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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Septic Shock

Intervention / Treatment
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* Drug: Metformin
* Other: standardized protocol


Participation Criteria
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Eligibility Criteria
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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.

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 |
| --- | --- |
| Active Comparator: Group C: (n=25) control.<br>patients will receive standardized protocol without receiving metformin. | Other: standardized protocol<br>* standardized protocol<br>|
| Active Comparator: Group D: (n=25) diabetic patients.<br>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. | Drug: Metformin<br>* 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.<br>Other: standardized protocol<br>* standardized protocol<br>|
| Active Comparator: Group ND: (n=25) non-diabetic patients.<br>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. | Drug: Metformin<br>* 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.<br>Other: standardized protocol<br>* standardized protocol<br>|

What is the study measuring?
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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. |