Local Anaesthetics Toxicity and Intralipid®

Adverse Effects Clinical Trial

— TOXALIP  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01602250
• Other study ID #: P100501
• Status: Completed
• Phase: Phase 2
• First received: February 23, 2012
• Last updated: December 20, 2016
• Start date: January 2011
• Est. completion date: August 2013

Study information

• Verified date: November 2012
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Ministry of Health
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 16
• Est. completion date: August 2013
• Est. primary completion date: August 2013
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 40 Years

Eligibility

Inclusion Criteria:

• Volunteers ASA1

Exclusion Criteria:

• Pregnancy

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Adverse Effects
• Toxicity

Intervention

Drug:
• placebo
Levobupivacaine 8 mg/min ropivacaine 8 mg/min
• Intralipid®
Levobupivacaine 8 mg/min ropivacaine 8 mg/min Intralipid® 120 ml in one min

Locations

Country	Name	City	State
France	CIC plurithématique Paris-Est (CIC-9304)	Paris

Sponsors (2)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris	Institut National de la Santé Et de la Recherche Médicale, France

Country where clinical trial is conducted

France, 

References & Publications (1)

Dureau P, Charbit B, Nicolas N, Benhamou D, Mazoit JX. Effect of Intralipid® 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.000000000000 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Duration of drug infusion		less than 15 minutes	Yes
Secondary	EEG : electroencephalogram	Detection of sub-clinical seizure activity	< 15 minutes	Yes
Secondary	ECG : electrocardiogram	Duration of PR, QRs intervals	< 15 minutes	Yes
Secondary	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	No