Evaluating the effects and safety of intravenous lipid emulsion on haloperidol-induced neurotoxicity in rabbit

Abstract

There are many reports on the effect of intravenous lipid emulsion (ILE) as an antidote in drugs related toxicities. We determined the effects of ILE on neurotoxicity of haloperidol (HA), a highly lipophilic antipsychotic, as a model of antipsychotics poisoning. We used six groups of five male rabbits. Two groups received distilled water intravenously followed by infusions of either 18 mL/kg of normal saline or ILE 20%, after 30 minutes. The third group received 18 mL/kg of normal saline after HA (2.6 mg/kg) administration. The three other groups received ILE 20% solution (6, 12, and 18 mL/kg) following HA injection. Catalepsy scores, temperature, pupil size, and mortality rate were measured at 0, 0.5, 1, 2, 3, 4, 8, and 24 hours after HA administration began. Blood and tissue samples were taken from all animals at 24 hours or at death time for biochemical, cell count, and pathological studies. ILE reversed cataleptic scores, miotic pupils, and hypothermia of HA intoxication much faster than normal saline (P < 0.001). Biochemical complications and mortality rate of the animals were significantly higher in the HA + 18 mL/Kg ILE group. ILE reversed sings of HA neurotoxicity; however, synergistic effect of high dose of ILE and HA increased complications and mortality.

Figure 1

Evaluation of rectal temperatures changes in haloperidol (HA) intoxicated rabbits that received various doses of intravenous lipid emulsion (ILE) or normal saline. Starting of HA or AWD infusion: zero time. ILE or normal saline were infused at 0.5 hour. Difference between ILE 6 and ILE 12 with NC was not significant at second hour. *P < 0.05, **P < 0.01, NS: not significant, ADW: aseptic distilled water.

Figure 2

Evaluation of pupil size (millimeter) changes in haloperidol (HA) intoxicated rabbits that received various doses of intravenous lipid emulsion (ILE) or normal saline. Starting of HA or AWD infusion: zero time. Infusion of ILE or normal saline was started at 0.5 hour. *P < 0.05, **P < 0.01, ***P < 0.001, NS: not significant, ADW: aseptic distilled water.

Figure 3

Evaluation of cataleptic score (malpositioned forelimb on back) changes in haloperidol (HAL) intoxicated rabbits that received various doses of intravenous lipid emulsion (ILE) or normal saline. Starting of HAL or AWD infusion: zero time. Infusion of ILE or normal saline was started at 0.5 hour. *P < 0.05, **P < 0.01, ***P < 0.001, ADW: aseptic distilled water. At the second hour, P  value of difference between means of latency time of ILE 12 and ILE 18 with HAL + normal saline <0.05. At the third hour, P value of difference between means of latency time of ILE 6, ILE 12, and ILE 18 with Hal + normal saline <0.001.

Figure 4

Evaluation of cataleptic score (extended and rotated forelimb) changes in haloperidol (HAL) intoxicated rabbits that received various doses of intravenous lipid emulsion (ILE) or normal saline. Starting of HAL or AWD infusion: zero time. Infusion of ILE or normal saline was started at 0.5 hour.  *P < 0.05, **P < 0.01, ***P < 0.001, NS: not significant, ADW: aseptic distilled water.

Figure 5

Evaluation of cataleptic score (standing time) in haloperidol (HAL) intoxicated rabbits that received various doses of intravenous lipid emulsion (ILE) or normal saline. Starting of HAL or AWD infusion: zero time. Infusion of ILE or normal saline was started at 0.5 hour. *P < 0.05, **P < 0.01, ***P < 0.001, NS: not significant, ADW: aseptic distilled water. At the 2nd hour, P value of difference between means of standing time of ILE 6, ILE 12, and ILE 18 <0.01. At the 2nd hour, P value of difference between means of standing time of ILE 6, ILE 12, and ILE 18 with HAL + normal saline <0.001.

Figure 6

Means of white blood cell (WBC) count in haloperidol (HAL) intoxicated rabbits that received various doses of intravenous lipid emulsion (ILE) or normal saline, at 24 hours after starting HAL or AWD infusion. *P < 0.05, ADW: aseptic distilled water.

Figure 7

The means of lung lesion scoring of rabbits treated by haloperidol (HAL) and intravenous lipid emulsion (ILE) or normal saline (NS). **P < 0.01, ***P < 0.001, ADW: aseptic distilled water.

Figure 8

Lung slides of rabbits treated by haloperidol (HAL) and intravenous lipid emulsion (ILE) or normal saline (NS). Magnification = ×400. (a) Received aseptic distilled water and 18 mL/kg ILE 20%. (b) Received HAL and 18 mL/kg normal saline. (c) Received HAL and 12 mL/kg of ILE 20%. (d) Received HAL and 18 mL/kg of ILE20%.