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Neuromuscular blocking agents

Efficacy and safety of sugammadex in the reversal of deep neuromuscular blockade induced by rocuronium in patients with end-stage renal disease

A comparative prospective clinical trial

de Souza, Camila M.; Tardelli, Maria A.; Tedesco, Helio; Garcia, Natalia N.; Caparros, Mario P.; Alvarez-Gomez, Jose A.; de Oliveira, Itamar S. Junior

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European Journal of Anaesthesiology: October 2015 - Volume 32 - Issue 10 - p 681-686
doi: 10.1097/EJA.0000000000000312
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Abstract

Introduction

In patients with chronic renal failure, physiological and pharmacological factors alter the pharmacokinetics and pharmacodynamics of nondepolarizing neuromuscular blocking agents (NMBAs), making the recovery of the neuromuscular function relatively unpredictable. In the presence of renal dysfunction, the clearance of neostigmine is reduced and the half-life is prolonged so that patients are exposed to enhanced cholinergic effects from the drug and as a consequence may suffer vomiting, bradycardia and bronchoconstriction.1

Sugammadex reverses the neuromuscular block (NMB) induced by aminosteroidal drugs such as rocuronium by encapsulating the drug molecules within the plasma, creating a highly stable complex that is mostly eliminated by the kidneys.2 Studies show that in patients with chronic renal failure, sugammadex, at a dose of 2 mg kg−1, effectively reverses a moderate NMB [defined as two twitches in the train of four (TOF)].3 However, there are no data available on the efficacy and safety of sugammadex in the reversal of profound NMB in such patients.

The aim of this study was to evaluate the efficacy and safety of sugammadex in the reversal of profound NMB induced by rocuronium in patients with end-stage renal disease (ESRD) undergoing dialysis therapy and to compare this with its effects in patients with normal renal function.

Materials and method

Study design and patient selection

This comparative prospective clinical study was approved by the Ethics Committee of the Universidade Federal de São Paulo, Sao Paulo, Brazil in September 2011 (Ethical Committee 1277/11, Chairperson Prof Jose Osmar Medina Pestana). It was also reviewed and approved by the Ethics Committee of the Hospital General Universitario Sta Lucia de Cartagena, Cartagena, Spain in September 2011 (Chairperson Dr Manuel Nombela Goméz). The study was registered at ClinicalTrials.gov (number NCT01785758) and was conducted in compliance with the current revision of the Declaration of Helsinki and the International Conference on Harmonization Guideline for good clinical practice in pharmacodynamic studies of NMBAs.4

Patients were eligible for the trial if they were aged between 18 and 65 years, were having general anaesthesia for kidney transplantation with a kidney from a deceased donor and required the administration of muscle relaxant drugs. The patients were 20 ASA (American Society of Anesthesiologists physical status classification) class I or II control patients with normal renal function [creatinine clearance (ClCr) >90 ml min−1) and 20 ASA class III patients with renal failure (ClCr <30 ml min–1) on dialysis for at least 3 months. The Cockcroft–Gault formula was used to calculate creatinine clearance.5 The data from patients with chronic renal disease were collected at the Hospital do Rim e Hipertensão – Fundação Oswaldo Ramos (Sao Paulo, Brazil), and the data from patients with preserved renal function were collected at Hospital General Universitario Santa Lucía de Cartagena, Cartagena, Spain) between 1 October 2011 and 31 January 2012. Exclusion criteria included previous neuromuscular disease, liver failure, history of malignant hyperthermia, allergy to opioids or neuromuscular blockers, pregnancy and current use of anticonvulsants, magnesium or aminoglycosides. All patients provided written informed consent.

Study procedures

Once in the operating room, all enrolled patients received 1 to 2 mg of intravenous (i.v.) midazolam before induction of anaesthesia and were monitored with ECG, pulse oximetry, noninvasive blood pressure, capnography, core body temperature (measured by an oesophageal probe), peripheral body temperature (measured by a sensor on the thenar eminence) and a bispectral index (BIS) depth of anaesthesia monitor (ASPECT BIS XP; Aspect Medical System Inc., One Upland Road, Norwood, Massachusetts, USA). Neuromuscular function was monitored continuously by acceleromyography at the adductor pollicis muscle with TOF-Watch SX (Organon Ireland Ltd., Swords Co., Dublin, Ireland). The data were transferred to a computer using the TOF-Watch software ver. 3.1 (Organon Ireland Ltd.) for further analysis. The left arm was positioned at a 90° angle to the thorax, resting on an arm board. After cleaning the skin with gauze soaked in alcohol solution, paediatric ECG-electrodes were placed over the ulnar nerve near the wrist, ensuring their centres remained 3 cm apart from each other. The acceleromyography transducer was attached to the distal phalanx of the thumb, perpendicular to its movement. The other fingers, as well as the arm, were immobilised and fixed to the arm board. Peripheral temperature was maintained above 32°C and was measured on this same limb via a sensor attached to the palm. For haemodialysis patients, monitoring was performed on the limb contralateral to the fistula. Central core temperature was maintained above 35°C.

