Drug overdoses and poisonings are global health problems resulting in several thousands deaths annually. In out-of-hospital setting, one of the most common causes of death is an overdose of tricyclic antidepressant, such as amitriptyline. In the hospital, on the other hand, local anaesthetic systemic toxicity is one of the most feared and potentially a life-threatening complication. Both tricyclic antidepressants and local anaesthetics lack specific antidotes. However, as they all are lipophilic drugs, intravenously administered lipid emulsion has been suggested as a potential treatment for both intoxications. Originally, the proposed mechanism of action of lipid emulsion was a lipid sink that entraps lipophilic drugs and prevents their action in target tissues. Nowadays, lipid emulsion is a recommended treatment for local anaesthetic systemic toxicity in, for instance, the UK and the US in spite of the fact that its actual mechanisms of action and benefit remain uncertain. In the first study of this thesis, the incidence of local anaesthetic systemic toxicity and the adoption rates of lipid emulsion treatment in Finnish anaesthesia departments were elucidated (I). The other studies of this thesis investigate the efficacy of intravenously administered lipid emulsion in both local anaesthetic toxicity and amitriptyline. The effect on lidocaine induced central nervous system toxicity were studied in human volunteers (II). The effect of lipid emulsion on levobupivacaine intoxication in a situation simulating seizures (III), on the tissue distribution of amitriptyline (IV), and on mitochondrial respiration in bupivacaine cardiac toxicity (V) were studied in pigs. In each of these studies an assessment of the degree of the entrapment of the drug by intravenous lipid emulsion was included. The incidence of local anaesthetic systemic toxicity in Finland is low, only 0.7 per 10,000 regional anaesthesias (I). Lipid emulsion treatment is adopted to less than half of the Finnish anaesthesia departments. In human volunteers, lipid emulsion does not affect the electroencephalography changes or the subjective symptoms caused by lidocaine. Lidocaine was also not entrapped into plasma, but its volume of distribution was slightly increased (II). In pigs, lipid emulsion has no effect on levobupivacaine intoxication which is exacerbated by acidosis and hypoxaemia as measured by reversing of electrocardiogram and haemodynamics from toxic changes (III). Levobupivacaine was also not entrapped into plasma. When lipid emulsion was infused in amitriptyline intoxication, amitriptyline was slightly entrapped into circulation and the brain amitriptyline concentration was reduced by 25% (IV). After higher lipid emulsion dose than recommended, recovery from bupivacaine cardiac toxicity was improved through peripheral vasoconstriction (V). Cardiac mitochondrial respiration was also slightly improved at the same time, and bupivacaine was slightly entrapped into plasma. To conclude, this is the first Finnish study to show that the incidence of local anaesthetic toxicity is very low: 0.7 per 10,000. Lipid emulsion can reduce amitriptyline brain concentration but has no effect on local anaesthetic systemic toxicity if used in clinically recommended doses. If a higher dose is administered, lipid emulsion improves recovery from local anaesthetic toxicity through peripheral vasoconstriction in pigs. The safety of the higher dose to men remains, however, unknown.
|Place of Publication||Helsinki : University of Helsinki|
|Publication status||Published - 2016|
|MoE publication type||G5 Doctoral dissertation (article)|
Fields of Science
- 3126 Surgery, anesthesiology, intensive care, radiology