Nebulized Analgesia for Laparoscopic Appendectomy Trial (NALA)

Evaluation of the Effect of Intraperitoneal Nebulized Ropivacaine on Morphine Consumption After Laparoscopic Appendectomy in Children. A Prospective, Randomized Double Blind Clinical Trial

The objective of this study is to assess whether the administration of nebulized intra-peritoneal ropivacaine at the onset of surgery, compared with nebulized saline, reduces morphine consumption after laparoscopic appendectomy surgery in children and adolescents.

Study Overview

• Status: Unknown
• Conditions: Appendicitis
• Intervention / Treatment: Drug: Ropivacaine; Drug: Normal saline

Detailed Description

The laparoscopic approach to pediatric appendectomy is gaining in popularity and has been demonstrated to reduce complications and improve resource utilization. The procedure has a documented association with high postoperative pain intensity, and is associated with substantial pain (pain scores >4 for >60% of the time) in 33% of patients. This is due to surgical manipulation, but also to the intraperitoneal insufflation of carbon dioxide required during laparoscopy which results in in peritoneal stretching, diaphragmatic irritation, changes in intra-abdominal pH as well as retention of insufflation gas in the abdominal cavity after surgery.

Opioid analgesics, especially morphine, are the most common pharmacological option for treating postoperative pain in pediatric patients. Although morphine is generally considered safe to use in pediatric patients, physicians and caregivers often hesitate to prescribe or administer opioids because of the perceived risk of addiction or undesirable side effects. Efforts to mitigate the use of opioids as systemic analgesia after surgery appears warranted. The topical administration of analgesics/anesthetics via the peritoneum is biologically advantageous as intra-abdominal gas insufflation and the resultant increased intra-abdominal pressure generates peritoneal inflammation and neuronal rupture with a linear relationship between abdominal compliance during the procedure and the severity of postoperative pain.

Intraperitoneal nebulization of local a anesthetic agent is a relatively novel approach to pain management after laparoscopy. Intraperitoneal nebulization of local anesthetic allows a uniform dispersion of the agent throughout the peritoneum and combines the analgesic benefits of gas conditioning and local anesthetic instillation. Microvibration-based aerosol humidification devices (i.e. cold nebulization) deliver significant amounts of local anesthetics in the abdominal cavity. Animal studies have confirmed the safety and bioavailability of nebulized ropivicaine in the abdominal cavity. The pharmacokinetics of nebulized ropivacaine 3 mg/kg is similar to that of instilled ropivacaine and maximal ropivacaine concentrations have been found to lie well within safe ranges. Human studies have confirmed favorable pharmacokinetics and pharmacodynamics of nebulized ropivacaine. Peak concentration is attained between 10 and 30 minutes following the end of aerosolized ropivacaine delivery. Aerosolized intraperitoneal local anesthetic is feasible, with ropivacaine concentrations remaining within safe levels.

In previous randomized controlled trials in adults, nebulization of ropivacaine 30 mg with the Aeroneb Pro system either before or after laparoscopic cholecystectomy reduces postoperative pain (effect size - 33% to - 50%) as well as completely prevents shoulder pain compared with nebulization of saline. Patients receiving ropivacaine nebulization consumed significantly less morphine than those in the control group (effects size 40% to -56%). Patients receiving ropivacaine nebulization mobilized quicker than those receiving placebo with a 33% reduction on unassisted walking time after surgery. The duration of analgesia after both pre- and postoperative nebulization (up to 48 hours) was significantly longer than the expected duration of ropivacaine, based on its mechanism of action. No adverse events were reported during the conduct of these trials. Ropivicaine nebulization has also been evaluated in the context of gynecological surgery; patients receiving Ropivacaine 30 mg before or after surgical stimulation reported significantly less postoperative pain (-50%) and consumed significant less morphine (-40%) and walked without assistance than those receiving ropivacaine instillation during the first 24 hours after surgery. Furthermore, the administration of intraperitoneal aerosolized bupivacaine just prior to incising the peri-renal fascia appears to be a simple, effective and low-cost method to reduce postoperative pain in children undergoing laparoscopic pyeloplasty in children.

Given the consistently safe and favorable results documented with adult patients, the working study hypothesis is that the intra-abdominal administration of nebulized ropivacaine immediately before the onset of surgery will reduce post-operative pain and morphine consumption after laparoscopic appendectomy in children and adolescents.