After a bolus of fentanyl (3 μg kg−1), induction of anesthesia was performed with a target-controlled infusion (TCI) of propofol (Marsh model, plasma target concentration = 4 μg ml−1). After loss of consciousness (defined as a BIS <60), 5 s of 50 Hz tetanic stimulation was applied followed by calibration of the acceleromyography transducer. After calibration, stimuli were applied every 15 s using TOF pulses at 2 Hz until a stable response was obtained [defined as three consecutive TOF measurements where the TOF ratio {ratio of the fourth twitch (T4) to the first twitch (T1) – T4/T1} had a maximum variation of ≤5%].2 Once calibration and stabilisation of the response was validated, TOF stimulation was performed every 15 s using an automatically calculated supramaximal stimulus of 0.2 ms duration.

A single i.v. dose of rocuronium (0.6 mg kg−1) was administered over 5 s and the time elapsed between the start of the injection and a 95% reduction in the first twitch of the TOF response was recorded (onset time). Tracheal intubation was performed 1 min after the initial dose irrespective of the TOF response. The NMB was maintained with a continuous infusion of rocuronium, started 15 min after the initial dose. The infusion rate was initially 4 mg kg−1 h−1 and subsequently adjusted to maintain neuromuscular blockade at a posttetanic count (PTC) of 1 to 3 until skin closure was complete. Anesthesia was maintained with TCI propofol and a remifentanil infusion (initial rate 0.05 μg kg−1 and adjusted as necessary) to maintain the BIS reading between 40 and 60, and mean arterial pressure (MAP) above 60 mmHg. At the end of surgery, after completion of skin closure, all infusions were discontinued and sugammadex (4 mg kg−1) was administered while the PTC was in the range of one to three counts.

Ventilation of the lungs was with a mixture of air and oxygen in equal volumes. The initial ventilatory parameters (tidal volume = 7 ml kg−1, respiratory rate = 12 breaths min−1 and I:E ratio = 1 : 2) were adjusted to maintain ETCO2 between 4.6 to 5.3 kPa.

Postoperative analgesia was initiated with morphine (0.1 mg kg−1) and metimazole (2 g) administered i.v. at the end of surgery.

Efficacy and safety assessments

The total dose of rocuronium used and the duration of the procedure were recorded.

The efficacy of sugammadex was evaluated by measuring the time, in minutes, from its administration until recovery of the TOF ratio to 0.9. Secondary efficacy variables were time from administration of sugammadex until recovery of the TOF ratio to 0.7 and 0.8.

In the postanesthetic recovery room, the safety of sugammadex was evaluated by monitoring neuromuscular function every 15 min for 2 h after its administration. Recurrence of NMB was defined as a decrease in the TOF ratio below 0.9 after complete recovery had been previously detected. We also monitored the oxygen saturation (SpO2), blood pressure and heart rate at 2, 5, 10, 30, 60 and 120 min after administration of sugammadex.

Statistical analysis

The sample size calculation was performed using the MedCalc Software 8.0 (www.medcalc.be), and was based on an estimated maximum difference of 120 s in the recovery time of the TOF ratio to at least 0.9 between the groups. For 90% power and considering the risk of a type I error as α of 0.05 or less, and of committing type II error as β of 0.10 or less, 18 patients in each group would be required.

The analyses were performed using SPSS 17 (SPSS Inc., Chicago, Illinois, USA). For categorical variables, we present absolute and relative frequencies and for numerical variables, summary measures (mean, quartiles, minimum, maximum and standard deviation). Association between two categorical variables was tested using the Chi-square or Fisher exact test. The comparison of means between the two groups was performed using the Student's t-test for independent samples, provided that data were normally distributed (confirmed by the Kolmogorov–Smirnov test). If data were not distributed normally, then the nonparametric Mann–Whitney test was used. The paired Student's t-test was used to evaluate paired samples from the same patient. For the evaluation of linear association between two variables, the Pearson correlation was used.

Results

The study included 20 patients with chronic renal failure undergoing dialysis and 20 patients with normal renal function. In one patient in the renal failure group, the TOF-Watch failed after the administration of sugammadex. This failure occurred after recovery of the TOF ratio to 0.8. This case was excluded from further analysis as the device could not be replaced and neuromuscular function could not be monitored objectively in the recovery unit.

No statistically significant differences were observed between the two groups in terms of baseline characteristics (Table 1). All patients in the renal failure group had received dialysis for longer than 3 months (15 haemodialysis, five peritoneal dialysis). The average time on dialysis was 55.1 ± 31.1 months, the maximum time was 132 months and the minimum time was 17 months.

