Clinical trial NCT02543658
Conditions: Acute Pancreatitis Intra-abdominal Hypertension
Keywords: Acute Pancreatitis Intra-abdominal hypertension Abdominal compartment syndrome Curative Effect Security Neostigmine
Sponsor: The First Affiliated Hospital of Nanchang University
Start date: 2015-09-01; Completion date: 2018-05-30
Enrollment: 80 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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.

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.

Arms: arm 1: Intramuscular injection of neostigmine on the basis of conventional conservative treatment arm 2: 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.
Interventions: intervention 1: Neostigmine Methylsulfate 1 MG/ML intervention 2: Conservative treatment
Intervention descriptions: intervention 1: 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. intervention 2: 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.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Board Name: Ethics Committee of the Frist Affiliated Hospital of Nanchang University  
Phone: 0791-88691867   Ext: yfykjk@126.com     
 
 
Neostigmine Treatment of Acute Pancreatitis Combined 
With Intra-abdominal Hypertension：A prospective, 
randomized, controlled trial 
NCT02543658 
 
 Approval Number: （2015）NO.011 
2015/6/2 


Introduction 
Acute pancreatitis (AP) is a common disease of digestive system, severe acute 
pancreatitis(SAP) with persistent organ failure is associated with an increased risk of 
death1. Intra-abdominal hypertension (IAH) is defined as persistent increase of 
intra-abdominal pressure (IAP) > 12 mm, according to the World Society for 
Abdominal Compartment Syndrome (WSACS)2 . IAH was considered as an early 
factor in the pathogenesis of SAP3. In a prospective study, IAH was diagnosed in 17% 
of patients with AP(most on admission), with a mortality rate of 37%4. This 
inflammation starts a cascade of pancreatic and visceral edema, acute peripancreatic 
fluid collections, capillary leakage causing ascites, paralytic ileus, and gastric 
dilatation leading to an elevated IAP5. 
When the intra-abdominal pressure (IAP) continues to rise above 20 mmHg, it 
may lead to new organ failure or acute deterioration of existing organ failure, 
this is called abdominal compartment syndrome (ACS) 2. ACS develops in AP is 
associated with a mortality rate of 49%5. Although surgical decompression results in 
prompt recovery from ACS, it has substantial morbidity associated with the 
management and complications of open abdomen. This includes infected pancreatic 
necrosis, intra-abdominal bleeding, development of post-operative fistulas and 
hernias5.  
Currently, non-operative strategies to counter IAH in AP should be considered 
initially, include sedation and analgesia, neuromuscular blockade, body positioning, 
nasogastric/ colonic decompression, promotility agents, diuretics and continuous renal 
replacement therapies, fluid resuscitation strategies, percutaneous catheter drainage 
(PCD)2, 3. Neostigmine is an anti-cholinesterase drugs, can enhance intestinal 
peristalsis, promote flatus defecation. Studies have reported that treatment with 
neostigmine may be effective at inducing colonic decompression among those with 
colonic pseudo-obstruction 6.WSACS suggest that neostigmine be used for the 
treatment of established colonic ileus not responding to other simple measures and 
associated with IAH2. However, no data exist on the effects of pharmacologic 
promotility therapy on IAP or outcomes among those with IAH/ACS2. The aim of this 
study was to evaluate the efficacy  of neostigmine on reducing IAP in AP patients 
with IAH. 
Methods 
Design: This is a single-center, two-armed, parallel group, superiority, 
randomized controlled clinical trial. AP patients with IAH (IAP ≥ 12 mmHg) received 
conservative treatment (gastrointestinal decompression, percutaneous catheter 
drainage of ascites and etc.), if IAP is still ≥ 12 mmHg after 24 hours were 
randomised into interventional group (intramuscular neostigmine bid to qid for 7 days) 
and conventional group (continuing conservative treatment).  


