Magnesium Sulfate in Children Undergoing Laparoscopic Appendectomy

The Effect of Intravenous Magnesium Infusion on the Opioid Consumption, the Circulatory, Metabolic and Hormonal Response to Intubation and Surgical Trauma During Anaesthesia for Laparoscopy in Children. Randomized Clinical Trial.

Magnesium sulfate is one of the most commonly used co-analgetics. Its antinociceptive effect is related to antagonizing NMDA (N-methyl-D-aspartate) receptors of the nervous system, has an anti-inflammatory effect by reducing the concentration of IL-6 (interleukin 6) and tumor necrosis factor alpha. In adult patients, the need for morphine in the perioperative period is reduced when magnesium infusion is used. In current guidelines for treatment of acute pain in children, magnesium sulfate may be considered as a co-analgetic. However, the strength of such a recommendation is low due to the lack of reliable scientific research confirming the effectiveness of magnesium infusion in the pediatric population. The aim of this study is to evaluate the efficacy of intravenous magnesium sulfate infusion on the opioid consumption, the circulatory, metabolic and hormonal response to intubation and surgical trauma during anesthesia for laparoscopic appendectomy in children.

Study Overview

• Status: Recruiting
• Conditions: Acute Appendicitis; Opioid Consumption; Complication of Treatment; Multimodal Analgesia
• Intervention / Treatment: Drug: Normal saline infusion; Drug: Intravenous magnesium sulfate

Detailed Description

Pain in the perioperative period is associated with surgical stimuli but also with laryngoscopy and intubation. According to the currently applicable ERAS (Enhanced Recovery After Surgery) doctrine, the recommended method of anesthesia is multimodal, low-opioid anesthesia. The essence of multimodal anesthesia is to combine different methods (e.g. general and regional anesthesia) and various anesthetic drugs in order to reduce the intraoperative use of opioids. The one of commonly used co-analgetic is magnesium. The use of magnesium infusion before induction of anesthesia may enhance the analgesic effect of the opioid administered before intubation. In current guidelines for the relief of acute pain in children, magnesium sulfate may be considered as a coanalgesic. It is based only on expert consensus opinion and/or data from small studies, retrospective studies, registries.

According to available data magnesium sulfate is superior to placebo in decreasing analgesic consumption and pain scores during the first 48 h after operation without any adverse effects in children with cerebral pals. In other groups of pediatric patients, the effectiveness of magnesium as a co-analgetic has not been proven. High quality randomized controlled trials are still missing.

The primary outcome of this study is to assess opioid consumption during the laparoscopic appendectomy. Number of patients requiring rescue dose of opioids will be measured.

The secondary aim is to examine total intraoperative fentanyl consumption, fluctuations of heart rate and blood pressure, metabolic, hormonal and inflammatory response (glucose, cortisol and IL-6 concentrations) and occurrence of side effects that may result from magnesium intake (decrease in blood pressure, bradycardia or allergic reaction).

In the pediatric population, the optimal perioperative magnesium dosage is 50 mg/kg as a bolus followed by an infusion of 15 mg/kg/hour until the end of the operation.

The general aim of the study is to evaluate the analgesic efficacy of intravenous magnesium sulfate as an adjunct to standard general anesthesia (involving intravenous induction and opioid with sevoflurane maintenance) for intubation and surgical trauma during anesthesia for laparoscopic appendectomy in children.

• Study Type: Interventional
• Enrollment (Estimated): 188
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Alicja Kuczerowska, MD; Phone Number: +48 601666694; Email: alicja.kuczerowska@uckwum.pl
• Study Contact Backup: Name: Maciej Kaszyński, PhD; Email: maciej.kaszyński2@wum.edu.pl

