Impact of Timing of Midazolam Administration on Incidence of Postoperative Nausea and Vomiting

Impact of Timing of Midazolam Administration on Incidence of Postoperative Nausea and Vomiting in Patients Undergoing Laparoscopic Gynecological Surgery; a Randomized Double-blinded Controlled Study

Postoperative nausea and vomiting (PONV), defined as nausea and/or vomiting occurring within 24 hours after surgery, affects between 20% and 30% of patients, As many as 70% to 80% of patients at high risk may be affected. The etiology of PONV is thought to be multifactorial, involving individual, anaesthetic and surgical risk factors. PONV results in increased patient discomfort and dissatisfaction and in increased costs related to length of hospital stay. Serious medical complications such as pulmonary aspiration, although uncommon, are also associated with vomiting.

Patients with a higher risk of PONV often require a combination or multimodal approach of 2 or more interventions for effective risk reduction. Thus, researchers have explored additional nontraditional antiemetics, such as midazolam, that would aid in the multimodal prevention of PONV.

Study Overview

• Status: Completed
• Conditions: Postoperative Nausea and Vomiting
• Intervention / Treatment: Drug: Midazolam injection

Detailed Description

Midazolam is often administered in the perioperative period to reduce anxiety in addition to causing sedation and amnesia. The pharmacologic qualities allow for a rapid onset, short duration, and short half-life. The clinical effects of midazolam result from an agonist action on the γ-aminobutyric acid A (GABAA) receptor throughout the central nervous system. Benzodiazepines do not work directly on the GABA receptor, so there is a physiologic ceiling effect, which contributes to their safety and low toxicity.

Although the exact antiemetic mechanisms remain unknown, researchers postulate that midazolam works on the chemoreceptor trigger zone by reducing the synthesis, release, and postsynaptic dopamine. It remains debatable whether midazolam reduces dopamine directly or blocks the reuptake of adenosine leading to an adenosine-mediated reduction of dopamine release. Additionally, the binding of midazolam to the GABA benzodiazepine complex may cause dopaminergic neuronal activity and the release of 5-hydroxytryptamine. The reduction of PONV may also be a secondary effect of the anxiolytic properties of benzodiazepines.

Despite literature demonstrating the PONV benefits of midazolam in the perioperative period, But the timing of administration of this drug is still not well established. As it is known that it has half-life of about 1.5 - 2.5 hours and the controversies remain whether to administer this drug preoperatively or postoperatively to prevent PONV. So this comparative study is designed to know the better time for administration of this drug to prevent PONV and to improve patient satisfaction.

• Study Type: Interventional
• Enrollment (Actual): 120
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Egypt
  • Qalubia
    • Banhā, Qalubia, Egypt, 13511
      • Samar Rafik Mohamed Amin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 60 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Female patients
• aged twenty to sixty years old
• The American Society of Anesthesiologists (ASA) physical status classification grade I or II
• Scheduled for laparoscopic gynecological surgeries under general anesthesia.

Exclusion Criteria:

• Patients who have gastrointestinal disorders,
• histories of PONV after a previous surgery,
• Renal or liver dysfunction,
• history of motion sickness,
• Have received any opioid, steroid, or antiemetic medication in the 24hs before surgery, and
• Pregnant or menstruating women.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pre-induction Group (I); will receive intravenous midazolam premedication 2mg in a volume of 3 ml, 15 minutes before induction of anesthesia	Drug: Midazolam injection; No premedication will be given to Patients in the group undergoing a standardized anesthesia protocol which include induction with thiopental (5 mg/kg) and fentanyl (1-2 μg/kg). Atracurium will be used as a muscle relaxant. After tracheal intubation, anesthesia will be maintained with isoflurane in a concentration of 0.8%-1.2%. Ventilation will be adjusted to produce normocapnia. At the end of surgery, reversal of residual neuromuscular blockade will be accomplished using i.v. atropine 20 μg/Kg and neostigmine 40 μg/kg.
Experimental: Pre-extubation Group (II); will receive intravenous midazolam 2mg in a volume of 3 ml 30 minutes before extubation at the end of surgery	Drug: Midazolam injection; No premedication will be given to Patients in the group undergoing a standardized anesthesia protocol which include induction with thiopental (5 mg/kg) and fentanyl (1-2 μg/kg). Atracurium will be used as a muscle relaxant. After tracheal intubation, anesthesia will be maintained with isoflurane in a concentration of 0.8%-1.2%. Ventilation will be adjusted to produce normocapnia. At the end of surgery, reversal of residual neuromuscular blockade will be accomplished using i.v. atropine 20 μg/Kg and neostigmine 40 μg/kg.
Placebo Comparator: Control Group (III); will receive 3 ml normal saline 15 minutes before induction of anesthesia plus 3 ml normal saline 30 minutes before extubation at the end of surgery.	Drug: Midazolam injection; No premedication will be given to Patients in the group undergoing a standardized anesthesia protocol which include induction with thiopental (5 mg/kg) and fentanyl (1-2 μg/kg). Atracurium will be used as a muscle relaxant. After tracheal intubation, anesthesia will be maintained with isoflurane in a concentration of 0.8%-1.2%. Ventilation will be adjusted to produce normocapnia. At the end of surgery, reversal of residual neuromuscular blockade will be accomplished using i.v. atropine 20 μg/Kg and neostigmine 40 μg/kg.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Post Operative Nausea Vomiting assessment	Nausea will be recorded according to the following scale: 0 none; 1 mild (patient able to eat); 2 moderate (oral intake significantly decreased); and 3 severe (no significant oral intake necessitating iv fluid). The absence of nausea will be defined as complete protection from nausea. An emetic episode will be defined as a single vomit or retch, or any number of continuous vomiting episodes or retches (one emetic episode should be separated from another by an absence of vomiting or retching for at least 1 min). The absence of emetic episodes will be defined as complete protection from vomiting.	24 hours postoperative

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
requirements of rescue antiemetic	Rescue medication (metoclopramide 10 mg) will be given intravenously if patient is nauseous for more than 15 min or experiences retching or vomiting during the observation periods. The treatment will be repeated if necessary	24 hours postoperative
Observer's Assessment of Alertness/ Sedation (OAA/S) scale	a six-point scale ranging from 5 to 0 that involves eliciting a response to increasingly intense stimuli that begin with speaking with a normal voice to prodding or shaking and finally to a painful stimulus (trapezius squeeze).	120 minutes postoperative
Pain intensity score	measured with a visual analog scale (VAS) from 0 (no pain) to 10 (the worst possible pain).	24 hours postoperative

Collaborators and Investigators

• Sponsor: Benha University

Study record dates

Study Major Dates

• Study Start (Actual): September 10, 2021
• Primary Completion (Actual): June 30, 2022
• Study Completion (Actual): July 31, 2022

Study Registration Dates

• First Submitted: September 13, 2021
• First Submitted That Met QC Criteria: September 16, 2021
• First Posted (Actual): September 27, 2021

Study Record Updates

• Last Update Posted (Actual): August 16, 2022
• Last Update Submitted That Met QC Criteria: August 13, 2022
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Signs and Symptoms, Digestive; Nausea; Vomiting; Postoperative Nausea and Vomiting; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Midazolam
• Other Study ID Numbers: RC-12-8-2021

Drug and device information, study documents

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