Local Anaesthetics Toxicity and Intralipid® (TOXALIP)

Prevention of Systemic Toxicity Induced by Levobupivacaine and Ropivacaine by Intralipid®

The systemic toxicity of local anaesthetics may be treated using lipid emulsions ("lipid rescue"). However, there is no evidence-based proof of the efficacy of the treatment. The aim of the intended protocol is to study the effect of the emulsion Intralipid® on the toxicity prodromes in volunteers receiving either levobupivacaine or ropivacaine. After a sensitization session with lidocaine, subjects will receive in a double blind, crossover manner an i.v. infusion of levobupivacaine or ropivacaine followed by a rapid infusion of Intralipid®. The primary outcome will be the time of appearance of early neurologic signs of toxicity. In addition, the EEG and ECG will be monitored and blood sampling will be performed in order to evaluate the changes in pharmacokinetics induced by the emulsion.

Study Overview

• Status: Completed
• Conditions: Toxicity; Adverse Effects
• Intervention / Treatment: Drug: placebo; Drug: Intralipid®

Detailed Description

Regional anaesthesia may induce toxic neurologic and cardiac reactions related to inadvertent intravenous injection or rapid absorption of local anaesthetics. Despite the appearance of the less toxic agents ropivacaine and levobupivacaine, the problem remains. Recently, a new therapeutics called "lipid rescue" emerged. This rapid injection of a lipid emulsion is supposed to act as a lipid sink, thus delaying the release of the toxic molecules to the target organs. Animal studies as well as clinical reports seem to favour this treatment. However, there is no evidence-based proof of the efficacy of this "lipid rescue".

The aim of the study is 1) to verify the efficacy of a lipid emulsion (Intralipid® 20%) on the toxicity induced by the local anaesthetics ropivacaine and levobupivacaine and 2) to compare the effect of the emulsion on the two agents.

Sixteen volunteers with strictly normal ECG and EEG will participate to the study.

After a sensitization session with lidocaine, the subjects will receive levobupivacaine or ropivacaine i.v. at a rate of 8 mg/min (max 120 mg) followed two minutes after the beginning of infusion by a bolus injection of Intralipid® 20% or of saline 120 mL in 1 minute. The infusion of local anaesthetics will be stopped immediately at the appearance of the early signs of toxicity. In addition to the recognition of the signs by the subject (trained by the sensitization session), an anaesthesiologist will ask if the subject has any symptom. A continuous monitoring of the EEG and of the ECG will be performed.

Sixteen subjects completing the study have been considered necessary to achieve a power of 90 % with an alpha risk of 5 %. A mean time to first signs of 3.8 ± 1.2 min has been considered in the placebo groups. A 45 % difference in the primary outcome has been considered. The study will be double blind crossover as a Latin square (four treatments, four sessions, four replications).

The investigators will consider the time between infusion initiation and appearance of the early signs of toxicity as primary outcome. The secondary outcomes will be the changes in ECG and EEG variables and the pharmacokinetic parameters observed. For that purpose, blood will be sampled until the 8th hour after the beginning of local anaesthetic infusion.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Paris, France, 75013
    • CIC plurithématique Paris-Est (CIC-9304)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 36 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Volunteers ASA1

Exclusion Criteria:

• Pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: levobupivacaine placebo	Drug: placebo; Levobupivacaine 8 mg/min ropivacaine 8 mg/min; Other Names: ropivacaine; levobupivacaine
Experimental: levobupivacaine Intralipid®	Drug: Intralipid®; Levobupivacaine 8 mg/min ropivacaine 8 mg/min Intralipid® 120 ml in one min
Experimental: ropivacaine Intralipid®	Drug: Intralipid®; Levobupivacaine 8 mg/min ropivacaine 8 mg/min Intralipid® 120 ml in one min
Placebo Comparator: ropivacaine placebo	Drug: placebo; Levobupivacaine 8 mg/min ropivacaine 8 mg/min; Other Names: ropivacaine; levobupivacaine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Duration of drug infusion	less than 15 minutes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
EEG : electroencephalogram	Detection of sub-clinical seizure activity	< 15 minutes
ECG : electrocardiogram	Duration of PR, QRs intervals	< 15 minutes
pharmacokinetics of local anesthetics (Area under the plasma concentration versus time curve (AUC))	blood concentration of local anesthetics during 8 hours post administration : Area under the plasma concentration versus time curve (AUC)"	8 h

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Institut National de la Santé Et de la Recherche Médicale, France
• Investigators: Principal Investigator: Dan Benhamou, Assistance Publique - Hôpitaux de Paris

Publications and helpful links

General Publications

• Dureau P, Charbit B, Nicolas N, Benhamou D, Mazoit JX. Effect of Intralipid(R) on the Dose of Ropivacaine or Levobupivacaine Tolerated by Volunteers: A Clinical and Pharmacokinetic Study. Anesthesiology. 2016 Sep;125(3):474-83. doi: 10.1097/ALN.0000000000001230.

Study record dates

Study Major Dates

• Study Start: January 1, 2011
• Primary Completion (Actual): August 1, 2013
• Study Completion (Actual): August 1, 2013

Study Registration Dates

• First Submitted: February 23, 2012
• First Submitted That Met QC Criteria: May 16, 2012
• First Posted (Estimate): May 18, 2012

Study Record Updates

• Last Update Posted (Estimate): December 21, 2016
• Last Update Submitted That Met QC Criteria: December 20, 2016
• Last Verified: November 1, 2012

More Information

Terms related to this study

• Keywords: Toxicity; Adverse effects; Anesthetics, local
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Sensory System Agents; Anesthetics; Anesthetics, Local; Pharmaceutical Solutions; Parenteral Nutrition Solutions; Fat Emulsions, Intravenous; Ropivacaine; Soybean oil, phospholipid emulsion; Levobupivacaine
• Other Study ID Numbers: P100501