Discussion
In our review of 241 patients undergoing liver transplantation, we found no statistically significant difference in postoperative bleeding outcomes in patients reversed with sugammadex vs. neostigmine. Compared with neostigmine, the use of sugammadex had slightly prolonged aPTT at the immediate postoperative period; however, it was associated with less risk of postoperative red blood cell transfusion and re-operation. In the secondary outcomes, acute organ rejection occurred slightly higher in the sugammadex group; however, this slight increase was not statistically significant. The sugammadex group had less PONV. Both groups had similar LOS.
Postoperative hemorrhage is one of the broad spectra of liver transplantation complications. Mueller et al. suggested that the most important risk factors for early postoperative bleeding are severe coagulopathy and thrombocytopenia.3 Everson et al. proposed that the most significant bleeding risk is in the setting of both severe coagulopathy and portal hypertension.7Abnormal coagulation reflected by prolongation of aPTT and PT are common laboratory findings in these patients. Patients with cirrhosis have been described as having a rebalanced hemostatic system due to a concurrent reduction in pro- and anti-hemostatic. systems8, 9However, the hemostatic balance in these patients is more fragile compared to healthy individuals. Both diffuse bleeding and thrombosis can occur during and after liver transplantation. After liver transplantation, it is presumed that the hemostatic system normalizes as the liver synthetic function is restored.
Clinical trials in healthy subject and surgical patients reported that sugammadex had transient aPTT and PTT prolongations.4,10 Based on the information supplemented by the Food and Drug Administration (FDA), healthy volunteers had increased aPTT and PT/INR up to 1 hour with administration doses up to 16mg/kg sugammadex.11Dirkmann et al. suggested the effect on coagulation may be explained by the cyclodextrin molecule binding the phospholipid, and the anticoagulant effects were likely an in vitro artifact observed in commercial phospholipid-dependent assays such as the aPTT.12 Other studies found that sugammadex does not affect platelet or factor Xa function.13,14 However, the sugammadex effect on postoperative bleeding is still controversial. Tas et al. reported that sugammadex was associated with a higher amount of postoperative bleeding than neostigmine after septoplasty in otherwise healthy patients.15
On the contrary, Raft et al. investigated postoperative bleeding in high-risk cancer patients, and they found sugammadex was not associated with increased postoperative bleeding.16 Moon et al . reported that sugammadex is not associated with increased bleeding tendency or morbidity in healthy patients undergoing living-donor hepatectomy.17 Our study had similar results as sugammadex was not associated with an increased bleeding profile. In fact, there was no instance of re-operation in the sugammadex group. To the best of our knowledge, this is the first effort to examine the bleeding risk of sugammadex in deceased donor liver transplantation.
In the secondary outcomes, the sugammadex group had slightly higher acute organ rejection (0.7% patients in the neostigmine group vs. 1.9% in the sugammadex group). However, both groups had a much lower acute organ rejection rate than large cohort studies. (27% in the Adult to Adult Living Donor Liver Transplantation cohort and 15.6% in the Scientific Registry of Transplant Recipients cohort.18Sugammadex creates a steroid complex with the aminosteroid neuromuscular blocking agents, and it has been shown to reduce other drugs’ efficacy by encapsulating drugs with similar structures such as oral contraceptive pills.11 Corticosteroids are a crucial component of immunosuppression therapy in liver transplantation and are administered during the peri-transplant period to prevent acute organ rejection. Rezonja et al. found the concomitant administration of high dose dexamethasone diminished the efficiency of sugammadex in the in vitro experiment.19 However, Rezonja et al. also found that dexamethasone does not diminish sugammadex reversal of neuromuscular blockade in a clinical study.20Furthermore, Arslantas et al. found no difference in the risk of adverse effects on short-term graft function in 42 patients who underwent kidney transplantation.21
Our study also showed that the sugammadex group had less PONV, which is consistent with previous work.3 Regarding hospital length of stay, the two groups had small differences: 7.0 days in the neostigmine group and 7.8 days in the sugammadex group. In a large cohort study, patients reversed with sugammadex had earlier first postop bowel movement compare to patients reversed with neostigmine22, which potentially could reduce the hospital length of stay.
There are several limitations to our study. First, the retrospective design of the study is certainly a limiting factor. Additionally, this data represents outcomes from a single-center, although our institution performs roughly 150 liver transplantations a year, and there were no significant differences in any of our demographic variables. Third, temporal factors exist as the neostigmine group was transplanted from 2015 to 2017, versus the sugammadex group which was transplanted from 2017 to 2018. Surgical techniques and surgeon experiences may have improved with time and could confound our results. Nevertheless, our study is the first study to evaluate the sugammadex effect on postoperative bleeding risk in the adult orthotopic liver transplantation population.