The use of rocuronium and sugammadex in paediatric renal transplantation

Editor, Rocuronium can be used in patients with severe renal failure (creatinine clearance <30 ml min−1) but the duration of muscle relaxation is longer and results in an increased risk of postoperative residual curarisation (PORC) and respiratory complications.1,2 Reversal of neuromuscular blockade (NMB), therefore, is important to prevent PORC. Reversal of NMB with cholinesterase inhibitors (in combination with muscarinic antagonists) has limitations because of their mechanism of action (ineffective against deeper levels of NMB) and is associated with undesirable cholinergic side-effects including bradycardia, hypotension, salivation, bronchoconstriction, nausea and vomiting. Furthermore, the metabolism and redistribution of cholinesterase inhibitors is delayed in severe renal failure, which potentiates the duration of their effects and increases the risk of side-effects.3,4 The use of succinylcholine is not absolutely contraindicated in patients with renal impairment, but is associated with a greater risk of dysrhythmias.5 Sugammadex may be of value in reducing the likelihood of PORC in this vulnerable patient population.6–8 The efficacy and safety of sugammadex in severe renal failure has only been reported in 15 adult patients and there are no data available regarding its use in patients with severe renal failure undergoing renal transplantation. We report the use of rocuronium and sugammadex in two paediatric patients with severe renal failure who underwent cadaveric renal transplantation. The safety and efficacy of sugammadex in severe renal failure and renal transplantation is also discussed. A 7-year-old female patient (weight 17.8 kg) was diagnosed with focal segmental chronic glomerulonephritis that had resulted in severe renal failure (creatinine clearance 5.13 ml min−1). The patient had been treated with peritoneal dialysis for 21 months and was scheduled for cadaveric renal transplantation. At the time that the donor kidney became available, the patient had only been fasted for 3 h and had a full stomach necessitating rapid sequence induction. Owing to the presence of hyperkalaemia (potassium 5.8 mmol l−1) secondary to the severe renal failure, rocuronium was preferred to succinylcholine in order to avoid any increase in serum potassium. Neuromuscular monitoring was performed using TOF-Watch SX (Schering-Plough Ireland Ltd, Dublin, Ireland) by measuring the effect of stimulation of the ulnar nerve on the activity of the adductor pollicis muscle. The electrodes were positioned near the wrist and ulnar nerve. The acceleromyographic transducer was firmly placed on the ventral aspect of the top of the thumb, perpendicular to the movement of the thumb, and continuous train-of-four (TOF) monitoring was initiated. Stimulation was supramaximal with square wave pulses of 0.2 ms in duration, delivered as TOF pulses of 2 Hz, at intervals of 5 min during surgery and 15 s at the end of the surgical procedure.9 Neuromuscular monitoring continued until recovery to a TOF ratio of 0.9. The data were recorded on a laptop computer using the TOFMON 2.5 monitoring programme (NV Organon, Oss, the Netherlands). The primary efficacy variable was defined as the time from the start of the administration of sugammadex to recovery of the TOF ratio to 0.9. No premedication was administered. After preoxygenation, rapid sequence induction was performed with propofol 3 mg kg−1, fentanyl 2 μg kg−1 and rocuronium 1.2 mg kg−1. This was followed by endotracheal intubation within 60 s, and the lungs were ventilated with oxygen and air (ratio 2 : 3). Anaesthesia was maintained with isoflurane and intravenous opioids. The TOF-Watch was used in an uncalibrated mode9 and monitoring was started after the administration of rocuronium. On request of the surgeon, repeat doses of rocuronium 0.3 mg kg−1 were administered to keep the TOF ratio at zero (total dose of rocuronium administered 42.7 mg). At the end of the procedure, neuromuscular monitoring showed a reappearance of T2, indicating moderate NMB. Reversal of rocuronium-induced NMB was performed with sugammadex 2 mg kg−1 (35.6 mg) according to the manufacturer's recommended dose. After 7 min, the TOF ratio had recovered to 0.69, still indicating moderate NMB. Another dose of sugammadex 2 mg kg−1 (35.6 mg) was therefore administered, which resulted in recovery of the TOF ratio to 0.9 within 195 s (Fig. 1). No clinical relevant changes from baseline were observed in blood pressure or heart rate after the sugammadex dose. Ten minutes after the administration of the second dose of sugammadex, the trachea was extubated and the patient was fully awake and discharged to the paediatric ICU. The patient's recovery from anaesthesia was uneventful and no signs of residual NMB or recurarisation were observed. Surgical recovery was uneventful and 24 h postoperatively the renal function had improved, with a creatinine clearance of 53.9 ml min−1.Fig. 1: TOF-Watch SX traces of the first twitch height (blue vertical lines) and train-of-four (TOF) ratio (red dots) and the different time points at which rocuronium and sugammadex were administered in the two cases. # represents the time point at which the TOF ratio was 0.69 (case 1) and the reappearance of T2 (case 2).A 14-year-old female patient (weight 45 kg) was diagnosed with a myelomeningocele leading to neurogenic bladder and vesicourethral reflux resulting in severe renal failure (creatinine clearance 20 ml min−1). The patient was treated with haemodialysis for 9 months and was then scheduled for cadaveric renal