Study Locations

• Poland
  • Warsaw, Poland, 02-091
    • Recruiting
    • Uniwersity Clinic Centre of Medical Uniwersity of Warsaw
    • Contact: Izabela Pągowska-Klimek, prof.; Email: izabela.pagowska-klimek@wum.edu.pl
    • Principal Investigator: Maciej Kaszyński, PhD
    • Sub-Investigator: Izabela Pągowska-Klimek, prof.
    • Sub-Investigator: Alicja Kuczerowska, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• ASA (American Society of Anesthesiologists) physical status class 1E, 2E, 3E (E - emergency)
• Patients undergoing laparoscopic appendectomy

Exclusion Criteria:

• Allergy to the magnesium sulfate or the excipient
• Hypermagnesemia
• Renal failure (GFR <30 ml/min)
• Myasthenia gravis
• Preoperative atrioventricular block
• Hypotension
• The use of digitalis glycosides
• The use of oral anticoagulants
• ASA physical status class 4E or higher
• Chronic treatment with analgesics
• Legal guardians or patient refusal

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Magnesium Sulfate; 10% magnesium sulfate intravenous bolus of 0.5 ml/kg (maximum 20 ml) over 5 min before induction of anesthesia followed by magnesium sulfate infusion at 0.15 ml/kg/h (maximum 6 ml/h) intraoperatively will be administered. The infusion will be discontinued before the patients' transfer to the postanesthesia care unit.	Drug: Intravenous magnesium sulfate; Intraoperative intravenous magnesium sulfate infusion.; Other Names: IVM (intravenous magnesium)
Placebo Comparator: Control; 0.9% NaCl (sodium chloride) intravenous bolus of 0.5 ml/kg (maximum 20 ml) over 5 min before induction of anesthesia followed by 0.9% NaCl infusion at 0.15 ml/kg/h (maximum 5ml/h) intraoperatively will be administered. The infusion will be discontinued before the patients' transfer to the postanesthesia care unit.	Drug: Normal saline infusion; Intraoperative intravenous normal saline infusion.; Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients requiring rescue dose of opioids.	Patients who experience a 20% increase in BP (Blood Pressure) or HR (Heart Rate) from baseline during surgery and the early post-extubation period will receive a bolus of fentanyl (1 mcg/kg) as rescue analgesia. The number of these patients will be compared between the groups. Baseline parameters will be recorded after premedication with an IV bolus of 0.05 mg/kg midazolam, just before intubation.	From tracheal intubation through to postanesthesia care unit admission (10 minutes after extubation).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The requirement for opioids during anesthesia	Total amount of fentanyl in micrograms per kilogram of body weight used during anesthesia (dose for induction of anesthesia + doses added during surgery and in the early post-extubation period).	From operating theatre admission through to postanesthesia care unit admission (10 minutes after extubation).
Hemodynamic reaction to tracheal intubation	A change in arterial blood pressure of more than 20% from baseline will be noted, and the fractions of these patients in each group will be compared. Baseline parameters will be recorded after premedication with an IV bolus of 0.05 mg/kg midazolam, just before intubation.	Pre-intubation - immediately after intubation.
Metabolic response to laparoscopic procedure	Glucose [mg/dl] levels will be measured and compared before and after laparoscopic procedure. The first blood sample will be taken 5 minutes after tracheal intubation, before the skin incision. The second blood sample will be taken immediately after the end of surgery, at the time of dressing application.	From 5 minutes after tracheal intubation until the end of surgery, defined as the completion of dressing application.
Hormonal response to laparoscopic procedure	Cortisol levels [mcg/dl] will be measured and compared before and after laparoscopic procedure. The first blood sample will be taken 5 minutes after tracheal intubation, before the skin incision. The second blood sample will be taken immediately after the end of surgery, at the time of dressing application.	From 5 minutes after tracheal intubation until the end of surgery, defined as the completion of dressing application.
Inflammatory response to laparoscopic procedure	IL-6 levels [pg/ml] will be measured and compared before and after laparoscopic procedure. The first blood sample will be taken 5 minutes after tracheal intubation, before the skin incision. The second blood sample will be taken immediately after the end of surgery, at the time of dressing application.	From 5 minutes after tracheal intubation until the end of surgery, defined as the completion of dressing application.
Magnesium blood level	Magnesium level [mg/dl] will be measured after initial bolus and just before the end of its infusion. The first blood sample will be taken 5 minutes after tracheal intubation, before the skin incision. The second blood sample will be taken immediately after the end of surgery, at the time of dressing application. Magnesium infusion will be discontinued after the second blood sample is collected.	From 5 minutes after tracheal intubation until the end of surgery, defined as the completion of dressing application.
Side effects of magnesium sulfate	Side effects of magnesium sulfate will be assessed by recording the rates of the following complications: hypotension & bradycardia (both defined as 2 SD (standard deviation) below the 50th percentile for age), allergic reaction. Need to discontinue the magnesium sulfate/placebo infusion due to side effects. Need to administer calcium gluconate.	From the beginning of magnesium sulfate application until transfer to the postanesthesia care unit (10 minutes after extubation).

