of organ failure impacts mortality in acute pancreatitis. Gut. 2020;69:604–605. doi: 10.1136/gutjnl-2019-318241.
    1. Kirkpatrick AW, Roberts DJ, De Waele J, et al. Intra-abdominal hypertension and the abdominal compartment syndrome: updated consensus definitions and clinical practice guidelines from the World Society of the Abdominal Compartment Syndrome. Intensive Care Med. 2013;39:1190–1206. doi: 10.1007/s00134-013-2906-z.
    1. Trikudanathan G, Vege SS. Current concepts of the role of abdominal compartment syndrome in acute pancreatitis: an opportunity or merely an epiphenomenon. Pancreatology. 2014;14:238–243. doi: 10.1016/j.pan.2014.06.002.
    1. Aitken EL, Gough V, Jones A, et al. Observational study of intra-abdominal pressure monitoring in acute pancreatitis. Surgery. 2014;155:910–918. doi: 10.1016/j.surg.2013.12.028.
    1. van Brunschot S, Schut AJ, Bouwense SA, et al. Abdominal compartment syndrome in acute pancreatitis: a systematic review. Pancreas. 2014;43:665–674. doi: 10.1097/MPA.0000000000000108.
    1. Ponec RJ, Saunders MD, Kimmey MB. Neostigmine for the treatment of acute colonic pseudo-obstruction. N Engl J Med. 1999;341:137–141. doi: 10.1056/NEJM199907153410301.
    1. Amaro R, Rogers AI. Neostigmine infusion: new standard of care for acute colonic pseudo-obstruction? Am J Gastroenterol. 2000;95:304–305.
    1. Loftus CG, Harewood GC, Baron TH. Assessment of predictors of response to neostigmine for acute colonic pseudo-obstruction. Am J Gastroenterol. 2002;97:3118–3122. doi: 10.1111/j.1572-0241.2002.07108.x.
    1. Korsten MA, Rosman AS, Ng A, et al. Infusion of neostigmine-glycopyrrolate for bowel evacuation in persons with spinal cord injury. Am J Gastroenterol. 2005;100:1560–1565. doi: 10.1111/j.1572-0241.2005.41587.x.
    1. Mehta R, John A, Nair P, et al. Factors predicting successful outcome following neostigmine therapy in acute colonic pseudo-obstruction: a prospective study. J Gastroenterol Hepatol. 2006;21:459–461. doi: 10.1111/j.1440-1746.2005.03994.x.
    1. Lu X, Xiao W, Kang X, et al. The effect of Chinese herbal medicine on non-biliogenic severe acute pancreatitis: a systematic review and meta-analysis. J Ethnopharmacol. 2014;155:21–29. doi: 10.1016/j.jep.2014.05.040.
    1. Qiong W, Yiping W, Jinlin Y, et al. Chinese medicinal herbs for acute pancreatitis. Cochrane Database Syst Rev. 2005;2005(1):CD003631. doi: 10.1002/14651858.CD003631.pub2.
    1. Sun JK, Li WQ, Ke L, et al. Early enteral nutrition prevents intra-abdominal hypertension and reduces the severity of severe acute pancreatitis compared with delayed enteral nutrition: a prospective pilot study. World J Surg. 2013;37:2053–2060. doi: 10.1007/s00268-013-2087-5.
    1. Mirtallo JM, Forbes A, McClave SA, et al. International consensus guidelines for nutrition therapy in pancreatitis. JPEN J Parenter Enteral Nutr. 2012;36:284–291. doi: 10.1177/0148607112440823.
    1. Pedersen SB, Langsted A, Nordestgaard BG. Nonfasting mild-to-moderate hypertriglyceridemia and risk of acute pancreatitis. JAMA Intern Med. 2016;176:1834–1842. doi: 10.1001/jamainternmed.2016.6875.
    1. Nawaz H, Koutroumpakis E, Easler J, et al. Elevated serum triglycerides are independently associated with persistent organ failure in acute pancreatitis. Am J Gastroenterol. 2015;110:1497–1503. doi: 10.1038/ajg.2015.261.
    1. Adiamah A, Psaltis E, Crook M, et al. A systematic review of the epidemiology, pathophysiology and current management of hyperlipidaemic pancreatitis. Clin Nutr. 2018;37:1810–1822. doi: 10.1016/j.clnu.2017.09.028.
