An update on remimazolam and anaphylaxis

Anaphylaxis is a severe reaction that can be life threatening in cases with major respiratory or cardiovascular reactions.1 The incidence of anaphylaxis during general anaesthesia ranges from 1:10 000 to 1:20 000 with a case fatality rate ranging from 3 to 9%.2 Remimazolam (CNS 7056) is a benzodiazepine with an ultra-short half-life that targets GABA receptors, specifically GABAAα subunits. Remimazolam is degraded by liver carboxyesterase. Remimazolam has remarkable activity with a fast onset and fast recovery profile; it also has moderate haemodynamic side effects.3 Remimazolam was initially developed for procedural sedation for procedures such as colonoscopy 4 and bronchoscopy.5 More recently, remimazolam has been developed for total intravenous anaesthesia in major noncardiac surgery.6,7 Remimazolam was officially approved as a novel anaesthetic agent in Japan in January 2020, and it then received marketing authorisation in Europe in March 2021 for the indication of procedural sedation.8 Recently, anaphylactic issues have been reported with the use of remimazolam,9–13 these 10 cases having been reported in Japan and South Korea. Clinical symptoms were frequently major cardiovascular events (hypotension, shock, and cardiac arrest),9–13 and less frequently respiratory or cutaneous signs.13 In all cases, the outcome was good, adequate resuscitation was provided, and epinephrine was used. Investigators were able to confirm the relationship between anaphylaxis and remimazolam in four patients in Japan and four patients in South Korea. Two patients never underwent skin tests rendering the imputation of remimazolam less clear. In the eight patients with skin tests 3–4 weeks after anaphylaxis, confirming the imputation of remimazolam, one of them showed a potential cross-reaction with midazolam.12 This patient received general anaesthesia with midazolam a few weeks before his anaphylaxis with remimazolam.12 No major clinical events were reported at the time but there may have been potential sensitisation with midazolam. Allergy to benzodiazepines is a rare but well described phenomenon.14 Thus, anaphylaxis to remimazolam, which is structurally similar to midazolam, is a potential complication and should be closely monitored in the coming years owing to the development and growing use of the product. Interestingly, in the majority of cases,9,10,13 skin tests revealed a positive reaction to remimazolam but not to midazolam. Consequently, isolated allergy to remimazolam is possible. At this point, some elements require further exploration. For instance, in large multicentre studies on procedural sedation or during prolonged infusion with total intravenous anaesthesia, no events compatible with anaphylaxis have been reported in previously published studies.5,7 As the rate of anaphylaxis remains very low, these studies might not have had the power to explore this adverse effect. Thus, it must be kept in mind that anaphylaxis after remimazolam infusion exists. Close monitoring of anaphylaxis of remimazolam would be a valuable asset in the future to better delineate the true incidence of this phenomenon and anaphylaxis secondary to benzodiazepines in general. The pathophysiology of anaphylaxis is a complex phenomenon, which involves immunoglobulin E (IgE) mediated pathways with an activation of mast cells and basophils, or non-IgE pathways with various activations such as neutrophils, endothelial cells, and others.15 Some antigens may induce both pathways. Given the very recent attribution of anaphylaxis to remimazolam, it is difficult to ascertain which mechanisms are involved, but the positivity of skin test reactions suggests a non-IgE mediated pathway.13,15 Overall, where allergy to remimazolam is suspected, no specific treatment can be administered. Remimazolam must be discontinued at once, and symptomatic treatment of circulatory or respiratory failure must be managed with epinephrine. Other symptomatic unspecific interventions must be performed according to clinical presentation. Immediate assay of histamine and tryptase are mandatory, with a second assay at day +1. Specific skin prick test 4 weeks after the event also appear to be mandatory, with different allergens being tested. Obviously, remimazolam must be tested, as well as midazolam since there is a potential cross-anaphylaxis. Finally, dextran 40 is an excipient in the solution of remimazolam and should also be tested,9 since this agent has been previously identified as an allergen. Moreover, it should be kept in mind that, for skin prick tests, only remimazolam solutions are available at the moment and not pure remimazolam. Hence, it is possible that other allergens may occur in the solution if unreported ingredients or contaminants are present. Finally, the dextran 40 used in prick tests may not be exactly the same as that in the remimazolam solution. Therefore, a negative prick test may not rule out an allergy to dextran.