The results showed that sugammadex reacts with nicardipine and labetalol under in vitro, producing precipitates that could be observed by both the naked eye and light microscopy.
A previous study also reported the formation of white precipitates when sugammadex was mixed with labetalol and, to a lesser degree with epinephrine, vasopressin and hydralazine [7]. Another experiment, in which 57 drugs used in anaesthesia were mixed with sugammadex, indicated that precipitation occurred with amiodarone (50 mg/ml), dobutamine (12.5 mg/ml), and protamine (1000 IU/ml); however, nicardipine and labetalol were not included in this previous study [5]. In contrast, we observed no precipitation in the mixtures of sugammadex with epinephrine, vasopressin or dobutamine. These discrepancy between the studies were probably due to differences in the drug concentrations and manufacturers.
Sugammadex, which is modified gamma-cyclodextrin, has a hydrophobic internal cavity and eight hydrophilic side chains. These structural properties make the complexes of lipophilic molecules and sugammadex water-soluble [8, 9]. Sugammadex and rocuronium form a rigid complex by two mechanisms. Firstly, hydrophobic interactions trap steroidal neuromuscular blocking agents in the cavity. Secondly, electrostatic binding occurs between the negatively charged carboxyl side chain of sugammadex and the positively charged quaternary nitrogen of rocuronium [10, 11]. In addition to aminosteroidal neuromuscular blocking agents, caution is required when using some other medications because they react with sugammadex. For example, the hormonal steroidal contraceptive, etonogestrel, is captured at a rate of 34% by 4 mg/kg sugammadex due to hydrophobic interactions [12]. Interactions due to the side chains of sugammadex have also been reported. For example, negatively charged sugammadex has been reported to react with positively charged protamine to form precipitate [6]. This mechanism may explain our experimental results, i.e. the positively charged amino groups of nicardipine and labetalol were assumed to react with the negatively charged sugammadex. These findings have clinical implications for anaesthesiologists. Firstly, nicardipine, labetalol and sugammadex can be administered within a short time in emergence situations. Insufficient fluid flushing between administrations of these drugs could lead to precipitate formation, resulting in occlusion within the IV tubing. Secondly, changes in the efficacy of sugammadex are also possible, suggesting that residual neuromuscular blockade can occur despite administration of the appropriate dose. Thirdly, the precipitate may form emboli that obstruct blood vessels, resulting in organ damage. Red blood cells have a diameter of 7 µm, so particles larger than this size can clog capillaries. In animal experiments, it has been reported that particles larger than 30 µm caused pulmonary embolism and cerebral infarction [13, 14].
This study had several limitations. Firstly, not all drug classes were included in the investigation. Additional experiments on the interactions of sugammadex with sedatives, narcotic drugs, analgesics, anti-emetics and fluids are required. Secondly, the drugs in this study were selected based on the author’s clinical setting. Drugs made by other manufacturers may show different reactions due to differences in additives or concentrations. Thirdly, it is not yet clear how various substances and enzymes in the plasma affect precipitation. The temperature and pH of plasma are also different from the experimental environment in the present study. Further studies regarding the effects of these reactions on the efficacy of sugammadex are required.