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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Neostigmine | Experimental | Intramuscular injection of neostigmine on the basis of conventional conservative treatment |
|
| Conservative treatment | Other | Intragastric administration of paraffin oil, 50ml,once every 8 hoursï¼›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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Neostigmine Methylsulfate 1 MG/ML | Drug | 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. |
| 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 |
| 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 |
| 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 |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Nonghua Lv, MD | the Frist Affiliated Hospital of Nanchang University | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Affiliated Hospital of Nanchang University | Nanchang | Jiangxi | 330006 | China |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 23100216 | Background | 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. | |
| 18520642 |
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Acute pancreatitis patients with intra-abdominal hypertension were first treated with conventional non-surgical therapy(such as: Enteral decompression with nasogastric and rectal tube,Glycerin enema, percutaneous drainage of ascites) for 24 hours. After 24 hours, the intra-abdominal pressure was still above 12 mmHg and they were randomized.
Between Sept 1, 2015, and Aug 15, 2017, we measured intra-abdominal pressure on patients with acute pancreatitis and selected patients with intra-abdominal hypertension, in the Pancreatic Intensive Care Unit of the Department of Gastroenterology, the First Affiliated Hospital of Nanchang University.
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| ID | Title | Description |
|---|---|---|
| FG000 | Neostigmine | Intramuscular injection of neostigmine Neostigmine Methylsulfate 1 MG/ML: The initial dose was 1mg intramuscular injection, q12h. If there is no defecation after 12 hours, the dose is increased to 1mg intramuscular injection, Q8H; if there is no defecation after 24 hours, the dose is increased to 1mg intramuscular injection, Q6 H. If the abdominal pressure drops below 12mmhg, stop using the drug, otherwise, it will be used for 7 days. Conservative treatment recommended by the guidelines, such as maintain the negative balance of fluid after the early recovery of fluid to stabilize the circulation, and to take appropriate sedative and analgesic treatment; negative pressure of the nasogastric tube attracts the contents of the stomach, and the glycerin is enema through the anus to promote defecation.Patients with ascites underwent percutaneous drainage. |
| FG001 | The Traditional Treatment | Conservative treatment recommended by the guidelines, such as maintain the negative balance of fluid after the early recovery of fluid to stabilize the circulation, and to take appropriate sedative and analgesic treatment; negative pressure of the nasogastric tube attracts the contents of the stomach, and the glycerin is enema through the anus to promote defecation.Patients with ascites underwent percutaneous drainage. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
A total of 80 out of 186 patients were included
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| ID | Title | Description |
|---|---|---|
| BG000 | Neostigmine | Intramuscular injection of neostigmine on the basis of conventional conservative treatment Neostigmine Methylsulfate 1 MG/ML: The initial dose was 1mg intramuscular injection, q12h. If there is no defecation after 12 hours, the dose is increased to 1mg intramuscular injection, Q8H; if there is no defecation after 24 hours, the dose is increased to 1mg intramuscular injection, Q6 H. If the abdominal pressure drops below 12mmhg, stop using the drug, otherwise, it will be used for 7 days. Conservative treatment: Intragastric administration of paraffin oil, 50ml, Q8H, 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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 | The primary outcome measure was decreased rate of IAP after randomisation. | Posted | Median | Inter-Quartile Range | percent change of IAP | From randomization to 7 days after treatment,Measured IAP every 6 hours |
|
6 months
The main adverse events observed were the effects of neostigmine on the cardiovascular system, such as arrhythmias and decreased blood pressure
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Neostigmine | Intramuscular injection of neostigmine Neostigmine Methylsulfate 1 MG/ML: The initial dose was 1mg intramuscular injection, q12h. If there is no defecation after 12 hours, the dose is increased to 1mg intramuscular injection, Q8H; if there is no defecation after 24 hours, the dose is increased to 1mg intramuscular injection, Q6 H. If the abdominal pressure drops below 12mmhg, stop using the drug, otherwise, it will be used for 7 days. Conservative treatment recommended by the guidelines, such as maintain the negative balance of fluid after the early recovery of fluid to stabilize the circulation, and to take appropriate sedative and analgesic treatment; negative pressure of the nasogastric tube attracts the contents of the stomach, and the glycerin is enema through the anus to promote defecation.Patients with ascites underwent percutaneous drainage. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Single cardiovascular failure | Cardiac disorders | Systematic Assessment | Emerging cardiovascular failure after randomization, |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Wenhua He | First affilitated hospital of Nanchang university | +8613879182642 | hewenhua@ncu.edu.cn |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jun 2, 2015 | May 4, 2020 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D010195 | Pancreatitis |