T1-4
Table 1:
Patient characteristics and study groups

The time to onset of rocuronium was 1.7 ± 1.0 min in the renal failure group and 1.8 ± 0.9 min in the control group (P = 0.810). There was no difference between the groups in either the total dose of rocuronium used during surgery or the length of surgery, although there was a difference in the hourly consumption of rocuronium (control group = 0.014 ± 0.003 mg kg−1 h−1, renal failure group = 0.011 ± 0.003 mg kg−1 h−1, P = 0.018). Sugammadex was given to all patients when the PTC was in the range 1 to 3. After administration of sugammadex, the mean time to recovery of the TOF ratio to 0.9 was 5.6 ± 3.6 min in the renal failure group and 2.7 ± 1.3 min in the control group (P = 0.003). These results, as well as the times to recovery of TOF ratio to 0.7 and 0.8 are summarised in Table 2 and presented in Fig. 1. Figure 1 also illustrates the wide variability in the times to recovery of the TOF ratios in the renal failure group. There was no correlation between ClCr and time to recovery of neuromuscular function after sugammadex in either group. In the renal failure group, a correlation was demonstrated between the duration of dialysis treatment and the time to recovery of the TOF ratio to 0.7 (r2 = 0.621) and 0.8 (r2 = 0.556), but there was no significant correlation with the time taken for the TOF ratio to recover to 0.9 (r2 = 0.378).

T2-4
Table 2:
Time (min) from sugammadex administration to recovery of train-of-four ratio to 0.7, 0.8 and 0.9
F1-4
Fig. 1:
Time (min) from sugammadex administration to recovery of the train-of-four ratio to 0.7, 0.8 and 0.9. In the diagrams, the thick horizontal line indicates the median value, the box ends represent the lower and upper quartiles and interquartile (IQ) range; the line beyond the box is the whiskers and indicates the lowest and the highest values within 1.5 times the IQ range. The black circles represent outliers (i.e. values between 1.5 and 3 times the IQ range) and the asterisks represent extremes (i.e. values more than 3 times the IQ range).

Over the first two postoperative hours after initial recovery of TOF ratio to 0.9, there were no cases of recurrence of neuromuscular blockade in either group. There were no significant changes in heart rate and oxygen saturation after administration of sugammadex. The values of MAP remained stable and similar between the groups throughout the observation period.

Discussion

This prospective comparative clinical trial was designed to evaluate the efficacy and safety of sugammadex for reversal of profound rocuronium-induced NMB in patients with chronic renal failure. The results of this study show that sugammadex reverses this type of NMB safely and efficiently. However, compared with patients with normal renal function, not only was the time required for this reversal prolonged, but there was also substantial variability in the recovery times in the patients with chronic renal failure. As observed by others,6–8 the time to onset of NMB after rocuronium administration was the same in both groups, and these times were comparable with the onset of rocuronium in patients with normal renal function previously reported in the literature.9,10

Staals et al.11 were the first to describe the pharmacokinetics of sugammadex in patients with renal disease. They used a bioanalytical method for pharmacokinetics assessment that did not differentiate between sugammadex in its free form and in its complex form encapsulating rocuronium; hence, all the pharmacokinetics variables described in that study represent the total amount of sugammadex present.12 Their study11 demonstrated that the pharmacokinetics of sugammadex is significantly altered by chronic renal failure, as renal excretion is the primary route of elimination of the drug. However, as the sugammadex-rocuronium complex is extremely stable, reversal of rocuronium NMB by sugammadex depends only on the encapsulation of rocuronium and not on the excretion of the sugammadex-rocuronium complex in the urine.13 Thus, a reduction in sugammadex clearance does not explain the differences we observed in the time to recovery of neuromuscular function after reversal of a profound block in our patients with chronic renal failure.

We learned from the same study11 that the volume of distribution (Vd) of sugammadex is relatively small. Sugammadex is poorly distributed to less vascularised tissues, staying mainly in the central compartment in which it exerts its action. Although drugs with a small Vd can have their onset time altered significantly by variations in their distribution volume, it has been shown that there is no difference in the sugammadex Vd between control and renal failure patients.11 However, it was not stated whether patients with kidney disease enrolled in the study underwent routine dialysis prior to surgery.11 In patients with chronic renal failure, weight gain between dialysis sessions represents water retention and this would be expected to increase the volume of distribution (Vd) of sugammadex,14,15 but dialysis close to surgery would remove this excess fluid. On account of the relative urgency of transplant surgery and a need to reduce donor organ ischemia time, in our institution, most patients undergoing cadaveric kidney transplantation are not routinely dialysed before surgery. Only patients with significant associated pathology noted on clinical examination (eg pulmonary oedema, hypertension, low oxygen saturation) or seriously abnormal laboratory tests are referred for dialysis before transplantation. Hence, our study patients with renal failure would demonstrate a very wide range of fluid retention: from those just after dialysis (very close to their dry weight), to those some significant time after dialysis (with significant fluid retention). Further studies are necessary to examine the effects of such fluid retention on the Vd of sugammadex and how this might compromise reversal of NMB after sugammadex administration.

