Year: 2012
Type: dissertation
Abstract: Drug overdoses are the most common intoxications requiring hospitalisation. Severe toxicity can also occur during regional anaesthetic procedures due to inadvertent intravascular injection or rapid absorption of large doses of local anaesthetic. In severe cases, the outcome may be the death of the patient, despite the best currently available treatment. Recently, a rapidly administered large dose of lipid emulsion has been proposed as a treatment alternative based on encouraging results from animal studies and published case reports of its successful use. The mechanism by which lipid emulsion mitigates intoxication is thought to be the entrapment of lipophilic drugs into a lipid sink formed by the lipid emulsion in plasma. This thesis consists of a series of studies on the entrapment effect of lipid emulsion on lipophilic drugs. The drugs studied are amiodarone (octanol:water distribution logP 7.24), bupivacaine (logP 3.31), mepivacaine (logP 2.16), and amitriptyline (logP 5.10). An anaesthetized pig model of intoxication was used in four of the studies, allowing evaluation of the effect of lipid therapy on the recovery from severe intoxication. A study comparing the entrapment of bupivacaine by a commercially available lipid emulsion to the experimental POPC/POPG lipid dispersion in pigs was performed after in vitro experiments suggesting that POPG/POPG dispersion had superior entrapment capability. In addition, a human study of the effect of lipid emulsion on the pharmacokinetics of a non-toxic intravenous dose of bupivacaine was also performed. When a toxic dose of amiodarone was infused concurrently with lipid emulsion in a pig model, amiodarone was highly entrapped and its hypotensive adverse effect prevented. Lipid emulsion infusion following severe amitriptyline intoxication entrapped amitriptyline for the duration of the infusion, but improved neither the pigs recovery nor survival compared to placebo. When pigs were infused with the lipid emulsion following severe bupivacaine or mepivacaine intoxication, no significant entrapment occurred and no improvement of recovery compared to placebo was detected. The POPC/POPG lipid dispersion did not cause superior entrapment of bupivacaine compared to Intralipid® in pigs. In human volunteers, lipid emulsion compared to placebo decreased the context-sensitive half-life of a non-toxic dose of bupivacaine from 45 minutes to 25 minutes, but did not affect free plasma concentrations. In summary, this thesis found little evidence for the current clinical use of lipid emulsion for the treatment of severe intoxications in the models used. Only in the case of amiodarone was a clear effect of lipid emulsion shown. This suggests that only extremely lipophilic substances are affected significantly by lipid emulsion in this setting.
Source: Työväentutkimus Vuosikirja
Author: Erik Litonius
Language: English
Subfield: Emergency Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2169216282