We tested the hypothesis that the solvent for etomidate was a factor in the incidence of pain and other side effects after injection, and that these were associated with histamine release. Nine of 10 volunteers who received etomidate in a propylene glycol formulation reported moderate to severe pain on injection; only one of 10 subjects who received a lipid emulsion formulation reported mild pain (P < 0.05). The incidence of venous sequelae in the injected vein over the next 8 days was 50% in the propylene glycol group and 0% in the lipid emulsion group (P < 0.05). In one volunteer in the propylene group, there was a 13-fold increase in histamine concentrations and in one subject a four-fold increase. In the lipid emulsion group, no volunteer had an increase in histamine concentrations > 1 ng ml-1. We conclude that etomidate formulated in propylene glycol may cause direct injury to vascular endothelium resulting in pain and venous sequelae, whereas etomidate in lipid emulsion does not. There was no relationship between pain or venous sequelae and histamine release.

No abstract

Propylene glycol (PG) is a widely used vehicle for water-insoluble drugs. Injection of drugs formulated with this solvent often results in pain, thrombosis, or thrombophlebitis that can be reduced by premedication with local anesthetics or opioids. Because osmolality and pH that are unphysiologic may cause these adverse effects, we assessed the contribution of PG to the osmolality of parenteral drug formulations. Osmolality of PG measured in distilled water showed that PG content and osmolality were directly related: 2% wt/vol PG, 264 mOsm/L; 100% PG, 15, 200 mOsm/L. The osmolalities of commercially available preparations of drugs dissolved in PG ranged from 365 mOsm/L (2% PG content) to 12,800 mOsm/L (83.46% PG), with most above 1000 mOsm/L. Replacement of PG by a solvent with lower osmolality in Germany has effectively reduced the incidence of side effects for one drug. Until PG can be replaced in drugs, we recommend diluting drugs in a large volume of saline solution; this may help to minimize the undesirable effects of this solvent.

We sought to determine if the solvent in the formulation of etomidate is responsible for haemolysis in patients. In a randomized, prospective, double-blind study of 49 patients undergoing otolaryngological surgery, patients received etomidate dissolved in propylene glycol or in lipid emulsion. Concentrations of free haemoglobin and haptoglobin were measured before and for up to 360 min after injection of etomidate. Free haemoglobin concentrations increased by 216.8 mg litre-1 in patients who received the propylene glycol formulation and by 11.8 mg litre-1 in the lipid emulsion group (P < or = 0.0004). Correspondingly, reductions in haptoglobin concentrations were significantly greater in the propylene glycol group (P < or = 0.002). We conclude that with respect to haemolysis, lipid emulsion is superior to propylene glycol as a solvent for etomidate.

Patients receiving intravenous morphine at doses of 0.3 and 1.0 mg/kg for general anesthesia have been reported to show significant elevations in plasma histamine that are associated with hemodynamic changes. We undertook a prospective, randomized, double-blind trial in which 0.15 mg/kg morphine or 0.3 mg/kg nalbuphine was administered intravenously to normal volunteers. Thirteen of 15 subjects receiving morphine and 10 of 14 subjects receiving nalbuphine had elevations in plasma histamine levels and symptoms of histamine release within 5 minutes of drug administration. Six subjects in the morphine group and five in the nalbuphine group exhibited levels of plasma histamine > 2.0 ng/ml, but these levels were not associated with hemodynamic changes and occurred 10 to 15 minutes after drug administration. Our study suggests that the opiate-induced elevation of plasma histamine derives from cutaneous mast cells.