The efficiency of reversal by sugammadex depends on the administration of a dose large enough to neutralise the NMB drug in circulation. It has been demonstrated that the sugammadex dose used in this study (4 mg kg−1) has an adequate margin of safety for reversal of profound NMB.16 However, the distribution of the drug after its initial administration is influenced by other factors, such as cardiac output, and it has been demonstrated that the time to recovery of neuromuscular function after reversal with sugammadex is influenced by cardiac output.17 A statistically significant inverse correlation was noted between the time to recovery of TOF ratio to 0.9 and cardiac output.17 Chronic renal failure may also cause changes in the function of various systems, especially the cardiovascular system. Systemic hypertension, haemodialysis and uremia can induce marked changes in the myocardium compromising both systolic and diastolic functions.18,19 The severity of these comorbidities depends on several factors that include not only the appropriate treatment but also the severity and progression of the disease. Cardiac output was not assessed in the patients included in this study, but, theoretically, one could postulate that patients with longer renal disease duration and longer on dialysis would have a greater impairment of cardiac function. If cardiac dysfunction is a cause of delayed recovery of neuromuscular function after reversal by sugammadex in this group, then different degrees of cardiac impairment could also explain the variability in recovery times observed in the renal group.20 However, although there was a direct correlation between time on dialysis and the time to recovery to a TOF ratio to 0.7 and to 0.8, there was no such correlation for recovery to a TOF ratio of 0.9. We should expect all aspects of TOF recovery to be affected similarly, and not only the times to TOF ratios of 0.7 and 0.8. In addition, the fact that the time to onset of rocuronium was the same in both groups suggests that myocardial depression is not the main mechanism responsible for the slower recovery after reversal seen in these patients.

It is recognised that outliers, especially with small sample sizes such as in this study, can not only have a major impact on the Pearson correlation21 coefficient, but also the existence of a correlation does not prove causation. Our findings generate hypotheses, but limitations in our methodology prevent us from drawing further conclusions on the specific mechanism responsible for the longer neuromuscular recovery time in patients with end-stage renal failure undergoing dialysis.

In patients with chronic renal disease, the sugammadex–rocuronium complex is highly stable, and although it remains in the plasma for days until it is cleared, largely through high-flow dialysis,22 it does not dissociate nor does it result in clinical complications or recurrence of neuromuscular blockade.23,24 Although the number of patients evaluated so far remains small, the safety of administering sugammadex to reverse rocuronium-induced NMB in patients with renal disease has been demonstrated,3,22 and this was partly corroborated by the current study.

A limitation of the current study was that the observation period after sugammadex administration was limited to 2 h. After renal transplantation, it would be expected that patients would have their renal function fully restored, but such recovery does not occur immediately, especially when the donor kidney comes from a recently deceased donor. Thus, a longer period of follow-up until renal function was re-established or, failing that, the first postoperative dialysis treatment had taken place, would have been more appropriate.

This is the first study to demonstrate that in patients with end-stage renal disease, sugammadex, at a dose of 4 mg kg−1, effectively reverses profound rocuronium-induced neuromuscular blockade. However, when compared with healthier individuals, the time to recovery of muscle function after reversal is longer and there is a much greater variability in the recovery times. Of great importance, once neuromuscular function had recovered, there were no signs of recurrence of NMB. We believe our results and those of others suggest that the restrictions on the use of sugammadex in patients with chronic renal failure should be readdressed.

Acknowledgements relating to this article

Assistance with the study: none.

Financial support and sponsorship: this work was supported by the Division of Anesthesiology, Pain and Intensive Care Medicine, Universidade Federal de São Paulo, São Paulo, Brazil, and the Division of Anesthesiology, Hospital General Universitario Sta Lucia de Cartagena, Cartagena, Spain.

Conflicts of interest: Maria Angela Tardelli has given paid lectures and attended conferences sponsored by Merck Sharp & Dohme. Helio Tedesco has given paid lectures, consultancy and received grants from Novartis, Pfizer, BMS, Veloxix and Sanofi. Jose Antonio Alvarez Gomez has given paid lectures, consultancy, received grants and attended conferences sponsored by Merck Sharp & Dohme, Scherinh-Plough, Glaxo-Smith Klein and Organon. Camila Machado de Souza, Natalia Navarro Garcia, Mario Parreno Caparros and Itamar Souza de Oliveira-Junior have no conflict of interest.

Presentation: this study was presented as a poster at the European Society of Anaesthesiology (ESA) Euroanaesthesia, 9 to 12 June 2012, Paris.

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