The primary outcome of this study was that chronic exposure to dexamethasone, while inducing resistance to rocuronium, did not have any significant effect on sugammadex reversal in this in vivo study on rats.
This result was contrary to our hypothesis. We considered the following reasons for this unexpected result. First, in rats, the circulation time is faster than that in humans. As the speed of the reversal was extremely fast, it was hard to determine differences in the recovery profiles that may have existed. The use of a single twitch stimulation would have been better. As TOF stimulation usually occurs every 10–15s, 1 Hz single twitch stimulation could have provided the more appropriate resolution to identify the fast recovery from deep neuromuscular block.
Second, we used only healthy young rats in this study. Patients in the intensive care unit may develop resistance to NMBAs during chronic treatment with glucocorticoid; additionally, co-administration of corticosteroid and NMBA can lead to prolonged weakness and even acute myelopathy. Hence, the use of sugammadex as an NMB reversal agent might have resulted in different recovery profiles if rats sick enough to receive ICU care were used in the study.
Third, chronic exposure to dexamethasone is known to induce nAChR upregulation and expression of the immature form of the receptor subunit, causing resistance to NMBA. However, sugammadex encapsulates NMBA molecules, regardless of the receptor’s sensitivity. This may be one of the reasons for no significant difference in the recovery profile with administration of sugammadex, despite the shorter duration of NMB in the group with long-term dexamethasone exposure. Use of anticholinesterases such as pyridostigmine and neostigmine as reversal agents would have resulted in different recovery profiles.
There are few in vivo studies on rats that demonstrate the effect of chronic dexamethasone exposure on sugammadex reversal. Previous studies have reported that resistance to rocuronium-induced NMB was observed in rats with chronic exposure to dexamethasone. The effects of glucocorticoids can be categorised as short-term and long-term treatment effects. The presynaptic effects have been observed during short-term treatment. Synthesis and increased release of acetylcholine have been observed.
The nAChR in the muscle forms a heteropentamer consisting of two alpha, one beta, and one delta subunit with one gamma subunit in the fetal AChR isoform, which is replaced by an epsilon subunit in the adult AChR isoform. During long-term treatment, changes occur in the nAChRs subunit. The epsilon subunit turns into the gamma subunit, which is an immature form that is resistant to NMBAs. Functional upregulation of the nAChRs is observed during both short-term and long-term glucocorticoid treatment, and this has been documented in burns and immobilisation injury[1, 17, 18].
According to a study by Lee et al., resistance to nondepolarising NMBAs, which occurs after immobilisation, might be related to the upregulation of α7-nAChRs. It has also been shown that α7-nAChRs expression occurs after protracted dexamethasone treatment.
One of the limitations is the dosage of sugammadex used in the study. There is no consensus on the recommended dose of sugammadex for an in vivo study using rats, as there are few such studies[15, 20]. Therefore, the dose of sugammadex was determined in a pilot study. The dose of sugammadex that resulted in faster recovery without resulting in an extremely rapid recovery from NMB was chosen. However, when a reduced dose of sugammadex was used, there was no significant difference in TTOFr. However, the concentration (dexamethasone 500 µg kg−1) used in this study far exceeds the typical clinical doses. In clinical concentrations of steroids, there would be no effect on sugammadex reversal.
In conclusion, chronic exposure to dexamethasone while inducing resistance to rocuronium did not have any significant effect on sugammadex reversal in this in vivo study on rats.