    1. De Laet IE, Malbrain M, De Waele JJ. A clinician's guide to management of intra-abdominal hypertension and abdominal compartment syndrome in critically Ill patients. Crit Care. 2020;24(1):97. doi: 10.1186/s13054-020-2782-1.
    1. Al-Bahrani AZ, Abid GH, Holt A, et al. Clinical relevance of intra-abdominal hypertension in patients with severe acute pancreatitis. Pancreas. 2008;36:39–43. doi: 10.1097/mpa.0b013e318149f5bf.
    1. Bhandari V, Jaipuria J, Singh M, et al. Intra-abdominal pressure in the early phase of severe acute pancreatitis: canary in a coal mine? Results from a rigorous validation protocol. Gut Liver. 2013;7:731–738. doi: 10.5009/gnl.2013.7.6.731.
    1. Crockett SD, Wani S, Gardner TB, et al. American Gastroenterological Association Institute guideline on initial management of acute pancreatitis. Gastroenterology. 2018;154:1096–1110. doi: 10.1053/j.gastro.2018.01.032.
    1. Arvanitakis M, Ockenga J, Bezmarevic M, et al. ESPEN guideline on clinical nutrition in acute and chronic pancreatitis. Clin Nutr. 2020;39:612–631. doi: 10.1016/j.clnu.2020.01.004.
    1. Reintam Blaser A, Starkopf J, Alhazzani W, et al. Early enteral nutrition in critically ill patients: ESICM clinical practice guidelines. Intensive Care Med. 2017;43:380–398. doi: 10.1007/s00134-016-4665-0.
    1. Vaknine S, Soreq H. Central and peripheral anti-inflammatory effects of acetylcholinesterase inhibitors. Neuropharmacology. 2020;168:108020. doi: 10.1016/j.neuropharm.2020.108020.
    1. Brinkman DJ, Ten Hove AS, Vervoordeldonk MJ, et al. Neuroimmune interactions in the gut and their significance for intestinal immunity. Cells. 2019;8(7):670. doi: 10.3390/cells8070670.
    1. van Westerloo DJ, Giebelen IA, Florquin S, et al. The vagus nerve and nicotinic receptors modulate experimental pancreatitis severity in mice. Gastroenterology. 2006;130:1822–1830. doi: 10.1053/j.gastro.2006.02.022.
    1. Zhang R, Deng L, Jin T, et al. Hypertriglyceridaemia-associated acute pancreatitis: diagnosis and impact on severity. HPB (Oxford) 2019;21:1240–1249. doi: 10.1016/j.hpb.2019.01.015.
    1. Ding Y, Zhang M, Wang L, et al. Association of the hypertriglyceridemic waist phenotype and severity of acute pancreatitis. Lipids Health Dis. 2019;18:93. doi: 10.1186/s12944-019-1019-2.
    1. Zheng X, Li L, Zhu Y, et al. Superoxide dismutase predicts persistent circulation failure and mortality in the early stage of acute pancreatitis. Dig Dis Sci. 2020;65:3551–3557. doi: 10.1007/s10620-020-06069-w.
    1. Wan J, He W, Zhu Y, et al. Stratified analysis and clinical significance of elevated serum triglyceride levels in early acute pancreatitis: a retrospective study. Lipids Health Dis. 2017;16:124. doi: 10.1186/s12944-017-0517-3.
    1. Pascual I, Sanahuja A, Garcia N, et al. Association of elevated serum triglyceride levels with a more severe course of acute pancreatitis: cohort analysis of 1457 patients. Pancreatology. 2019;19:623–629. doi: 10.1016/j.pan.2019.06.006.
    1. Wan MH, Li J, Huang W, et al. Modified Da-Cheng-Qi decoction reduces intra-abdominal hypertension in severe acute pancreatitis: a pilot study. Chin Med J (Engl) 2012;125:1941–1944.
    1. Chen X, Yang K, Jing G, et al. Meta-analysis of efficacy of rhubarb combined with early enteral nutrition for the treatment of severe acute pancreatitis. JPEN J Parenter Enteral Nutr. 2020;44:1066–1078. doi: 10.1002/jpen.1789.
    1. Mao EQ, Tang YQ, Fei J, et al. Fluid therapy for severe acute pancreatitis in acute response stage. Chin Med J (Engl) 2009;122:169–173.

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