Trial organization, committees and boards 
The designer of the trial is the first affiliated hospital of Nanchang University, 
China（http://www.cdyfy.com/）. The study protocol was approved by the Ethics 
Committee of the First Affiliated Hospital of Nanchang University on the April 20th, 
2015 ( approval No. 2015 [003]). The study is performed in accordance with the 
declaration of Helsinki.  An independent data safety and monitoring committee 
(DSMC) will evaluate the progress of the trial and examine the safety variables at 
regular intervals. All physicians involved in the study will repetitively be asked to 
report any potential adverse events. All possible adverse events will be listed and 
discussed with the DSMS, and reported to the Ethics Committee of the First Affiliated 
Hospital of Nanchang University. Informed consent will be obtained from each 
participating patient in oral and written form prior to randomisation. If a patient is 
unable to sign by himself/herself, his / her family member will be authorized to sign 
it. 
Study population  
AP patients with IAH (IAP ≥ 12 mmHg) with IAH assessed for eligibility, if IAP 
is still ≥ 12 mmHg after received conservative treatment (gastrointestinal 
decompression, percutaneous catheter drainage of ascites and etc.) for 24 hours, 
participants will be signed informed consent and randomized into two groups if they 
meet all the inclusion criteria and no exclusion criteria.  
Inclusion criteria  
The inclusion criteria are: 
1) 
Age 18-70 year ; 
2) 
The diagnosis of acute pancreatitis according to the revised Atlanta 
classification: (a) upper abdominal pain; (b) serum amylase or lipase >3x 
upper limit of normal range; (c) characteristic findings on pancreatic imaging; 
3) 
IAH is defined is defined by the World Society of Abdominal 
Compartment Syndrome (WSACS): ≥ 12 mmHg 
4) 
After 24 hours of conventional treatment such as gastrointestinal 
decompression or percutaneous drainage of ascites, the IAP was still ≥ 12 
mmHg; 
5) 
The onset time of acute pancreatitis was within 2 weeks. 
6) 
 Signed the informed consent. 
Exclusion criteria 
 The exclusion criteria are: 
1) History of laparotomy;  
(2) Mechanical ileus or abdominal hemorrhage were considered clinically;  


(3) Those who have contraindications to neostigmine: patients with angina, 
myocardial infarction, ventricular tachycardia, bradycardia, acute circulatory failure, 
epilepsy, bronchial asthma, mechanical intestinal obstruction, urinary tract infarction, 
hyperthyroidism, serious arrhythmia, bladder operation, intestinal fistula, etc; 
 (4) Allergic to neostigmine;  
(5) Pregnant or lactating patients. 
Sample size  
This study is a superior efficacy trial, hypothesizing a reduction in the primary 
endpoint in favour of the neostigmine treatment. The sample size was calculated 
based on our previous clinical observation data, that the decrease rate of IAP was 30% 
after treatment with neostigmine for 24 hours, and 5% in conventional treatment at 24 
hours. Therefore, an absolute reduction in primary endpoint of 25% is anticipated. 
With a two-sided confidence level of 95% and 80%,With a 2-sided 5% alpha, power 
of 80%, and 10% loss to follow-up, the sample size was set at 40 cases per group, a 
total of 80 cases  
Diagnosis of IAH and time of randomization  
We measure IAP every 6 h for all AP patients in the pancreatic intensive care unit. 
IAP is measured indirectly (using intravesicular pressure as measured through a 
bladder catheter) 2 . Based on IAP, IAH is graded as follows; Grade 1 wherein IAP 
ranges between 12 and 15 mmHg, Grade 2 wherein IAP ranges between 16 and 
20 mmHg, Grade 3 with IAP between 21 and 25 and Grade 4 with IAP >25 mmHg. 
AP patients with IAH (IAP ≥ 12 mmHg) with IAH will assessed for eligibility, if 
patients meeting all inclusion criteria and no exclusion criteria can be randomized 
after signed informed consent.  
Randomization method  
A randomization list is generated by a computer program, and the randomization 
information will sealed in envelopes. After randomization, the data will be record case 
report form by the Clinical esearch coordinator. Participants will be allocated to 
interventional group and conventional group and in a 1: 1 ratio. Blinding: participants 
will be blinded until the allocation to prevent patients being assigned to interventional 
group and conventional group. From assignment to intervention, blinding cannot be 
provided considering the study characteristics. 
Study duration  
The planned starting date of the study is September 2015, and the planned 
finishing date is December 2017.  
Primary Endpoints  
The primary outcome measure was decreased rate of IAP after randomization. 
We will measure the IAP in 3 hours after randomization, and then once every 6 hours 
for 7 consecutive days. Finally, we compared the IAP at each time point after 


