Effect of Metformin Use on Mortality in Diabetic and Non Diabetic Patients With Sepsis and Septic Shock.

We aimed to determine if metformin use in both diabetic and non diabetic patients with sepsis and septic shock affects 28 day mortality and its effect on inflammatory markers. Plasma rennin, serum lactate concentration and IL6 will be measured for predicting 28 days in-hospital mortality in patients with sepsis.

Study Overview

• Status: Not yet recruiting
• Conditions: Septic Shock
• Intervention / Treatment: Other: standardized protocol; Drug: Metformin

Detailed Description

Sepsis, is a life-threatening condition arises when the body's response to infection causes injury to its own tissues, followed by suppression of the immune system. Signs and symptoms include fever, increased heart rate, increased breathing rate, and confusion.There may be symptoms of a specific infection, such as cough, or painful urination.

Sepsis is caused by many organisms including bacteria, viruses and fungi. . Risk factors include extreme of ages, a weakened immune system. Previously, a sepsis diagnosis required the presence of at least two systemic inflammatory response syndrome criteria.

Sepsis requires immediate treatment with intravenous fluids and antimicrobials in ICU. If fluids is not enough to maintain blood pressure, the use of medications that raise blood pressure becomes necessary. Mechanical ventilation and dialysis may be needed. A central venous catheter and an arterial catheter may be placed. corticosteroid use is controversial.

Metformin is a biguanide antihyperglycemic agent. It works by decreasing glucose production in the liver, by increasing the insulin sensitivity of body tissues, and by increasing GDF15 secretion, which reduces appetite.

Metformin is a first-line therapy for type 2 diabetes mellitus, taken by mouth and well tolerated. Common adverse effects include diarrhea, nausea, and abdominal pain.

Metformin inhibit pathways linked to inflammation, immune reactions, mammalian target of rapamycin (mTOR) signaling, and cell senescence. Some of the changes were confirmed by Western blot. Therefore, metformin prevented part of the deleterious actions of pro-inflammatory cytokines in human β-cells, which was accompanied by islet proteome modifications.

• Study Type: Interventional
• Enrollment (Anticipated): 75
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Osama Khaled Ahmed Abodeef, resident; Phone Number: +201018089621; Email: Miniosama_2010@yahoo.com
• Study Contact Backup: Name: Abualauon Mohamed Abedalmohsen, MD; Phone Number: +201020170603; Email: abualauon77@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• both sexes aged ≥18 years old complaining of sepsis or septic shock with anticipated stay >24 hours, and signed informed consent by patient or next-of-kin.

Exclusion Criteria:

• Age less than 18 years old, chronic kidney disease stage IV/V (baseline eGFR <30ml/min/1.73m2), patients with acute coronary syndrome, or do not resuscitate order. Patients could be enrolled at any point during their admission.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Group C: (n=25) control.; patients will receive standardized protocol without receiving metformin.	Other: standardized protocol; standardized protocol
Active Comparator: Group D: (n=25) diabetic patients.; diabetic patients will receive standardized protocol and receiving metformin 500 mg every 8 hours since admission regardless of their random blood sugar with measurement of random blood sugar every hour and dextrose 25% infusion will be used if needed and also insulin infusion will be used when appropriate with target random blood sugar 140-180 in diabetic patients.	Other: standardized protocol; standardized protocol; Drug: Metformin; Patient screening will be done using SOFA scoring and NEWS Supplemental oxygen will be supplied. Intubation and mechanical ventilation may be required Venous access will be established.CBC, chemistries, liver function tests,coagulation studies ,Peripheral blood cultures, urinalysis, microbiological cultures from suspected sources (eg, sputum, urine,etc),(ABG) and serum lactate will be obtained Crystalloids will be given at 30 mL/kg, started by one hour and completed within three hours Empiric antibiotic therapy is targeted at the suspected organism(s) In patients with lactic acidosis and severe acidemia, Sodium bicarbonate will be used to maintain the arterial pH above 7.15 In patients having persistent hypoperfusion vasopressors will be added Evaluation of volume status will be done using straight leg raising test and ultrasound guided IVC collapsibility index Plasma rennin, serum lactate and IL6 concentrations will be measured on admission and at one week.
Active Comparator: Group ND: (n=25) non-diabetic patients.; patients will receive standardized protocol and receiving metformin 500 mg every 8 hours since admission regardless of their random blood sugar with measurement of random blood sugar every hour and dextrose 25% infusion will be used if needed and also insulin infusion will be used when appropriate with target random blood sugar 100-140 in non diabetic patients.	Other: standardized protocol; standardized protocol; Drug: Metformin; Patient screening will be done using SOFA scoring and NEWS Supplemental oxygen will be supplied. Intubation and mechanical ventilation may be required Venous access will be established.CBC, chemistries, liver function tests,coagulation studies ,Peripheral blood cultures, urinalysis, microbiological cultures from suspected sources (eg, sputum, urine,etc),(ABG) and serum lactate will be obtained Crystalloids will be given at 30 mL/kg, started by one hour and completed within three hours Empiric antibiotic therapy is targeted at the suspected organism(s) In patients with lactic acidosis and severe acidemia, Sodium bicarbonate will be used to maintain the arterial pH above 7.15 In patients having persistent hypoperfusion vasopressors will be added Evaluation of volume status will be done using straight leg raising test and ultrasound guided IVC collapsibility index Plasma rennin, serum lactate and IL6 concentrations will be measured on admission and at one week.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
28 day Mortality.	death within 28 day of sepsis and septic shock where the occurrence of sepsis is hour 0 day 0.	28 day.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma rennin concentration (pg/ml) will be measured on admission and at one week.		On admission and at 1 week after admission.
IL6 concentration (ng/ml) will be measured on admission and at one week.	Level of inflammatory mediators on admission and at 1 week after admission.	On admission and at 1 week after admission.
Serum lactate concentration (mmol/L) will be measured on admission and at one week.		On admission and at 1 week after admission.

