The present study constitutes the first randomized controlled trial to evaluate sugammadex use following a rocuronium bolus and continuous infusion in the OLT setting. Our main finding is that, as was expected, sugammadex results in a considerably shorter recovery time than neostigmine, although the absolute value was longer than expected, considering previously reported data in the literature regarding other (non OLT) operative settings. The mean recovery time for sugammadex in our population was 9.4 min, which is longer than that reported in other studies after sevoflurane anaesthesia15, with 33% of patients requiring more than 10 minutes to achieve a TOFR > 0.9. This should be taken into account in clinical practice when waking patients up at the end of transplantation. However, sugammadex retained its well-known advantage as it regards recovery time over neostigmine, which had a mean recovery time of 34.6 min. Of important note is the fact that 19% of the patients in the neostigmine group required more than 60 minutes to recover from NMB, with a maximum value that exceeded 100 minutes.Previous studies using rocuronium-sugammadex in patients affected by liver disease undergoing hepatic resection have demonstrated the well-known advantage of sugammadex over neostigmine in the above-mentioned setting24-25. However, OLT differs greatly from general surgery or liver resection surgery: for instance, blood loss and duration of surgery may be significantly greater in OLT. Furthermore, the severity of the liver disease can play a role: the patients enrolled onto our study were more critical than those enrolled by Fujita and colleagues24 and Abdutalif and colleagues25 given their end-stage liver disease (see the AST and ALT, bilirubin, serum albumin and gamma glutamyl transferase values for example). In addition, in the study by Fujita and colleagues, rocuronium continuous infusion was targeted at obtaining T1 at TOF-stimulation, a lower degree of NMB compared with our study, in which deep NMB was achieved. These findings probably explain the lower total dose of rocuronium infused in the above-cited studies compared with our study.
Moreover, there exists some evidence in the literature, considering various operative settings, to suggest that higher total doses of rocuronium may be related to longer recovery times; for example, Llaurado and colleagues described a relationship between total rocuronium dose and recovery time in a cohort of obese patients following sugammadex administration27. Abdulatif and colleagues demonstrated the safe use and efficacy of sugammadex in the specific setting of cirrhotic patients with a mean recovery time of 3.1 min 25. The higher rocuronium dosage used in the present study compared with that by Abdulatif et al. could, in part, explain our longer recovery times. It should also be noted, however, that the total duration of surgery required in our setting was significantly longer than in the cases considered by Abdulatif et al.; we administered rocuronium via continuous infusion at a fixed dose (in accordance with the study protocol), a modality that could have overexposed the patient (for instance in the anehepatic phase) to the NMBD.
In the literature, an experimental study has investigated the possibility of interactions occurring between sugammadex and other drugs, and indeed it has been found that flucloxacillin, fusidic acid and tormifene have the potential to exert a displacement interaction with sugammadex.28 An in vitro study has also demonstrated possible interferences between corticosteroids and sugammadex action,29 whereas, Rezonja and colleagues, published an in vivo randomized controlled trial in which they demonstrated that dexamethasone does not alter sugammadex recovery time 30. The opposite was later concluded by Saleh and colleagues, who, evaluating dexamethasone use for the prevention of post-operative nausea and vomiting in children undergoing strabismus surgery, demonstrated a delayed reversal of rocuronium-induced NMB by sugammadex.31 To make the picture even more complex, it was recently demonstrated by Ozer and colleagues that sugammadex recovery times are reduced when administered in conjunction with steroids, especially desamethasone 32. All the patients in our study received a high intraoperative dose (3.5-5 mg/kg) of methylprednisolone hemisuccinate as immunosuppressant just before hepatic vascular unclamping. In an experimental study on rats, Saleh and colleagues evaluated the effect of very high (non clinical) steroids dosages on the resulting behaviour of sugammadex on rocuronium, but, once again, no significant affect was detected.31 Human studies into the potential interference between corticosteroids and sugammadex action are still lacking.Kandemir and colleagues, in their animal study, found that when methylprednisolone was used in combination with remifentanil, sugammadex action was prolonged due to a synergistic effect.33 This result contrats with that reported by Zwiers and colleagues, in which these two drugs were used individually and no alterations in the clinical effect of sugammadex were reported.28 However, in the different context of OLT, the pharmacokinetics of remifentanil are best described by a two-compartment model