Abstract
Objective
Sugammadex rapidly reverses neuromuscular blockade (NMB) induced by rocuronium. NMB induced by rocuronium is prolonged in patients with liver dysfunction, because the drug is mainly excreted into the bile. However, the efficacy and safety of sugammadex in terms of reversing rocuronium-induced NMB in patients with liver dysfunction undergoing hepatic surgery have not been evaluated. This observational study investigated the efficacy and safety of sugammadex after continuous infusion of rocuronium in patients with liver dysfunction undergoing hepatic surgery.
Methods
Remifentanil/propofol anesthesia was administered to 31 patients: 15 patients in the control group, and 16 patients from a group with liver dysfunction. Rocuronium (0.6 mg/kg) was administered, followed by continuous infusion. The enrolled patients were then subdivided into two groups according to the dose of sugammadex. In the first group a single dose of sugammadex (2.0 mg/kg) was given at the reappearance of the second twitch (T2). In the second group a single dose of sugammadex (4.0 mg/kg) was given at the first twitch response if T2 did not reappear in 15 minutes after stopping rocuronium. The primary outcome was time from administration of sugammadex to recovery of a train-of-four ratio to 0.9.
Results
The dose of rocuronium required in the liver dysfunction group was lower than that in the control group (6.2 vs. 8.2 μg/kg/min, p = 0.002). The mean time from the administration of sugammadex to recovery of the train-of-four ratio to 0.9 was not significantly different between the liver dysfunction group and the control group (2.2 minutes vs. 2.0 minutes in the 2 mg/kg administration group, p = 0.44 and 1.9 minutes vs. 1.7 minutes in the 4 mg/kg administration group, p = 0.70, respectively). No evidence of recur
Keywords
digestive system surgical procedures: hepatic; gamma-Cyclodextrins: sugammadex; liver diseases; neuromuscular blockade; neuromuscular nondepolarizing agents: rocuronium;
1. Introduction
The continuous infusion of rocuronium results in stable drug concentrations with a constant degree of paralysis and is currently a relatively common method.1, 2, 3 The elimination of rocuronium is mainly dependent upon the excretion of the unchanged drug via the bile, although up to 33% of administered rocuronium is excreted in the urine within 24 hours.4Therefore, neuromuscular blockade (NMB) induced by rocuronium tends to be prolonged after surgery in patients with liver dysfunction5, 6, 7, 8 or hepatic surgery with normal liver function.9
Sugammadex, a modified γ-cyclodextrin, is the first in a new class of medications that are classified as selective relaxant binding agents.10, 11, 12, 13, 14 Sugammadex functions by encapsulating free circulating steroidal nondepolarizing neuromuscular blocking agents such as rocuronium, following which the rocuronium–sugammadex complex is rapidly excreted in the urine, provided the patients have normal renal function in the presence of sugammadex.12 The procedure results in a rapid decrease of free rocuronium in the plasma and rapid migration of rocuronium away from the synaptic cleft and back into the circulation.14 Several clinical studies have demonstrated the rapid reversal of NMB induced by rocuronium after the administration of sugammadex in patients who are at high risk, such as in patients with renal failure,15 elderly patients,16 or in cardiac patients.17 However, there have been no reports of sugammadex in patients with liver dysfunction. In one study sugammadex was reported to reverse rapidly NMB induced by continuous infusion of rocuronium in patients undergoing hepatic surgery with normal liver function.9 Although liver dysfunction or hepatic surgery is one of the risk factors for a residual muscle-relaxant effect, the efficacy and safety of sugammadex in patients with liver dysfunction undergoing hepatic surgery have not been demonstrated. In this observational study, we report on evaluation of the efficacy and safety of sugammadex for the reversal of NMB after continuous infusion of rocuronium in patients with liver dysfunction undergoing hepatic surgery.
2. Methods
2.1. Ethics
Ethical approval for this observational study (Ethical Committee No.10-108) was provided by the Independent Ethics Committee of Kyushu Medical Center, Fukuoka, Japan (Chairperson Dr T. Muranaka) on February 23, 2011, and the study was conducted in compliance with the current revision of the Declaration of Helsinki, the International Conference on Harmonisation guidelines, Good Clinical Practice, and current regulatory recommendations. Written informed consent was obtained from all patients.
