Incompatibility of the short-acting benzodiazepine remimazolam with common perioperative medication

Abstract

Background: Remimazolam is a relatively new benzodiazepine with growing use in procedural sedation and general anaesthesia. Initiated by case reports, the physical incompatibility of remimazolam with ringer's acetated and ringer's lactated solution has been reported. More recently, remifentanil, fentanyl, rocuronium, vecuronium, dexmedetomidine, and midazolam, have been investigated and suggested safe for coadministration with remimazolam. Apart from case reports, incompatibility for other frequently used drugs remains unknown.

Methods: Sixty-five drugs and intravenous fluids were tested for possible precipitation with remimazolam in a simulated y-site administration. Equal volumes of the test drug were injected into the remimazolam solution, examined and photo documented at 1, 15, 30 and 60 min after mixture. Examination was taken by two independent investigators. pH was measured before, and 60 min after mixing the drugs.

Results: Seventeen (26.15%) drugs or fluids showed precipitation, 47 (72.31%) did not show any sign of interaction. Propofol could not be assessed, because of the turbidity of the substance itself. Precipitation occurred immediately and remained stable in all timestamps. The incompatible drug-remimazolam-mixtures had a median pH of 7.15 (6.67, 8.01), the non-precipitating mixtures a median pH of 4.75 (3.8, 5.6). The pH-values of both groups were significantly different (Mann-Whitney-U-test; p < .00001). There is an increasing risk for precipitation with more basic baseline pH-levels of the tested drug. No interaction was seen in baseline pH below 5.

Conclusions: Remimazolam (Byfavo^®) is incompatible with ampicillin/ sulbactam, calcium gluconate, clindamycin, dexamethasone, dimenhydrinate, an 148mval/l electrolyte - glucose 1% solution (E148G1^®), furosemide, a 4% gelatine volume expander (gelafundin^®), heparin sodium, insulin, meropenem, sodium bicarbonate 8.4%, prednisolone, the crystalloid infusions jonosteril^® and sterofundin^®, thiopental and tranexamic acid. The results strongly affirm remimazolam's safety requirements: A separate line for remimazolam and an approved compatible baseline infusion is mandatory and an alternative way to administer bolus medication is required.

Keywords: Coadministration; Incompatibility; Interaction; Precipitation; Remimazolam; Simulated y-site administration.

Fig. 1

pH level of the drug-remimazolam mixtures in relation to the precipitation status. Box and whisker chart showing pH levels of the precipitating mixtures on the left (red) and the non-precipitating mixtures on the right (green). The box shows median and Quartiles, the whiskers are defined by 1.5 times interquartile range. Outliers are shown as dots. Mean pH is indicated as x. The baseline pH of pure remimazolam is, 3.44.

Fig. 2

pH of the test drugs before mixing, grouped in pH ranges on the x axis. Fractions of precipitating drugs in red and non-precipitating drugs in green presented on the y axis. The absolute numbers shown in each respective column. The fraction of precipitating drugs in each individual column is also shown as percentage under each column. There was no drug tested with a baseline pH between 9 and 9.99

Fig. 3

Precipitating mixtures at 1 min after injection. Tubes from left to right: remimazolam (plain), clindamycin, ampicillin/sulbactam, dimenhydrinate, sterofundin^®, meropenem, tranexamic acid, E148G1^®, gelafundin^®, jonosteril^®, calcium gluconate, dexamethasone, insulin, thiopental, prednisolone, heparin sodium, sodium bicarbonate, and furosemide