transplantation. For an identical reason as in case 1 (potassium 5.7 mmol l−1), rocuronium 1.2 mg kg−1 was used to provide NMB. Anaesthesia and neuromuscular monitoring were performed in an identical way to case 1, with the exception that tetanic stimulation (50 Hz tetanic stimulation of the ulnar nerve for 5 s) and a calibration procedure (CAL 2 sequence) were undertaken prior to the administration of rocuronium. The total dose of rocuronium administered was 121.5 mg. Reversal of moderate rocuronium-induced NMB was performed with sugammadex 2 mg kg−1 (90 mg). After 135 s, the TOF ratio had recovered to 0.9 (Fig. 1). No clinically relevant changes were observed in blood pressure or heart rate after the sugammadex dose. Eleven minutes after the administration of sugammadex, the trachea was extubated and the patient was fully awake and discharged to the paediatric ICU. The patient's recovery from anaesthesia was uneventful and no signs of residual NMB or recurarisation were observed. Surgical recovery was again uneventful and 24 h postoperatively the renal function slightly improved, with a creatinine clearance of 30.9 ml min−1. The reversal of rocuronium-induced NMB with sugammadex in the first patient was incomplete after the first dose of sugammadex. A second dose of sugammadex was required and NMB reversal was complete after 195 s. The first dose of sugammadex was given based on the results of the neuromuscular monitoring which had been used in an uncalibrated mode. The use of TOF testing, however, may not be reliable in detecting residual NMB even when full twitches are present.8 Moreover, by using the monitoring in an uncalibrated mode, this may have introduced error, resulting in a more profound degree of NMB than expected with subsequent underdosing of sugammadex and inadequate reversal. It is important, therefore, to use neuromuscular monitoring in the correct way including the calibration procedures described in guidelines9 in order to prevent misinterpretation of the monitoring results. In the second patient, the recovery of the TOF ratio to 0.9 was fast and complete within 135 s. In both the patients, there were no signs of recurarisation and sugammadex was well tolerated. These findings are in line with the results of the previously reported data in animal and human studies, which showed sugammadex safely produces a rapid and complete reversal of rocuronium-induced NMB without recurarisation even in severe renal failure.6,7,10 Owing to the limited number of publications, further evidence has been deemed necessary in order to provide conclusive and sufficient support for the use of sugammadex in severe renal failure.11 The use of sugammadex in severe renal failure is still under debate and no information is available of its use in renal transplantation. Sugammadex is renally excreted, with up to 97% cleared within 24 h in normal renal function. In severe renal failure, however, the clearance of sugammadex is reduced by 17-fold and the elimination half-life is increased 15-fold.6,7,10 Nevertheless, the efficacy of reversal is not altered and no safety concerns have been reported.6,7,10 The available evidence suggests that the sugammadex–rocuronium complex will remain stable over time, but that patients with renal impairment will retain the complex for a longer time period. The sugammadex–rocuronium complex exists in equilibrium with a very low dissociation constant (Kd 0.1 × 10–6 M) because of the strong binding.12,13 Recurarisation due to dissociation of the complex is, therefore, unlikely. Furthermore, high-flux haemodialysis has been shown to be effective in reducing the sugammadex (including the sugammadex–rocuronium complex) concentration in patients with severe renal failure.14 Sugammadex is rapidly cleared unchanged via glomerular filtration without tubular secretion, absorption or metabolism.15 After unclamping of the arterial vessels (resulting in reperfusion of the transplanted kidney), immediate urine production is seen in more than 90% of patients; this marks the onset of restoration of glomerular function. In our patients, urine production was observed 2 and 2.5 min after reperfusion of the transplanted kidney. The time interval between reperfusion and the administration of sugammadex was 61 and 66 min in cases 1 and 2, respectively. Theoretically, once the glomerular filtration resumes in the early postoperative period, sugammadex may be renally excreted in small amounts. The creatinine clearance 24 h after reperfusion of the transplanted kidney was improved in both the patients. Therefore, it may be assumed that sugammadex can be used in patients undergoing renal transplantation as the pathway of renal clearance will be available after perfusion of the transplanted kidney within 24 h and sugammadex may be cleared in small amounts in a similar way to patients with moderate renal failure (creatinine clearance 30–50 ml min−1).11 This hypothesis needs to be proven in further studies in which plasma and urinary sugammadex levels are measured at several time points following reperfusion of the transplanted kidney. We believe that patients undergoing renal transplantation may benefit from the combined use of rocuronium and sugammadex, as this allows rapid and complete reversal of NMB, thereby reducing the risk of PORC and respiratory complications. Acknowledgements relating to this article Assistance with the study: none. Financial support and sponsorship: none. Conflicts of interest: RVC and HDB have provided lectures about sugammadex sponsored by the pharmaceutical company Merck Sharp & Dome. MLAT has no conflicts of interest to declare.