Incompatibility of remimazolam besylate with Ringer's acetate infusion resulting in total occlusion of an intravenous catheter

Abstract

Remimazolam besylate is an ultra-short-acting benzodiazepine derivative recently approved in Japan for general anaesthesia. However, less attention has been paid to the compatibility of remimazolam with infusion solutions, and the mechanism underlying the incompatibility remains unknown. The patient was a 65-year-old man who underwent a high tibial osteotomy. After the induction of general anaesthesia using remimazolam solution (5 mg/mL), we noticed precipitate completely blocking the lumen of the intravenous tube connected to a Ringer's acetate Physio140 drip. The mixture of remimazolam solution (5 mg/mL) with Physio140 solution immediately resulted in the formation of substantial precipitate. Nuclear magnetic resonance analysis revealed that the precipitate was remimazolam. Ultraviolet spectrophotometry revealed that the mixture of remimazolam solution with higher ratios of Physio140 resulted in significantly lower solubility, concomitant with an increase in pH. It would be important to consider the remimazolam concentration and infusion solution pH to avoid the production of precipitates.

Keywords: anaesthesia; drug interactions; safety.

Figure 1

Precipitation produced by the mixture of remimazolam and Ringer’s acetate. (A) Gross appearance of the mixture of remimazolam solution at 5 mg/mL and equal volume of Ringer’s acetate Physio140. (B) Proton nuclear magnetic resonance spectra (500 MHz) of the precipitate. The precipitate was washed with distilled water and dried, and the precipitation was dissolved in CDCl₃. The spectra of the sample were δ 8.56 (d, J=4.0 Hz, 1H), 8.16 (d, J=8.0 Hz, 1H), 7.78 (td, J=7.7, 1.7 Hz, 1H), 7.70 (dd, J=8.6, 2.3 Hz, 1H), 7.63 (d, J=2.3 Hz, 1H), 7.34–7.32 (m, 1H), 7.28 (d, J=8.6 Hz, 1H), 6.85 (d, J=1.1 Hz, 1H), 4.04–4.02 (m, 1H), 3.65 (s, 3H), 2.86–2.74 (m, 4H) and 2.32 (s, 3H) using tetramethylsilane as an internal reference, which are consistent with that of remimazolam. (C) Solubility of remimazolam. Concentration of remimazolam was measured by ultraviolet absorption compared with remimazolam at 5 mg/mL. Remimazolam amount in supernatant was calculated as per cent of absorbance of supernatant at 230 nm to those of mixture. Precipitations were developed at a ratio of 1:1 to 1:4 (open), but not 1:8 or standard remimazolam solution at 5 mg/mL (closed). Bars, SD. ***P<0.001 compared with control. ND, not detectable. All experiments were performed at least three times.