randomization with that before randomization. 
Secondary endpoints 
The following secondary endpoints will be analysed: (1) increase in Stool 
Volume at 1-7 days After randomization; (2) new-onset ACS; (3) new-onset organ 
failure, organ function will be monitored daily in all patients by the modified Marshall 
scoring system. (4) timing of enteral nutrition; (5) deterioration of IAH; (6) the 
Security of Neostigmine; (7) days in Hospital; (8) days in ICU and (9) medical 
expenses, which include all medications, services, salaries of healthcare professionals, 
equipment and day care costs.  
Intervention  
In this study, intramuscular injection of neostigmine will be the interventions. 
Patients will be randomized into interventional group and conventional group. The 
intervention will be started after randomized in all cases. 
In interventional group, patients will undergo intramuscular injection of 
neostigmine on the basis of conventional conservative treatment. The initial dose of 
neostigmine was 1mg, ntramuscular 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. 
The conventional group and interventional group will receive conservative 
treatment as follows: gastrointestinal decompression with nasogastric tube and rectal 
tub; 50ml paraffin oil will injection into gastric cavity through gastric tube , once every 
8 hours; lycerin enema bid to tid to promotes defecation; patients with ascites undergo 
percutaneous puncture drainage.  
Timing for surgical decompression 
There will be a multidisciplinary discussion among surgeons, interventional 
doctors, gastroenterologists, and critical care physicians to decide whether to operate, 
when non-operative strategies to counter IAH fails. In general, surgical 
decompression is justified at IAP greater than 25 mmHg and presence of progressive 
organ dysfunction and fulminant ACS3. 
General treatment regimen 
After initial fluid resuscitation, removal of excess fluid by using intravenous 
albumin and diuretics, or renal replacement therapy if needed. Sedation and analgesia 
be optimized to avoid agitation and respirator dyssynchrony2. Patients with an IAP 
<15 mmHg will receive enteral nutrition through the nasal jejunal tube, the rate was 
initiated at 20 mL/h and increased gradually by 15 mL every 8 h to the goal rate, 
depending on the patient’s tolerance7.  EN will be temporarily stopped when the 
IAP > 15 mmHg, and parenteral nutrition (PN) will be initiated. All patients with 


infected pancreatic necrosis(IPN) will receive broad-spectrum antibiotic therapy 
according to institutional protocols. Antibiotic treatment is tailored based on blood 
cultures and culture from material collected during drainage. If patients with IPN and 
an indication for intervention will underwent either initial endoscopic transluminal 
drainage or PCD followed, if necessary, by endoscopic or surgical necrosectomy.  
Data collection 
During hospitalization, clinical data on baseline characteristics and outcomes were 
collected using standardized case record forms (CRF). An independent monitor checks 
the source data and CRF data after all patients completed the clinical study. 
Follow up  
All patients were followed up for 1, 3 and 6 months after discharge. During these 
visits, all patients will receive routine CECT, exocrine and endocrine pancreatic 
function tests. 
Statistical analysis  
Demographic and baseline characteristics will be analysed using descriptive 
analysis. After the last patient has completed the follow-up, there will be a blind 
assessment of all primary and secondary endpoints. Both intention to treat analysis(all 
patients are analysed according to their initially assigned study arm regardless of 
adherence to study protocol) and per protocol analysis(enrolled patients who finished 
the study conforming to the requirements of the study protocol) will be performed. 
Primary and secondary endpoints were compared between treatment groups. 
Descriptive statistics includes mean, standard deviation, median, quartiles and relative 
frequency. T test will be performed for continuous variable in the case of normal 
distribution, and Kruskal-Wallis test in the absence of a normal distribution. The X2 
test will be performed for categorical variables, and relative risk for dichotomous 
variables. Two tailed P < 0.05 was considered statistically significant. 
 
 
References. 
1. Banks PA, Bollen TL, Dervenis C, et al. Classification of acute pancreatitis--2012: 
revision of the Atlanta classification and definitions by international consensus. Gut 
2013;62:102-11. 
2. 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;39:1190-206. 
3. Trikudanathan G, Vege SS. Current concepts of the role of abdominal 
compartment syndrome in acute pancreatitis - an opportunity or merely an 
epiphenomenon. Pancreatology 2014;14:238-43. 


4. Aitken EL, Gough V, Jones A, et al. Observational study of intra-abdominal 
pressure monitoring in acute pancreatitis. Surgery 2014;155:910-8. 
5. van Brunschot S, Schut AJ, Bouwense SA, et al. Abdominal compartment 
syndrome in acute pancreatitis: a systematic review. Pancreas 2014;43:665-74. 
6. Ponec RJ, Saunders MD, Kimmey MB. Neostigmine for the treatment of acute 
colonic pseudo-obstruction. N Engl J Med 1999;341:137-41. 
7. 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;37:2053-60.