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Intravenous lipid emulsion entraps amitriptyline in blood and may lower its brain concentration in pigs

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Heinonen, J.; Litonius, E.; Backman, J. T.; Neuvonen, P. J.; Rosenberg, P. H.

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European Journal of Anaesthesiology (EJA): June 2013 - Volume 30 - Issue - p 3-3
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Background and Goal of Study: Amitriptyline has been shown to be entrapped by intravenous lipid emulsion (ILE) in the circulation1. However, its toxicological therapeutic potential still remains uncertain despite encouraging case reports2. We studied the effect of ILE on amitriptyline concentration in plasma and tissues after its partial distribution in the body, and on haemodynamic recovery.

Materials and Methods: Twenty anaesthetized (2% isoflurane) and monitored pigs, received amitriptyline 10 mg/kg in a central vein in 15 min. After a distribution phase of 30 min the pigs were given ILE (Intralipid® 20%) or Ringer's solution in randomized order in a peripheral vein; a 1.5-ml/kg bolus in 1 min followed by a 0.25-ml•kg-1•min-1 infusion for 29 min. Arterial blood samples were taken during treatment, and brain and heart tissue samples were taken at the end. Amitriptyline levels in plasma (total and non-lipid bound) and in tissue samples were measured using HPLC. Statistics: Mann-Whitney test.

Results and Discussion: Twenty min after start of ILE infusion plasma total amitriptyline concentration was significantly higher than in Ringer group (median (IQR) 0.93 (0.82-1.14) vs 0.69 (0.66-0.92) mg/l), and stayed so until the end of the experiment (0.68 (0.61-0.90) vs 0.51 (0.49-0.65) mg/l). Unentrapped (non-lipid bound) concentrations in ILE group did not differ from total concentrations in Ringer group. Brain and heart amitriptyline concentrations were about 20 and 8 times higher, respectively, than those in plasma. Brain amitriptyline concentration was lower after ILE vs Ringer (10.8 (9.2-13.1) vs 15.3 (11.4-19.1) mg/kg); in heart there was no difference. Amitriptyline caused a 20-30% drop in mean arterial pressure (MAP) which returned to near baseline in 30 min. During ILE/Ringer infusion MAP was stable except in two ILE group pigs that developed severe hypotension (MAP< 25 mmHg) and were given adrenaline. Cardiac conduction times did not differ between groups.

Conclusions: ILE entrapped amitriptyline in the circulation after its distribution into tissues. This entrapment possibly drew amitriptyline from brain. However, ILE did not promote haemodynamic recovery from the intoxication; rather the contrary as during ILE infusion 2/10 pigs were near cardiac arrest.

References:

1. Litonius ES, et al. Basic Clin. Pharmacol. Toxicol. 2012;110:378-83.
    2. Waring WS. Expert Rev. Clin. Pharmacol. 2012;5:437-44.
    © 2013 European Society of Anaesthesiology