Acute Pancreatitis, Intra-abdominal Hypertension
Conditions
Keywords
Acute Pancreatitis, Intra-abdominal hypertension, Abdominal compartment syndrome, Curative Effect, Security, Neostigmine
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.
Interventions
DRUGNeostigmine 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.
COMBINATION_PRODUCTConservative 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.
Sponsors
The First Affiliated Hospital of Nanchang University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change of IAP After Treatment | From randomization to 7 days after treatment,Measured IAP every 6 hours | Monitor the intra-abdominal pressure within 1 to 7 days after randomization, and calculate the percent change compared with that before randomization |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| New-onset Organ Failure | From randomization to discharge or death, assessed up to 3 months | Incidence of organ failure from randomization to discharge or death, assessed up to 3 months |
| Timing of Enteral Nutrition | Start time of enteral nutrition after randomization, assessed up to 30 days | From date of randomization to enteral nutrition, assessed up to 30 days |
| Number of Participants With Deterioration of IAH | From randomization to 7 days | IAP rebound ≥ 5mmHg or increase ≥ 20mmHg within 1-7 days after grouping |
| Number of Participants With Adverse Effects on the Cardiovascular System | From randomization to 7 days | 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 |
| The Change of Stool Volume at 1-7 Days After Randomization | From randomization to 7 days | 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. |
| New-onset Abdominal Compartment Syndrom | From randomization to discharge or death, assessed up to 4 weeks | 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 |
| Death of 90 Days | From randomization to 90 days after onset. | Death during from randomization to 90 days after onset. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Medical Expenses | From randomisation to 6 months | Medical expenses within 6 months after randomisation |
| Days in Hospital | From randomisation to 6 months | Days in hospital within 6 months after randomisation |
| Days in ICU | From randomisation to 6 months | Days in ICU within 6 months after randomisation |
Countries
China
Participant flow
Recruitment details
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.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 40 |
| 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. | 40 |
| Total | 80 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lack of Efficacy | 0 | 4 |
Baseline characteristics
| Characteristic | Total | Neostigmine | Conservative Treatment |
|---|---|---|---|
| Age, Continuous | 48 yeas STANDARD_DEVIATION 14 | 46 yeas STANDARD_DEVIATION 13 | 49 yeas STANDARD_DEVIATION 14 |
| Cause of pancreatitis Alcoholic | 8 Participants | 4 Participants | 4 Participants |
| Cause of pancreatitis Biliary | 26 Participants | 12 Participants | 14 Participants |
| Cause of pancreatitis Hyperlipidemic | 41 Participants | 21 Participants | 20 Participants |
| Cause of pancreatitis Idiopathic | 5 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 80 Participants | 40 Participants | 40 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment China | 80 Participants | 40 Participants | 40 Participants |
| Sex: Female, Male Female | 19 Participants | 13 Participants | 6 Participants |
| Sex: Female, Male Male | 61 Participants | 27 Participants | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 10 / 40 | 11 / 40 |
| other Total, other adverse events | 0 / 40 | 0 / 40 |
| serious Total, serious adverse events | 8 / 40 | 4 / 40 |
Outcome results
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
Time frame: From randomization to 7 days after treatment,Measured IAP every 6 hours
Population: The primary outcome measure was decreased rate of IAP after randomisation.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Neostigmine | Percent Change of IAP After Treatment | percent change of IAP at 24 hours | -18.7 percent change of IAP |
| Neostigmine | Percent Change of IAP After Treatment | percent change of IAP at 7 days | -27.2 percent change of IAP |
| Conservative Treatment | Percent Change of IAP After Treatment | percent change of IAP at 24 hours | -5.4 percent change of IAP |
| Conservative Treatment | Percent Change of IAP After Treatment | percent change of IAP at 7 days | -20.0 percent change of IAP |
Secondary
Death of 90 Days
Death during from randomization to 90 days after onset.
Time frame: From randomization to 90 days after onset.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Neostigmine | Death of 90 Days | 10 Participants |
| Conservative Treatment | Death of 90 Days | 11 Participants |
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
Time frame: From randomization to discharge or death, assessed up to 4 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Neostigmine | New-onset Abdominal Compartment Syndrom | 2 Participants |
| Conservative Treatment | New-onset Abdominal Compartment Syndrom | 4 Participants |
Secondary
New-onset Organ Failure
Incidence of organ failure from randomization to discharge or death, assessed up to 3 months
Time frame: From randomization to discharge or death, assessed up to 3 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Neostigmine | New-onset Organ Failure | 12 Participants |
| Conservative Treatment | New-onset Organ Failure | 16 Participants |
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
Time frame: From randomization to 7 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Neostigmine | Number of Participants With Adverse Effects on the Cardiovascular System | 8 Participants |
| Conservative Treatment | Number of Participants With Adverse Effects on the Cardiovascular System | 4 Participants |
Secondary
Number of Participants With Deterioration of IAH
IAP rebound ≥ 5mmHg or increase ≥ 20mmHg within 1-7 days after grouping
Time frame: From randomization to 7 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Neostigmine | Number of Participants With Deterioration of IAH | 4 Participants |
| Conservative Treatment | Number of Participants With Deterioration of IAH | 8 Participants |
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.
Time frame: From randomization to 7 days
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Neostigmine | The Change of Stool Volume at 1-7 Days After Randomization | The change of stool volume at 24 hours | 870 ml/day |
| Neostigmine | The Change of Stool Volume at 1-7 Days After Randomization | The change of stool volume at 7th day | 1025 ml/day |
| Conservative Treatment | The Change of Stool Volume at 1-7 Days After Randomization | The change of stool volume at 24 hours | 60 ml/day |
| Conservative Treatment | The Change of Stool Volume at 1-7 Days After Randomization | The change of stool volume at 7th day | 370 ml/day |
Secondary
Timing of Enteral Nutrition
From date of randomization to enteral nutrition, assessed up to 30 days
Time frame: Start time of enteral nutrition after randomization, assessed up to 30 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Neostigmine | Timing of Enteral Nutrition | 3 days |
| Conservative Treatment | Timing of Enteral Nutrition | 4 days |
Other Pre-specified
Days in Hospital
Days in hospital within 6 months after randomisation
Time frame: From randomisation to 6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Neostigmine | Days in Hospital | 20 days |
| Conservative Treatment | Days in Hospital | 19 days |
Other Pre-specified
Days in ICU
Days in ICU within 6 months after randomisation
Time frame: From randomisation to 6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Neostigmine | Days in ICU | 12 days |
| Conservative Treatment | Days in ICU | 12 days |
Other Pre-specified
Medical Expenses
Medical expenses within 6 months after randomisation
Time frame: From randomisation to 6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Neostigmine | Medical Expenses | 95.3 thousand(RMB) |
| Conservative Treatment | Medical Expenses | 102.3 thousand(RMB) |