Neostigmine Treatment of Acute Pancreatitis Combined With Intra-abdominal Hypertension

The Curative Effect and Security of Neostigmine Treatment of Acute Pancreatitis Combined With Intra-abdominal Hypertension

Acute pancreatitis(A) often complicated with Intra-abdominal Hypertension. After the onset of acute pancreatitis, capillary leakage causing ascites,upper gastrointestinal tract obstruction and paralytic ileus leading to an elevated IAP, severe IAH leads to ACS with high mortality. Neostigmine is an anti-cholinesterase drugs, can enhance intestinal peristalsis, promote flatus defecation. The aim of this study was to determine the effect of neostigmine on reducing abdominal pressure and clinical prognosis in patients with AP by promoting intestinal peristalsis and defecation.

Study Overview

• Status: Completed
• Conditions: Acute Pancreatitis; Intra-abdominal Hypertension
• Intervention / Treatment: Drug: Neostigmine Methylsulfate 1 MG/ML; Combination product: Conservative treatment

Detailed Description

Acute pancreatitis(AP) runs a severe course in around 20% of patients and is associated with a mortality up to 30%. Intra-abdominal hypertension(IAH）is a common complication of severe acute pancreatitis(SAP). The inflammation of the pancreas starts a cascade of pancreatic and visceral edema, acute peripancreatic fluid collections, capillary leakage causing ascites, paralytic ileus, and gastric dilatation by upper gastrointestinal tract obstruction leading to an elevated intra-abdominal pressure (IAP). A sustained or repeated pathological elevation in IAP ≥12 mmHg is defined as IAH, it generally occurs often within the first week after onset of SAP. Persistent and serious IAH (IAP >20 mmHg ) often leads to new onset organ failure or acute worsening of existing organ failure, which is defined as ACS and associated with a mortality rate of 49%.

In the past practice, many patients with ACS undergo decompressive laparotomy, which obviously has a risk of complications. Therefore, numerous medical, nonmedical, and minimally invasive therapies have been introduced. Neostigmine is an anti-cholinesterase drugs, can enhance intestinal peristalsis, promote flatus defecation. World Society for Abdominal Compartment Syndrome (WSACS)guidelines,suggest that neostigmine be used for the treatment of established colonic ileus not responding to other simple measures and associated with IAH.However, no data exist on the effects of pharmacologic promotility therapy on IAP or outcomes among those with IAH/ACS. The aim of this study was to evaluate the efficacy of neostigmine on reducing IAP in AP patients with IAH.

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Jiangxi
    • Nanchang, Jiangxi, China, 330006
      • Affiliated Hospital of Nanchang University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 66 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age 18-70 year ;
2. The diagnosis of acute pancreatitis according to the revised Atlanta classification.
3. IAH is defined as IAP ≥ 12 mmHg by the World Society of Abdominal;Compartment Syndrome (WSACS);
4. After 24 hours of conventional treatment(such as gastrointestinal decompression or percutaneous drainage of ascites), the IAP of AP patients with IAH was still ≥ 12 mmHg;
5. The onset time of acute pancreatitis was within 2 weeks;
6. Signed the informed consent.

Exclusion Criteria:

1. Previous history of laparotomy;
2. Mechanical ileus or abdominal hemorrhage were considered clinically;
3. Those who have contraindications to neostigmine: 1) Patients with angina; 2) myocardial infarction; 3) ventricular tachycardia; 4) bradycardia; 5) acute circulatory failure; 6) epilepsy; 7) bronchial asthma; 8) mechanical intestinal obstruction; 9) urinary tract infarction; 10) hyperthyroidism; 11) serious arrhythmia; 12) bladder operation; 13) intestinal fistula;
4. Allergic to neostigmine;
5. Pregnant or lactating patients.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Neostigmine; Intramuscular injection of neostigmine on the basis of conventional conservative treatment	Drug: Neostigmine Methylsulfate 1 MG/ML; The initial dose was 1mg, intramuscular injection(IM) once every 12 hours. If there is no defecation after 12 hours, the dose is increased to 1mg IM once every 8 hours; if there is no defecation after 24 hours, the dose is increased to 1mg IM once every 6 hours. If the abdominal pressure drops below 12mmhg, neostigmine will be stopped, otherwise it will be used continuously for 7 days.; Other Names: Prostigmin; Combination product: Conservative treatment; Intragastric administration of paraffin oil, 50ml,once every 8 hours；gastrointestinal decompression with nasogastric tube and rectal tub; lycerin enema promotes defecation; patients with ascites undergo percutaneous puncture drainage. Other conservative medical treatment recommended by the guidelines.; Other Names: Non-surgical treatment
Other: Conservative treatment; Intragastric administration of paraffin oil, 50ml,once every 8 hours；gastrointestinal decompression with nasogastric tube and rectal tub; lycerin enema promotes defecation; patients with ascites undergo percutaneous puncture drainage. Other conservative medical treatment recommended by the guidelines.	Combination product: Conservative treatment; Intragastric administration of paraffin oil, 50ml,once every 8 hours；gastrointestinal decompression with nasogastric tube and rectal tub; lycerin enema promotes defecation; patients with ascites undergo percutaneous puncture drainage. Other conservative medical treatment recommended by the guidelines.; Other Names: Non-surgical treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change of IAP After Treatment	Monitor the intra-abdominal pressure within 1 to 7 days after randomization, and calculate the percent change compared with that before randomization	From randomization to 7 days after treatment,Measured IAP every 6 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Change of Stool Volume at 1-7 Days After Randomization	After randomization, the change of stool volume (ML) was calculated every 24 hours.For example, the amount of stool volume decreased or increased in 24 hours after grouping compared to before grouping.	From randomization to 7 days
New-onset Abdominal Compartment Syndrom	Abdominal compartment syndrome is defined as a sustained IAP>20 mmHg (with or without an APP<60 mmHg) that is associated with new organ dysfunction/failure	From randomization to discharge or death, assessed up to 4 weeks
New-onset Organ Failure	Incidence of organ failure from randomization to discharge or death, assessed up to 3 months	From randomization to discharge or death, assessed up to 3 months
Death of 90 Days	Death during from randomization to 90 days after onset.	From randomization to 90 days after onset.
Timing of Enteral Nutrition	From date of randomization to enteral nutrition, assessed up to 30 days	Start time of enteral nutrition after randomization, assessed up to 30 days
Number of Participants With Deterioration of IAH	IAP rebound ≥ 5mmHg or increase ≥ 20mmHg within 1-7 days after grouping	From randomization to 7 days
Number of Participants With Adverse Effects on the Cardiovascular System	Due to that neostigmine has an inhibitory effect on the cardiovascular system, new-onset cardiovascular failure after grouping is considered as a possible adverse event related to neostigmine.Cardiovascular failure was defined as circulatory systolic blood pressure <90 mm Hg, despite adequate fluid resuscitation, or need for inotropic catecholamine support	From randomization to 7 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Days in Hospital	Days in hospital within 6 months after randomisation	From randomisation to 6 months
Days in ICU	Days in ICU within 6 months after randomisation	From randomisation to 6 months
Medical Expenses	Medical expenses within 6 months after randomisation	From randomisation to 6 months

Collaborators and Investigators

• Sponsor: The First Affiliated Hospital of Nanchang University
• Investigators: Study Chair: Nonghua Lv, MD, The Frist Affiliated Hospital of Nanchang University