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Length of stay in the hospital after completing anesthesia	Length of stay in the hospital after completing anesthesia is defined as the time period from extubation (endotracheal tube removal) to discharge from the hospital. The mean length of hospital stay in the control and study groups will be compared.	From the time of extubation until the time of discharge from the hospital, through study completion, an average of 3 days.

Collaborators and Investigators

• Sponsor: Medical University of Warsaw
• Investigators: Study Director: Izabela Pągowska-Klimek, prof., Medical University of Warsaw

Publications and helpful links

General Publications

• Cettler M, Zielinska M, Rosada-Kurasinska J, Kubica-Cielinska A, Jarosz K, Bartkowska-Sniatkowska A. Guidelines for treatment of acute pain in children - the consensus statement of the Section of Paediatric Anaesthesiology and Intensive Therapy of the Polish Society of Anaesthesiology and Intensive Therapy. Anaesthesiol Intensive Ther. 2022;54(3):197-218. doi: 10.5114/ait.2022.118972.
• Benzon HA, Shah RD, Hansen J, Hajduk J, Billings KR, De Oliveira GS Jr, Suresh S. The Effect of Systemic Magnesium on Postsurgical Pain in Children Undergoing Tonsillectomies: A Double-Blinded, Randomized, Placebo-Controlled Trial. Anesth Analg. 2015 Dec;121(6):1627-31. doi: 10.1213/ANE.0000000000001028.
• O'Flaherty JE, Lin CX. Does ketamine or magnesium affect posttonsillectomy pain in children? Paediatr Anaesth. 2003 Jun;13(5):413-21. doi: 10.1046/j.1460-9592.2003.01049.x.

Study record dates

Study Major Dates

• Study Start (Actual): September 9, 2024
• Primary Completion (Estimated): September 1, 2027
• Study Completion (Estimated): October 1, 2027

Study Registration Dates

• First Submitted: August 5, 2024
• First Submitted That Met QC Criteria: August 17, 2024
• First Posted (Actual): August 20, 2024

Study Record Updates

• Last Update Posted (Estimated): November 12, 2024
• Last Update Submitted That Met QC Criteria: November 9, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: children; pediatric population; adjuvant; inflammatory response; magnesium sulfate; multimodal analgesia; laparoscopic appendectomy; metabolic stress response; hormonal response
• Additional Relevant MeSH Terms: Intestinal Diseases; Infections; Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Cecal Diseases; Intraabdominal Infections; Appendicitis; Calcium-Regulating Hormones and Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Reproductive Control Agents; Anesthetics; Central Nervous System Depressants; Sensory System Agents; Analgesics; Anti-Arrhythmia Agents; Membrane Transport Modulators; Anticonvulsants; Calcium Channel Blockers; Tocolytic Agents; Magnesium Sulfate
• Other Study ID Numbers: Mg01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The datasets used and/or analysed during the study will be available from the corresponding author on reasonable request.

IPD Sharing Time Frame

The study protocol will be available to other researchers continuously after its publication.

The Clinical Study Report will be published after the study completion.

• IPD Sharing Access Criteria: The datasets used and/or analysed during the study will be available from the corresponding author on reasonable request.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; CSR

Drug and device information, study documents

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