2.2. Patient selection
This study was conducted at the Kyushu Medical Center between February and June 2011. Patients were eligible for inclusion if they were aged ≥18 years, American Society of Anesthesiologists-physical status (ASA-PS) Class I–III, and were scheduled to undergo hepatic surgery. Patients were excluded from the study if they had significant renal dysfunction (creatinine level > 2 mg/dL), known or suspected neuromuscular disorders, or a history of malignant hyperthermia. Patients who were obese (body mass index > 35 kg/m2), and women who were pregnant or breastfeeding were also excluded.
Thirty-seven patients were enrolled in this study, of which, 17 were classified as the control group undergoing hepatic surgery and 20 as the liver dysfunction group undergoing hepatic surgery (see below for further details about classification of liver function). Six patients (2 from the control group and 4 from the liver dysfunction group) were excluded because of the poor recording of train-of-four (TOF) traces and recovery variables. Therefore, data from 15 patients in the control group and 16 patients in the liver dysfunction group were analyzed in this study.
2.3. Method used to classify liver function
To classify the patients according to their liver function, we used the Liver Damage (LD) classification system, which consists of measuring five items (Table 1).18, 19, 20, 21 The degree of LD as a guide to liver function was defined by the Liver Cancer Study Group of Japan based on ascites, serum bilirubin, serum albumin, indocyanine green retention rate at 15 minutes (ICGR15), and prothrombin activity. The severity of each finding was evaluated separately. The degree of liver damage was classified as A, B or C, based on the highest grade that contained at least two findings. The LD classification uses ICGR15, which is different from the Child–Pugh classification. ICGR15 reflects liver excretory function and has been reported to be a significant predictor of postoperative liver function and mortality.19 Therefore, the LD classification is frequently used to predict the prognosis of patients who are undergoing hepatic surgery in our hospital. In this study, patients were classified into two groups, one, the control group included patients with normal liver function who were scheduled for hepatic surgery, and the other, the liver dysfunction group, included patients with LD-B (n = 11) or LD-C (n = 5) who were scheduled for hepatic surgery.
2.4. Study procedures and efficacy assessments
Anesthesia was induced and maintained with continuous infusion of remifentanil and propofol using the target controlled infusion system (Terufusion TCI pump; TERUMO, Tokyo, Japan). After the induction of anesthesia, neuromuscular function was monitored continuously by acceleromyography at the thumb using the TOF-Watch SX (Organon Ireland, a division of MSD Swords, Dublin, Ireland). The acceleromyography transducer was attached to the distal phalanx of the thumb, and repeated TOF stimulation was applied to the ulnar nerve at the wrist at 15-second intervals. Neuromuscular monitoring was continued at least until the TOF ratio recovered to 0.9 after administration of sugammadex. After calibrating the TOF-Watch SX, a single intravenous (i.v.) dose of rocuronium (0.6 mg/kg) was administered. Neuromuscular data were collected and processed using the TOF-Watch SX Monitoring Program (Organon, Netherlands). After the disappearance of the first twitch response (T1), tracheal intubation was performed followed by mechanical ventilation with a mixture of oxygen and air. If T1 did not disappear, an additional dose of rocuronium (0.1 mg/kg) was administered. At the reappearance of T1, continuous infusion of rocuronium (initiated at 7 μg/kg/min) was started. The infusion dose of rocuronium was adjusted to maintain the depth of the NMB at T1 and then discontinued on completion of surgery. We subdivided the enrolled patients into two groups according to the doses of sugammadex administration. In the first group, at the reappearance of the second twitch response (T2), a single i.v. dose of sugammadex (2 mg/kg) was given. In the second group, if T2 did not reappear within 15 minutes after termination of rocuronium, a single i.v. dose of sugammadex (4 mg/kg) was administered. Patients were not permitted to receive a second dose of sugammadex. After confirming that the TOF ratio recovered to 0.9 and assessing the recovery from NMB by clinical examination, tracheal extubation was performed. The TOF ratio and recurrent NMB were checked after extubation until the patient was moved to the recovery room.
Blood pressure, heart rate, electrocardiography, peripheral capillary oxygen saturation (SpO2), central core temperature, finger-tip skin temperature, and end-tidal CO2 were recorded throughout the operations. Central core temperature and finger-tip skin temperature were maintained above 35°C and 32°C, respectively, by using forced-air warming blankets. A continuous epidural infusion of 0.2% ropivacaine or continuous subcutaneous infusion of fentanyl was used for postoperative analgesia.
