Effect of Sugammadex on Postoperative Bleeding and Coagulation Parameters After Septoplasty: A Randomized Prospective Study

Background

Acetylcholinesterase inhibitors are frequently used to reverse the effects of nondepolarizing neuromuscular blockers. However, acetylcholinesterase inhibitors have several disadvantages, such as development of residual blockade and hemodynamic adverse effects [1]. Sugammadex, a γ-cyclodextrin derivative, is a new reversing agent that has been in use recently. Sugammadex is preferred because of its advantages during extubation and recovery and low risk of residual blockade [2]. It has been known that with sugammadex some changes in coagulation parameters occurred without documented clinical consequences. There are still controversies about the relation between sugammadex and bleeding [3]. Septoplasty is an operative procedure with expected early postoperative respiratory complications and bleeding. These complications can be decreased with appropriate anesthesia methods [4]. The aim of the present study is to evaluate the effects of sugammadex on postoperative nausea-vomiting, pain, coagulation parameters and amount of postoperative bleeding.

Material and Methods

HEMOSTATIC ANALYSES:

The blood samples for routine preoperative analysis were taken into citrate including tubes for PT and aPTT measurements. The blood samples were centrifuged at 2000×g for 10 minutes at 4⁰C and plasma samples were studied immediately. PT and aPTT measurements were performed by original reagent on ERBA Analyser.

STATISTICAL ANALYSIS:

Shapiro-Wilk tests were used for normality assumption of data. Student t test was used for total bleeding, age and operation time. One-way ANOVA with repeated measure was used for MAP, MHR, SpO₂ and postoperative bleeding in different time periods (during first hour, second hour and third hours) and Fisher exact test was used for postoperative pain and nausea-vomiting.

Results

There was no difference between patient characteristics such as age (p=0.719), gender (p>0.05), surgery duration (p=0.190) and ASA classification (p>0.05) (Table 1). The groups were similar regarding the postoperative pain (p=0.848), nausea-vomitting (p=0.512). SpO2 (p=0.276), MAP (p=0.280) and MHR (p=0.697) values of two groups were not different (Table 2). The preoperative and postoperative coagulation parameters (PT and aPTT) were presented in Table 3. The difference between preoperative and postoperative coagulation parameters (PT and aPTT) were calculated for each group to evaluate the change in coagulation parameters. Shapiro-Wilk test was used to show normal distribution of the data. To evaluate the change in coagulation parameters Mann-Whitney U test was used for comparison of groups. No statistical difference was found between PT (p=0.953) and aPTT (p=0.734) difference values of Group N and Group S (Table 4). The amount of postoperative bleeding measured by nasal tip dressings in Group S was significantly higher than Group N in all measurement time periods (p=0.024, Table 5). The average amount of total bleeding was 2.48 milliliters in neostigmine group and 4.13 milliliters in sugammadex group. The total amount of bleeding was also found significantly higher in Group S than Group N (p=0.033, Table 6).

Discussion

Septoplasty is a common operative procedure in otolaryngology that requires neuromuscular blockage and intubation when performed under general anesthesia. Bleeding and respiratory complications can be observed in the postoperative period [4]. Residual neuromuscular blockade is one of the undesired effects of acetylcholinesterase inhibitors for the reversal of nondepolarizing neuromuscular blockade [1]. It is preferred mainly because of its advantages over neostigmine during extubation and recovery period and should take place in the anestesia drawer [5]. Clinical trials on healthy volunteers has shown that sugammadex is a safe agent with rare and mild side effects [6]. There are no reported data about interaction of sugammadex with laboratory tests except coagulation parameters (PT, aPTT, INR,) and progesterone level. These reported interactions have been reported at blood levels achieved after administration of 16 mg·kg−1 sugammadex. However clinical significancy of these findings is unknown since number of clinical trials have been insufficent [7]. According to the information supplemented by the European Medicines Agency, administration of 4 and 16 mg·kg−1 of sugammadex in healthy volunteers resulted in maximum and mean prolongations of the aPTT by 17% and 22%, respectively and PT by 11% and 22%, respectively. And these mean aPTT and PT prolongations were limited and of short duration (≤30 minutes) [8]. Soon after the sugammadex administration, prolongation of coagulation time has been reported recently [9]. De Kam et al. reported that after administration of sugammadex at doses 4 and 16 mg·kg−1, a dose-dependent, limited, temporary, and clinically irrelevant prolongation in PT and aPTT was observed. They stated that this effect may be related to decrease in Factor Xa activity but later they did not find any effect of sugammadex on Xa activity in patients pretreated with heparin [10]. In another study conducted by same authors on 26 healthy volunteers, aspirin and sugammadex were administered together and no clinically relevant reduction in platelet aggregation was observed. They also stated that sugammadex was well tolerated by volunteers [11]. Raft et al. conducted a retrospective study performed in patients at high risk of postoperative bleeding (laparotomy for cancer surgery requiring suction drains) and they concluded sugammadex at doses of 2 and 4 mg·kg−1 was not associated with increased bleeding measured by amount of blood in suction drains and dressings. Despite its limitations because of retrospective design, this study has been a remarkable study in this field [3]. In 2014 Rahe et al. in a study of patients undergoing joint surgery, compared the PT and aPTT levels of patients given sugammadex, neostigmine with glycopyrrolate or atropine or placebo/spontaneous recovery and they found limited levels of increase and reported there was no other increase in incidence of bleeding [12]. Haemostatic mechanisms must work both for coagulation and prevention of thrombosis during surgical procedures. Although routine preoperative assessment with coagulation tests (PT, aPTT, platelet count) is recommended, it is not always possible to identify coagulation disorders and determine the postoperative bleeding risks [13]. Preoperative coagulation tests (platelet count, PT and aPTT) were normal in our study population. Sugammadex has an elimination half-life of 100–150 minutes so blood samples were taken 120 minutes after administration of sugammadex for PT and aPTT measurements in all patients [14]. We did not investigate the postoperative platelet count since sugammadex has no reported effect on platelet count and aggregation [15]. This is the limitation of our study. We found no significant change of PT and aPTT values after administration of sugammadex or neostigmine. But amount of bleeding measured by nasal tip dressings was significantly higher in sugammadex group than neostigmine group without a change in PT and aPTT values. Anesthesiologist should consider the cons and pros of sugammadex use in patients with these risk factors. The transient increases in aPTT and PT and INR reported in the previous studies were primarily the result of reversal with 16 mg·kg1 sugammadex. We administered 2 mg·kg1 sugammadex and none of our patients needed an additional dose. This may explain why no increase in PT and aPTT was observed in our study. The increased amount of postoperative bleeding that we found in our study may be due to the fact that increased bleeding tendency can be observed without any change in standard coagulation tests [15].

Conclusions

In conclusion, our study demonsrated that sugammadex increases postoperative bleeding, but without significantly affecting PT and aPTT values. This study is one of the first to investigate the postoperative blood loss after sugammadex use. We think that future studies investigating the effects of sugammadex on haemostasis tests other than the routine coagulation tests can clarify the mechanisms leading to increased postoperative bleeding after sugammadex use. Our results need to be supported with clinical studies that will be designed with low- and high-dose sugammadex in different surgery types. Although life-threatening postoperative bleeding is uncommon after septoplasty, in operations like adenoidectomy and tonsillectomy, the safety of sugammadex as a reversing agent and the safe dose ranges need to be verified.