• Study Type: Interventional
• Enrollment (Anticipated): 200
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Robert Baird, MDCM MSc; Phone Number: 24438 514 412 4400; Email: robert.baird@mcgill.ca
• Study Contact Backup: Name: Pablo Ingelmo, MD; Phone Number: 24886 514 412 4400; Email: pablo.ingelmo@mcgill.ca

Study Locations

• Canada
  • Quebec
    • Montreal, Quebec, Canada, H4A 3J1
      • Recruiting
      • Montreal Children's Hospital
      • Contact: Robert Baird, MDCM MSc; Phone Number: 24438 514 412 4400; Email: robert.baird@mcgill.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 7 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Children and adolescents aged 7-18 years old
• ASA Score I (American Society of Anesthesiologists classification) [Appendix 1]: a normal healthy patient.
• ASA Score II (American Society of Anesthesiologists classification): A patient with mild systemic disease
• Patients scheduled for laparoscopic appendectomy surgery

• Uncomplicated appendicitis

  • Hemodynamically stable patient
  • No evidence of appendiceal perforation based on preoperative clinical and imaging assessment
  • Diagnosed to have simple acute appendicitis by intraoperative laparoscopy
• Patients who have provided a written informed assent
• Caregivers who have provided a written informed consent

Exclusion Criteria:

• ASA Score III (American Society of Anesthesiologists classification): A patient with severe systemic disease
• ASA Score IV (American Society of Anesthesiologists classification): A patient with severe systemic disease that is a constant threat to life
• ASA Score V (American Society of Anesthesiologists classification): A moribund patient who is not expected to survive without the operation
• Hemodynamically unstable patient
• Evidence of appendiceal perforation on based on preoperative clinical and imaging assessment
• Perforated or gangrenous appendicitis diagnosed during laparoscopic surgery
• Postoperative admission in an intensive care unit with sedation or ventilatory assistance
• Cognitive impairment or mental retardation
• Progressive degenerative diseases of the CNS
• Seizures or chronic therapy with antiepileptic drugs
• Severe hepatic or renal impairment
• Allergy to one of the specific drugs under study
• Alcohol or drug addiction
• Failure to successfully undergo a laparoscopic appendectomy
• A significant communication problem including language barrier, precluding phone follow up
• Participation in a concomitant research study
• Inability to assure complete follow up
• Failure to acquire informed consent and assent

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ropivacaine Group; This group will receive nebulized ropivacaine 0.5% based on ideal body weight at a dose of 0.5 mg/kg with a maximum total dose of 30 mg. This will be administered once at the onset of pneuomoperitoneum during appendectomy.	Drug: Ropivacaine; Ropivicaine will be administered via in-line nebulization using the Aeroneb Pro™ system; Other Names: Naropin
Placebo Comparator: Placebo group; This group will receive placebo (normal saline) based on ideal body weight at a dose of 0.5 mg/kg with a maximum total dose of 30 mg. This will be administered at the onset of pneuomoperitoneum during appendectomy.	Drug: Normal saline; Normal saline will be administered via in-line nebulization using the Aeroneb Pro™ system; Other Names: 0.9% saline
No Intervention: Non-enrolled group; This group will not receive either intervention (ropivicaine) or placebo (normal saline), but will have primary and secondary endpoints evaluated.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Post-operative morphine consumption	The total dose of Morphine (in mg/kg) and the route of administration received after surgery will be recorded. The oral morphine dose will be converted as 1mg IV= 2mg PO.	During hospital admission (24-48 hours)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Post-operative Pain	This will be serially evaluated using a Visual Analog Score	During hospital admission (24-48 hours)
Time to unassisted walking		During hospital admission (24-48 hours)
In-hospital length of stay		During hospital admission (24-48 hours)
Postoperative recovery quality	This will be evaluated via a standardized telephone questionnaire	Two weeks after hospital discharge
Surgeon satisfaction	this will be evaluated via a questionnaire	Immediately after surgery

Collaborators and Investigators

• Sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre
• Collaborators: Montreal Children's Hospital of the MUHC
• Investigators: Principal Investigator: Robert Baird, MDCM MSc, Assistant Professor of Pediatric Surgery

Publications and helpful links

General Publications

• Baird R, Ingelmo P, Wei A, Meghani Y, Perez EV, Pelletier H, Auer G, Mujallid R, Emil S, Laberge JM, Puligandla P, Shaw K, Poenaru D. Nebulized analgesia during laparoscopic appendectomy (NALA): A randomized triple-blind placebo controlled trial. J Pediatr Surg. 2019 Jan;54(1):33-38. doi: 10.1016/j.jpedsurg.2018.10.029. Epub 2018 Oct 5.

Study record dates

Study Major Dates

• Study Start: January 1, 2016
• Primary Completion (Anticipated): June 1, 2017
• Study Completion (Anticipated): July 1, 2017

Study Registration Dates

• First Submitted: December 3, 2015
• First Submitted That Met QC Criteria: December 3, 2015
• First Posted (Estimate): December 8, 2015

Study Record Updates

• Last Update Posted (Estimate): March 22, 2016
• Last Update Submitted That Met QC Criteria: March 21, 2016
• Last Verified: March 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Infections; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; Cecal Diseases; Intraabdominal Infections; Appendicitis; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Sensory System Agents; Anesthetics; Anesthetics, Local; Ropivacaine
• Other Study ID Numbers: 14-120-PED

Plan for Individual participant data (IPD)

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