that takes into account a central and a peripheral volume of distribution. In addition, the functional status of the liver did not significantly affect the pharmacokinetics of remifentanil, although body weight also influences the volumes of distribution with implications for the pharmacokinetic behaviour of remifentanil.34These findings are an intriguing matter that requires further research since the volume of distribution after OLT may be deeply altered – often increased – and could, therefore, lead to the redistribution of remifentanil and consequently a possible interaction between remifentanil-methylprednisolone and sugammadex function following liver reperfusion. However, this is only a speculative proposal to explain the longer recovery times of sugammadex in OLT.To understand the unexpected relatively long recovery time of sugammadex in more detail, we performed Pearson and Spearman tests to explore the possible correlations between peri-operative variables and recovery time, but no statistically significant strong correlations were found (Table 3). However, postoperative liver AST and ALT, and the amount of intra-operative colloids were found to show a positive trend with shorter sugammadex recovery times, denoting a possible moderate correlation. Intra-operative colloids may influence cardiac output. Thus, higher amounts of colloid administration could result in a faster redistribution of rocuronium from the peripheral compartment into the central one, where it is then encapsulated by sugammadex and eliminated by the kidney. It may also be possible that graft function influences sugammadex performance, since rocuronium is mostly eliminated by liver uptake, thus contributing to the elimination of NMB by adding to the action of sugammadex. However, the sample size of this study was not calculated with the view of investigating these potential interactions with sugammadex, so further randomized controlled trials of adequate numerosity will be required to understand these possibilities any further.The pharmacokinetics of rocuronium are highly variable in cirrhotic patients, with some authors noting longer onset and offset times.35-37 Given this premise, a physician might argue against its use in patients undergoing OLT, in favour of a non-organ-specific metabolized NMB, such as cisatracurium, with a more favourable metabolism.38 However, the possibility of rapidly reversing rocuronium activity with sugammadex offers advantages in the context of fast track surgery in general and in OLT in particular, providing anaesthetists with the possibility of extubating the patient in the operating room or shortly after intensive care admission. There is also evidence that early extubation after OLT improves patient outcome and saves costs17,18. However this fast track approach needs to fulfil some important criteria, such as haemodynamic and respiratory stability, no expected graft dysfunction, no large intraoperative blood loss, normal pH, normothermia, uncomplicated surgery, and good teamwork between surgeons, anaesthesiologists and intensivists.39 Obviously, complete recovery from NMB to avoid respiratory failure due to PORC is mandatory and rocuronium-sugammadex use provides a valid option, especially because extubation failure after surgery and the need for reintubation represent an important mortality risk factor40.A possible negative consequence of sugammadex use is the potential need for urgent surgery within 24 hours of transplant, due to bleeding for example, as sugammadex may be still circulating in the blood and, if rapid sequence induction is chosen, rocuronium will not provide a valid NMB option, thus necessitating the use of succinylcholine, with its well-known side-effects .An increased risk of bleeding after sugammadex administration has been reported, and De Kam et al. found an increase in the INR and aPTT ratio time after its use, although in the absence of any clinical impact and recent evidence supports the older findings 41,42. Our results did not found increased coagulation laboratory test values and confirmed no clinically significant augmented bleeding.In light of the results of our study, it may be advisable to administer sugammadex with a reasonable margin of time (i.e., 15 minutes) before the actual extubation of the OLT recipient patient.A limitation to our study should also be noted; all the OLT patients included in the study were characterised by haemodynamic stability, so our findings can’t be extended to patients with poor haemodynamic conditions.
Anaesthetic management can be an important source of bias during OLT, but anaesthetic conduct in our study adhered very strictly to an internal protocol applied to all OLT. As a consequence, anaesthetic variability was minimal as the protocol regarded all aspects not related to NMB management. This ‘standardised’ anaesthetic practice in OLT translated into the lack of any statistically significant differences in intra-operative variables (such as bleeding, fluids, transfusion) between the sugammadex and neostigmine group. Additionally, all OLT were performed with the same surgical team dedicated to solid organ transplant surgery, further decreasing the potential for treatment bias, such as different surgery durations times.