2.5. Safety assessments
Adverse events (AEs) and serious adverse events (SAEs) were assessed in all patients. SAEs were defined as any untoward medical occurrence, such as death, a life-threatening side effect, a need to prolong hospitalization, or persistent disability. SpO2 and respiratory rate were monitored in all patients for at least 24 hours after the operation and any clinical evidence of recurrent NMB was reported. Blood biochemistry was assessed and hematology analysis was repeated once daily from postoperative day (POD) 1 to POD 7.
2.6. Statistical analysis
The efficacy variable was the time from administration of sugammadex to recovery of the TOF ratio to 0.9. We used the Mann–Whitney U test for analysis of differences of the time between the liver dysfunction group and the control group, and the data were shown as median, minimum, and maximum. The other numerical data were compared by unpaired t test. The χ2 test was used for categorical data. Data are expressed as mean ± standard deviation unless otherwise specified. A statistically significant difference was defined as p < 0.05. All analyses were performed using Stata version 11.0 (Stata Corporation, College Station TX, USA).
3. Results
3.1. Baseline characteristics
There were no significant differences in age, weight, height or sex between the two groups (Table 2). The ASA-PS, Child–Pugh classification and ICG15R were worse in the liver dysfunction group than that in the control group.
3.2. Summary of anesthesia and efficacy of rocuronium
The duration of anesthesia was not significantly different between the two groups (Table 2). The mean dose of propofol and remifentanil injected were not significantly different between the two groups (data not shown). However, the mean time from the administration of 0.6 mg/kg rocuronium to the reappearance of T1 was significantly longer in the liver dysfunction group than in the control group. Total dose and mean continuous infusion rate of rocuronium was significantly lower in the liver dysfunction group than in the control group (Table 2). These results indicate that the rate of rocuronium metabolism and excretion were lower in the liver dysfunction group.
3.3. Efficacy of sugammadex
The time from the administration of 2 mg/kg sugammadex to the recovery of the TOF ratio to 0.9 was not significantly different between the liver dysfunction group and control group (p = 0.44) (Table 3). The mean time was 2.2 minutes in the liver dysfunction group and 2.0 minutes in the control group, and the mean difference in recovery time between the two groups was 0.2 minutes. The time from the administration of 4 mg/kg sugammadex to the recovery of TOF ratio to 0.9 was not significantly different between the liver dysfunction group and control group (p = 0.70). The mean time was 1.9 minutes in the liver dysfunction group and 1.7 minutes in the control group, and the mean difference in recovery time between the two groups was 0.2 minutes. These data indicate that NMB can be quickly reversed by sugammadex treatment, even in patients with liver dysfunction undergoing hepatic surgery after continuous infusion of rocuronium. We further analyzed these data using the unpaired t test and the results confirmed that there were no significant differences in recovery time between the two groups (data not shown). However, because a small number of patients were involved in the present study, a large number of patients should be investigated in a future study to confirm the statistical accuracy of the present findings.
3.4. AEs and SAEs
We carefully monitored the clinical status of patients for at least 24 hours after extubation. Sugammadex was generally well tolerated. No clinically relevant changes were reported for heart rate or blood pressure. No abnormal or pathological electrocardiographic waves were observed. Twenty-three patients (11 in the control group and 12 in the liver dysfunction group) had at least one AE postoperatively: these AEs were the development of fever (≥38°C; n = 7), nausea (n = 9), constipation (n = 10), fatigue (n = 2) and diarrhea (n = 2). There were no differences in AEs between the liver dysfunction group and control group. Most of these AEs were considered to be mild by the investigators and no relation to the sugammadex dose and time point was found. No patient had clinical evidence of residual NMB or recurrence of NMB as determined by the investigators. None of the patients were discontinued from the study because of an AE.
A decrease in SpO2 (<95%) was reported in one patient in the liver dysfunction group. We hypothesize that this was due to the use of opioids for postoperative analgesia, because the respiratory rate was decreased in the patients and no clinical evidence of recurrence of NMB was found.
One patient in the liver dysfunction group, a 60 year-old man with LD-C, died on POD 97 due to hepatic failure as the result of cholestatic liver cirrhosis. He had four hepatic surgeries for recurrence of liver cell carcinoma, which might have had an effect on the development of hepatic failure. It has been reported that sugammadex does not have any effect on hematological or biochemical variables.12, 22, 23 Taken together, it may not be possible that sugammadex caused hepatic failure in this patient.