| D059325 | Intra-Abdominal Hypertension |
| ID | Term |
|---|---|
| D010182 | Pancreatic Diseases |
| D004066 | Digestive System Diseases |
| D003161 | Compartment Syndromes |
| D009135 | Muscular Diseases |
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| ID | Term |
|---|---|
| D009388 | Neostigmine |
| D000072700 | Conservative Treatment |
| ID | Term |
|---|---|
| D050338 | Phenylammonium Compounds |
| D000644 | Quaternary Ammonium Compounds |
| D000588 | Amines |
| D009930 | Organic Chemicals |
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|
|
| Conservative treatment | Combination Product | Intragastric administration of paraffin oil, 50ml,once every 8 hoursï¼›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. |
|
|
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 |
| From randomisation to 6 months |
| Medical Expenses | Medical expenses within 6 months after randomisation | From randomisation to 6 months |
| 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. |
| 23476830 | Background | 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. |
| 12490958 | Background | Tracey KJ. The inflammatory reflex. Nature. 2002 Dec 19-26;420(6917):853-9. doi: 10.1038/nature01321. |
| 10839541 | Background | 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. |
| 24212240 | Background | 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. |
| 18026931 | Background | 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. |
| 23673399 | Background | 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. |
| 24921201 | Background | 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. |
| 25062870 | Background | 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. |
| 10403850 | Background | 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. |
| 35241135 | Derived | 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. |
| BG001 | Conservative Treatment | Intragastric administration of paraffin oil, 50ml, Q8H, 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. |
| BG002 | Total | Total of all reporting groups |
| yeas |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| Cause of pancreatitis | Count of Participants | Participants |
|
| OG001 | Conservative Treatment | Intragastric administration of paraffin oil, 50ml, Q8H, 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. Conservative treatment: Intragastric administration of paraffin oil, 50ml, Q8H, 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. |
|
|
| Secondary | 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. | Posted | Median | Inter-Quartile Range | ml/day | From randomization to 7 days |
|
|
|
| Secondary | 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 | Posted | Count of Participants | Participants | From randomization to discharge or death, assessed up to 4 weeks |
|
|
|
| Secondary | New-onset Organ Failure | Incidence of organ failure from randomization to discharge or death, assessed up to 3 months | Posted | Count of Participants | Participants | From randomization to discharge or death, assessed up to 3 months |
|
|
|
| Secondary | Death of 90 Days | Death during from randomization to 90 days after onset. | Posted | Count of Participants | Participants | From randomization to 90 days after onset. |
|
|
|
| Secondary | Timing of Enteral Nutrition | From date of randomization to enteral nutrition, assessed up to 30 days | Posted | Median | Inter-Quartile Range | days | Start time of enteral nutrition after randomization, assessed up to 30 days |
|
|
|
| Secondary | Number of Participants With Deterioration of IAH | IAP rebound ≥ 5mmHg or increase ≥ 20mmHg within 1-7 days after grouping | Posted | Count of Participants | Participants | From randomization to 7 days |
|
|
|
| Secondary | 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 | Posted | Count of Participants | Participants | From randomization to 7 days |
|
|
|
| Other Pre-specified | Days in Hospital | Days in hospital within 6 months after randomisation | Posted | Median | Inter-Quartile Range | days | From randomisation to 6 months |
|
|
|
| Other Pre-specified | Days in ICU | Days in ICU within 6 months after randomisation | Posted | Median | Inter-Quartile Range | days | From randomisation to 6 months |
|
|
|
| Other Pre-specified | Medical Expenses | Medical expenses within 6 months after randomisation | Posted | Median | Inter-Quartile Range | thousand(RMB) | From randomisation to 6 months |
|
|
|
| 10 |
| 40 |
| 8 |
| 40 |
| 0 |
| 40 |
| EG001 | The Traditional Treatment | Conservative treatment recommended by the guidelines, such as maintain the negative balance of fluid after the early recovery of fluid to stabilize the circulation, and to take appropriate sedative and analgesic treatment; negative pressure of the nasogastric tube attracts the contents of the stomach, and the glycerin is enema through the anus to promote defecation.Patients with ascites underwent percutaneous drainage. | 11 | 40 | 4 | 40 | 0 | 40 |
|
| Cardiovascular and respiratory failure | Cardiac disorders | Systematic Assessment | Patient has both cardiovascular and respiratory failure |
|
| Cardiovascular and renal failure | Cardiac disorders | Systematic Assessment | The patient has both cardiovascular and renal failure |
|
| Cardiovascular, respiratory and renal failure | Cardiac disorders | Systematic Assessment | The patient has both cardiovascular, respiratory and renal failure |
|
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| D009140 |
| Musculoskeletal Diseases |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D009861 |
| Onium Compounds |
| D013812 | Therapeutics |