Publications and helpful links

General Publications

• Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, Wang H, Abumrad N, Eaton JW, Tracey KJ. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000 May 25;405(6785):458-62. doi: 10.1038/35013070.
• Ponec RJ, Saunders MD, Kimmey MB. Neostigmine for the treatment of acute colonic pseudo-obstruction. N Engl J Med. 1999 Jul 15;341(3):137-41. doi: 10.1056/NEJM199907153410301.
• Banks PA, Bollen TL, Dervenis C, Gooszen HG, Johnson CD, Sarr MG, Tsiotos GG, Vege SS; Acute Pancreatitis Classification Working Group. Classification of acute pancreatitis--2012: revision of the Atlanta classification and definitions by international consensus. Gut. 2013 Jan;62(1):102-11. doi: 10.1136/gutjnl-2012-302779. Epub 2012 Oct 25.
• Vidal MG, Ruiz Weisser J, Gonzalez F, Toro MA, Loudet C, Balasini C, Canales H, Reina R, Estenssoro E. Incidence and clinical effects of intra-abdominal hypertension in critically ill patients. Crit Care Med. 2008 Jun;36(6):1823-31. doi: 10.1097/CCM.0b013e31817c7a4d.
• Kasi PM. The use of intravenous neostigmine in palliation of severe ileus. Case Rep Gastrointest Med. 2013;2013:796739. doi: 10.1155/2013/796739. Epub 2013 Feb 14.
• Tracey KJ. The inflammatory reflex. Nature. 2002 Dec 19-26;420(6917):853-9. doi: 10.1038/nature01321.
• Schneider L, Jabrailova B, Soliman H, Hofer S, Strobel O, Hackert T, Buchler MW, Werner J. Pharmacological cholinergic stimulation as a therapeutic tool in experimental necrotizing pancreatitis. Pancreas. 2014 Jan;43(1):41-6. doi: 10.1097/MPA.0b013e3182a85c21.
• Shaikh N, Kettern MA, Hanssens Y, Elshafie SS, Louon A. A rare and unsuspected complication of Clostridium difficile infection. Intensive Care Med. 2008 May;34(5):963-6. doi: 10.1007/s00134-007-0922-6. Epub 2007 Nov 20.
• Kirkpatrick AW, Roberts DJ, De Waele J, Jaeschke R, Malbrain ML, De Keulenaer B, Duchesne J, Bjorck M, Leppaniemi A, Ejike JC, Sugrue M, Cheatham M, Ivatury R, Ball CG, Reintam Blaser A, Regli A, Balogh ZJ, D'Amours S, Debergh D, Kaplan M, Kimball E, Olvera C; Pediatric Guidelines Sub-Committee for the World Society of the Abdominal Compartment Syndrome. 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 Jul;39(7):1190-206. doi: 10.1007/s00134-013-2906-z. Epub 2013 May 15.
• van Brunschot S, Schut AJ, Bouwense SA, Besselink MG, Bakker OJ, van Goor H, Hofker S, Gooszen HG, Boermeester MA, van Santvoort HC; Dutch Pancreatitis Study Group. Abdominal compartment syndrome in acute pancreatitis: a systematic review. Pancreas. 2014 Jul;43(5):665-74. doi: 10.1097/MPA.0000000000000108.
• Trikudanathan G, Vege SS. Current concepts of the role of abdominal compartment syndrome in acute pancreatitis - an opportunity or merely an epiphenomenon. Pancreatology. 2014 Jul-Aug;14(4):238-43. doi: 10.1016/j.pan.2014.06.002. Epub 2014 Jun 17.
• He W, Chen P, Lei Y, Xia L, Liu P, Zhu Y, Zeng H, Wu Y, Ke H, Huang X, Cai W, Sun X, Huang W, Sutton R, Zhu Y, Lu N. Randomized controlled trial: neostigmine for intra-abdominal hypertension in acute pancreatitis. Crit Care. 2022 Mar 3;26(1):52. doi: 10.1186/s13054-022-03922-4.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2015
• Primary Completion (Actual): August 15, 2017
• Study Completion (Actual): May 30, 2018

Study Registration Dates

• First Submitted: August 27, 2015
• First Submitted That Met QC Criteria: September 4, 2015
• First Posted (Estimate): September 7, 2015

Study Record Updates

• Last Update Posted (Actual): October 5, 2021
• Last Update Submitted That Met QC Criteria: October 2, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: Acute Pancreatitis; Neostigmine; Intra-abdominal hypertension; Security; Abdominal compartment syndrome; Curative Effect
• Additional Relevant MeSH Terms: Digestive System Diseases; Cardiovascular Diseases; Vascular Diseases; Musculoskeletal Diseases; Muscular Diseases; Pancreatic Diseases; Compartment Syndromes; Hypertension; Pancreatitis; Intra-Abdominal Hypertension; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Agents; Enzyme Inhibitors; Cholinesterase Inhibitors; Parasympathomimetics; Neostigmine
• Other Study ID Numbers: FAHONCU

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No