4. Discussion
In this study, we demonstrated that sugammadex rapidly reversed NMB induced by continuous infusion of rocuronium in patients with liver dysfunction as well as the controls undergoing hepatic surgery. Furthermore, no recurrence of NMB was observed in either group. Sugammadex was determined to be safe and well tolerated in both groups. The major route of elimination of rocuronium is biliary excretion, with urinary elimination being a minor pathway.4 Liver dysfunction induces moderate changes in the pharmacodynamics of rocuronium. These changes, most likely due to pharmacokinetic alterations, are consistent with data obtained for other muscle relaxants having a steroid structure.7 Previous studies have shown that the plasma clearance of rocuronium was significantly reduced by 15–30% in cirrhotic groups compared with normal groups.4, 7 Miert reported that the time to a 25% recovery of T1/control after rocuronium administration (0.6 mg/kg) was prolonged significantly from 42.3 minutes to 53.7 minutes in a cirrhotic group compared with a healthy group.5 In our study, the time from the administration of rocuronium at a dose of 0.6 mg/kg to the reappearance of T1 was significantly prolonged in the liver dysfunction group compared to the control group, and the infusion rate of rocuronium required to maintain an appropriate NMB was significantly lower in the liver dysfunction group than in the control group (Table 2). Our data show that the excretion of rocuronium was delayed in patients with liver dysfunction. These results are consistent with data reported in previous studies.4, 5, 6, 7
There have been no animal studies or clinical trials for sugammadex with liver dysfunction. In the worst case scenario, using a population pharmacokinetic–pharmacodynamic interaction model of sugammadex to simulate the reversal of rocuronium-induced NMB showed that the recovery time was prolonged by 2.55 minutes when sugammadex at a dose of 2 mg/kg was given at the reappearance of T2 in patients with severe liver dysfunction.4However, in our study, the mean time from the administration of sugammadex (at 2 mg/kg or 4 mg/kg) to the recovery of the TOF ratio to 0.9 did not differ significantly in the liver dysfunction group and control group (Table 3). In addition, no recurrence of NMB was observed in any of the patients. These data indicate that there is no prolongation in recovery time and no recurrence of NMB even in patients with liver dysfunction with delayed excretion of rocuronium. These collective findings indicate that sugammadex is effective for reversing NMB after continuous infusion of rocuronium in patients with liver dysfunction undergoing hepatic surgery.
In this study, we used a 4 mg/kg dose of sugammadex at the appearance of T1, although a dose of 4 mg/kg is recommended at 1–2 post-tetanic count.22 The depth of NMB was maintained at T1 during the operation until stopping rocuronium, and the reappearance of T2 was not observed for up to 15 minutes in almost half of the patients. For this reason, a sufficient dose of sugammadex 4 mg/kg was used for these patients in order to avoid NMB by incomplete clearance of rocuronium, as reported in a previous study.1 In the high dose of sugammadex administration groups (4 mg/kg), the mean time to recovery of the TOF ratio to 0.9 was not significantly different from those in the low dose of sugammadex administration groups (2 mg/kg) (p = 0.33 in the liver dysfunction group, p = 0.96 in the control group). Furthermore, there were no differences in AEs between the two groups, indicating there were no differences in efficacy or safety between both doses in patients with liver dysfunction undergoing hepatic surgery. However, no observational study has investigated the safety and effectiveness of sugammadex to reverse the effects of an infusion of rocuronium in patients with liver dysfunction. In one study sugammadex was reported to rapidly reverse NMB in patients undergoing hepatic surgery with normal liver function.9 Therefore, this is the first report of an observational study of the efficacy and the safety of sugammadex in patients with liver dysfunction undergoing hepatic surgery. It has been reported that the higher doses of sugammadex of 16 mg/kg in surgical patients24 and 32 mg/kg in healthy volunteers25 are effective and safe. The purpose of the present study was to investigate the efficacy and safety of sugammadex in such high-risk patients, thus, further studies should be conducted to determine the optimization of sugammadex in these patients.
In conclusion, the administration of sugammadex can be effective for the reversal of NMB induced by continuous infusion of rocuronium even in patients with liver dysfunction undergoing hepatic surgery. Recovery to a TOF ratio of 0.9 occurred rapidly and without any sign of recurrence of NMB in any patients. Sugammadex was determined to be safe and well tolerated. Sugammadex promises to be useful for limiting the risk of residual postoperative paralysis in these patients. Only a small number of patients were included in the present study, therefore, further investigations under similar conditions using the required amount of sugammadex in a large number of patients with liver dysfunction undergoing hepatic surgery are warranted.
Acknowledgments
We thank Mr. Junji Kishimoto for advice with statistical analysis. No external funding, apart from the support of the authors' institution, was available for this study.