Collaborators and Investigators

• Sponsor: Assiut University
• Investigators: Study Chair: Osama Khaled Ahmed Abodeef, resident, Assiut University; Study Director: Abualauon Mohamed Abedalmohsen, MD, Assiut University; Principal Investigator: Nagwa Mostafa Ibrahim, MD, Assiut University

Publications and helpful links

General Publications

• Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992 Jun;101(6):1644-55. doi: 10.1378/chest.101.6.1644.
• Deutschman CS, Tracey KJ. Sepsis: current dogma and new perspectives. Immunity. 2014 Apr 17;40(4):463-75. doi: 10.1016/j.immuni.2014.04.001.
• Sehgal M, Ladd HJ, Totapally B. Trends in Epidemiology and Microbiology of Severe Sepsis and Septic Shock in Children. Hosp Pediatr. 2020 Dec;10(12):1021-1030. doi: 10.1542/hpeds.2020-0174.
• Annane D, Bellissant E, Bollaert PE, Briegel J, Keh D, Kupfer Y, Pirracchio R, Rochwerg B. Corticosteroids for treating sepsis in children and adults. Cochrane Database Syst Rev. 2019 Dec 6;12(12):CD002243. doi: 10.1002/14651858.CD002243.pub4.
• Giusti L, Tesi M, Ciregia F, Marselli L, Zallocco L, Suleiman M, De Luca C, Del Guerra S, Zuccarini M, Trerotola M, Eizirik DL, Cnop M, Mazzoni MR, Marchetti P, Lucacchini A, Ronci M. The Protective Action of Metformin against Pro-Inflammatory Cytokine-Induced Human Islet Cell Damage and the Mechanisms Involved. Cells. 2022 Aug 8;11(15):2465. doi: 10.3390/cells11152465.
• Raith EP, Udy AA, Bailey M, McGloughlin S, MacIsaac C, Bellomo R, Pilcher DV; Australian and New Zealand Intensive Care Society (ANZICS) Centre for Outcomes and Resource Evaluation (CORE). Prognostic Accuracy of the SOFA Score, SIRS Criteria, and qSOFA Score for In-Hospital Mortality Among Adults With Suspected Infection Admitted to the Intensive Care Unit. JAMA. 2017 Jan 17;317(3):290-300. doi: 10.1001/jama.2016.20328.

Study record dates

Study Major Dates

• Study Start (Anticipated): December 1, 2022
• Primary Completion (Anticipated): December 31, 2024
• Study Completion (Anticipated): January 31, 2025

Study Registration Dates

• First Submitted: October 3, 2022
• First Submitted That Met QC Criteria: October 6, 2022
• First Posted (Actual): October 7, 2022

Study Record Updates

• Last Update Posted (Actual): October 7, 2022
• Last Update Submitted That Met QC Criteria: October 6, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Shock, Septic; Shock; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: Metformin use in sepsis

Drug and device information, study documents

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