INTRODUCTION: Intravenous lipid emulsion (ILE) has been shown to ameliorate toxicity from lipophilic xenobiotics, attributed in part through sequestration to circulating lipid droplets (sink). We postulated additional benefit with plasma exchange therapy undertaken subsequent to lipid injection, hypothesising enhanced blood carriage of lipophilic toxin to increase yield when combined with an extracorporeal method of elimination. METHODS: Instrumented rabbits underwent clomipramine infusion at 3.2 mg/kg/min to target mean arterial pressure (MAP) of 50% baseline, then continuously at 2 mg/kg/min to death or 90 min. Resuscitation with saline (Control), sodium bicarbonate (BIC), ILE, or lipid emulsion plus cycled plasma exchange (LEPE), was commenced on attaining target MAP. RESULTS: Greater survival was observed in animals receiving lipid emulsion from both LE and LEPE groups (Control median 12.0 [IQR 10.5 – 20] min, BIC median 30 [IQR 19 – 33] min, LE 85 [IQR 30 – 90] min, LEPE 90 min; P 0.0001). No difference was observed in MAP, Heart Rate, or Electrocardiograph QRS duration between surviving LE and LEPE animals at 90 min. Mean plasma exchange of 52%circulating plasma volume returned only 0.04% of the administered clomipramine load in LEPE group animals. CONCLUSIONS: Infusion of lipid emulsion resulted in greater survival in this rabbit model of intravenous clomipramine toxicity. Plasma exchange performed in conjunction with administration of lipid emulsion failed to result in significant extracorporeal clomipramine elimination. Intravascular lipid sequestration of clomipramine appears an inadequate sole explanation for the beneficial effects of lipid emulsion.
INTRODUCTION: Intravenous lipid emulsion (ILE) has been shown to ameliorate toxicity from lipophilic xenobiotics, attributed in part through sequestration to circulating lipid droplets (sink). We postulated additional benefit with plasma exchange therapy undertaken subsequent to lipid injection, hypothesising enhanced blood carriage of lipophilic toxin to increase yield when combined with an extracorporeal method of elimination. METHODS: Instrumented rabbits underwent clomipramine infusion at 3.2 mg/kg/min to target mean arterial pressure (MAP) of 50% baseline, then continuously at 2 mg/kg/min to death or 90 min. Resuscitation with saline (Control), sodium bicarbonate (BIC), ILE, or lipid emulsion plus cycled plasma exchange (LEPE), was commenced on attaining target MAP. RESULTS: Greater survival was observed in animals receiving lipid emulsion from both LE and LEPE groups (Control median 12.0 [IQR 10.5 – 20] min, BIC median 30 [IQR 19 – 33] min, LE 85 [IQR 30 – 90] min, LEPE 90 min; P 0.0001). No difference was observed in MAP, Heart Rate, or Electrocardiograph QRS duration between surviving LE and LEPE animals at 90 min. Mean plasma exchange of 52%circulating plasma volume returned only 0.04% of the administered clomipramine load in LEPE group animals. CONCLUSIONS: Infusion of lipid emulsion resulted in greater survival in this rabbit model of intravenous clomipraminetoxicity. Plasma exchange performed in conjunction with administration of lipid emulsion failed to result in significant extracorporeal clomipramine elimination. Intravascular lipid sequestration of clomipramine appears an inadequate sole explanation for the beneficial effects of lipid emulsion.
Authors: Michael R Fettiplace; Kinga Lis; Richard Ripper; Katarzyna Kowal; Adrian Pichurko; Dominic Vitello; Israel Rubinstein; David Schwartz; Belinda S Akpa; Guy Weinberg Journal: J Control Release Date: 2014-12-04 Impact factor: 9.776