Adjuvant Use of Neostigmine in Sepsis and Septic Shock.

Study Overview
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Brief Summary
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The inflammatory response represents an important, central component of sepsis. Therefore, it is believed that blunting inflammation will decrease mortality. In vivo test series with mice that had undergone cecal ligation and puncture (recognized sepsis model), physostigmine salicylate significantly inhibited the release of various cytokines (tumor necrosis factor α, interleukin1β, and interleukin 6). These results were similar to those obtained by vagus nerve stimulation. In animal sepsis model using physostigmine not only decreased inflammation but also, diminished the decrease in blood pressure following infection. Animals treated with the peripheral choline esterase inhibitor neostigmine showed no difference compared with physostigmine-treated animals. Therefore, this study aims to investigate the efficacy of choline esterase inhibitors as adjuvant therapy in patients with sepsis or septic shock. Outcome measures include: percentage reduction in procalcitonin blood level, percentage of patients achieving significant reduction in procalcitonin levels, Mean Sequential Organ Failure Assessment score, percentage decrease in lactate dehydrogenase blood level, length of stay in hospital intensive care unit, and in hospital mortality.

Official Title
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Safety and Efficacy of Neostigmine Infusion as Adjuvant Therapy in Sepsis and Septic Shock

Conditions
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Sepsis, Septic Shock

Intervention / Treatment
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* Drug: Neostigmine
* Drug: Standard therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-85 years. Patients diagnosed with sepsis or septic shock according to Third International Consensus Definitions for Sepsis and Septic Shock mentioned above. Patients who have ≥ 2 of the following four criteria plus documented infection: Fever ≥ 38 °C or hypothermia ≤ 36 °C. Tachycardia ≥ 100/min. Tachypnea ≥ 20/min or hyperventilation. Leukocytosis ≥ 12000/mm3 or leukopenia ≤ 4000/mm3 or ≥ 10% immature neutrophils in the differential count. Exclusion criteria: Known hypersensitivity to choline esterase inhibitors. Known absolute contra-indications against choline esterase inhibitors such as, myotonic dystrophy; depolarization block by depolarizing muscle relaxants; intoxication by irreversibly acting cholinesterase inhibitors; closed craniocerebral trauma; obstruction in the gastrointestinal tract (mechanical constipation); obstruction in the urinary tract (mechanical urinary retention) Known relative contraindications against choline esterase inhibitors: bronchial asthma; bradycardia; AV-conduction disturbances. Having undergone solid organ transplantation. Pregnant and lactating women. Participation in another clinical trial. Presence of primary or concomitant illness, impending death.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neostigmine group<br>This arm will receive -in addition to standard therapy for sepsis and septic shock-Neostigmine methylsulfate ampoule diluted in normal saline, and administered as continuous infusion for five days. The rate of infusion is 0.2 mg/hr. | Drug: Neostigmine<br>* Neostigmine continuous infusion plus standard therapy for sepsis and septic shock.<br>* Other names: Choline esterase inhibitor;|
| Placebo Comparator: Standard group<br>This arm will receive the standard therapy for sepsis and septic shock only and followed for five days. | Drug: Standard therapy<br>* Standard therapy for sepsis and septic shock<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sequential organ failure assessment (SOFA score) | Increase in SOFA score is associated with worse outcome. | Change from baseline SOFA score at five days |