A Randomized Controlled Trial Comparing Imipenem and Tigecycline Versus Imipenem and Tigecycline With GM-CSF for the Management of Spontaneous Bacterial Peritonitis Presenting With Septic Shock.

Study Overview
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Brief Summary
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Study population: A total of 90 consecutive patients of decompensated cirrhosis of any etiology, presenting to the Institute of Liver and Biliary Sciences with SBP with septic shock will be included. Study design: Randomized controlled trial Study period: August 2019 to December 2021. Sample size: Assuming that the response rate is 90% with GM-CSF and 60% without GM-CSF after day 5. With alpha 5 and power 80,we need to enroll 76 cases (38 cases with each). Further assuming 20 % drop-out due to various reasons, it was decided to enroll 90 cases randomly allocated into two groups (i.e., 45 in each) by block randomization method by taking block size as 6. So for the present study, it was decided to enroll 90 cases in all. Group A will be given Imipenem and Tigecycline. Patients with recent hospitalisation will be given Colistin in addition. Group B will be given: To another group we will give Imipenem and Tigecycline and GMCSF.Patients with recent hospitalisation will be given Colistin in addition. The dose of antibiotic will be given at dosage Inj Imipenem 1gm i.v. TDS Inj Tigecycline 100mg stat f/b 50mg i.v. OD Inj GM-CSF 500mcg s.c. OD Inj Colistin 9 MIU i.v. stat f/b 4.5 MIU i.v. BD Monitoring and assessment At the baseline, all patients will undergo investigational evaluation as described Daily monitoring of following parameters: Haemoglobin, Total peripheral leucocyte counts, Platelet counts, Renal function tests Liver function tests and Chest X rays will be undertaken Ascitic fluid analysis will be done on day 0, day 2 and day 5 Stopping rule:If the patient develops a TLC of more than 50,000, the dose of the GM CSF will be reduced to half and the treatment continued. If, even after the reduction, the TLC rises to more than 50,000, then the treatment will be stopped and the patient excluded. Expected outcome of the project: Addition of GM-CSF to standard antibiotic regimen helps resolve SBP and improves outcome in decompensated liver cirrhotic patients.

Official Title
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Imipenem and Tigecycline Versus Imipenem and Tigecycline With GM-CSF for the Management of Spontaneous Bacterial Peritonitis Presenting With Septic Shock.

Conditions
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Spontaneous Bacterial Peritonitis

Intervention / Treatment
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* Drug: Imipenem
* Drug: Tigecycline
* Drug: GMCSF
* Drug: Colistin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Spontaneous Bacterial Peritonitis (SBP) with shock in a cirrhotic Hospital acquired SBP with shock Difficult to treat SBP Exclusion Criteria: Refractory Shock Cardiac comorbidities (known Coronary Artery Disease) Chronic Kidney Disease on Maintenance Hemodialysis < 18 years. Advanced Hepatocellular Carcinoma Post liver transplant HIV + ve, Immunosuppressive therapy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Imipenem+Tigecycline+GM-CSF<br> | Drug: Imipenem<br>* Inj Imipenem 1gm i.v. TDS<br>Drug: Tigecycline<br>* Inj Tigecycline 100mg stat f/b 50mg i.v. OD<br>Drug: GMCSF<br>* Inj GM-CSF 500mcg s.c. OD<br>Drug: Colistin<br>* Inj Colistin 9 MIU i.v. stat f/b 4.5 MIU i.v. BD<br>|
| Active Comparator: Imipenem+Tigecycline<br> | Drug: Imipenem<br>* Inj Imipenem 1gm i.v. TDS<br>Drug: Tigecycline<br>* Inj Tigecycline 100mg stat f/b 50mg i.v. OD<br>Drug: Colistin<br>* Inj Colistin 9 MIU i.v. stat f/b 4.5 MIU i.v. BD<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Resolution of Spontaneous Bacterial peritonitis in both groups | Response is defined by resolution of SBP in terms of total counts < 500,Neutrophil<250 | Day 5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reversal of shock in both groups | Blood pressure more than 90/60 mmHg with no inotropes requirement | Day 2 | 
| Survival in both groups |  | Day 7 | 
| Survival in both groups |  | Day 28 | 
| Change in ascitic fluid metabolites Nitric Oxide in both groups | change is defined as percentage reduction in nitric oxide | Day 28 | 
| Change in ascitic fluid macrophage population in both groups | change is defined as percentage reduction in macrophage population | Day 28 | 
| Development of Hepatic Encephalopathy in both groups. | Hepatic Encephalopathy will be measured as per West Haven criteria | Day 28 | 
| Development of Acute Kidney Injury in both groups | AKIN criteria will be used for Acute kidney injury | Day 28 | 
| Development of Pneumonia in both groups. | Pneumonia will be confirmed based on imaging and clinically | Day 28 | 
| Development of organ failures in both groups. | Organ failure will be as per APACHE score | Day 28 | 
| Development of coagulopathy in both groups. | Coagulopathy is defined as INR > 1.5 | Day 28 | 
| Resolution of Spontaneous Bacterial peritonitis in both groups | Response is defined by resolution of SBP in terms of total counts < 500,Neutrophil<250 | Day 2 |