Adjuvant Use of Neostigmine in Sepsis and Septic Shock.

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

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.

Study Overview

• Status: Completed
• Conditions: Sepsis, Septic Shock
• Intervention / Treatment: Drug: Neostigmine; Drug: Standard therapy

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 2

Contacts and Locations

Study Locations

• Egypt
  • EL-Gharbia
    • Tanta, EL-Gharbia, Egypt, 31527
      • Tanta University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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:

  1. Fever ≥ 38 °C or hypothermia ≤ 36 °C.
  2. Tachycardia ≥ 100/min.
  3. Tachypnea ≥ 20/min or hyperventilation.
  4. 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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Neostigmine group; 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; Neostigmine continuous infusion plus standard therapy for sepsis and septic shock.; Other Names: Choline esterase inhibitor
Placebo Comparator: Standard group; This arm will receive the standard therapy for sepsis and septic shock only and followed for five days.	Drug: Standard therapy; Standard therapy for sepsis and septic shock

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Mansoura University
• Investigators: Study Chair: Mamdouh M El-Shishtawy, Professor, Faculty of Pharmacy-Mansoura University

Publications and helpful links

General Publications

• El-Tamalawy MM, Soliman MM, Omara AF, Rashad A, Ibrahim OM, El-Shishtawy MM. Efficacy and Safety of Neostigmine Adjunctive Therapy in Patients With Sepsis or Septic Shock: A Randomized Controlled Trial. Front Pharmacol. 2022 Mar 7;13:855764. doi: 10.3389/fphar.2022.855764. eCollection 2022.

Study record dates

Study Major Dates

• Study Start (Actual): March 6, 2019
• Primary Completion (Actual): August 10, 2021
• Study Completion (Actual): October 1, 2021

Study Registration Dates

• First Submitted: October 8, 2019
• First Submitted That Met QC Criteria: October 16, 2019
• First Posted (Actual): October 17, 2019

Study Record Updates

• Last Update Posted (Actual): July 10, 2024
• Last Update Submitted That Met QC Criteria: July 9, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Toxemia; Shock, Septic; Shock; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Agents; Enzyme Inhibitors; Antimetabolites; Gastrointestinal Agents; Hypolipidemic Agents; Lipid Regulating Agents; Nootropic Agents; Lipotropic Agents; Cholinesterase Inhibitors; Parasympathomimetics; Choline; Neostigmine
• Other Study ID Numbers: 2019-3

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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