Sugammadex Reversal of Rocuronium-Induced Neuromuscular Blockade: a Comparison with Neostigmine–Glycopyrrolate and Edrophonium–Atropine
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Sugammadex Reversal of Rocuronium-Induced Neuromuscular Blockade: A Comparison with Neostigmine–Glycopyrrolate and Edrophonium–Atropine Ozlem Sacan, MD BACKGROUND: Sugammadex is a modified ␥ cyclodextrin compound, which encap- sulates rocuronium to provide for a rapid reversal of residual neuromuscular Paul F. White, MD, PhD blockade. We tested the hypothesis that sugammadex would provide for a more rapid reversal of a moderately profound residual rocuronium-induced blockade Burcu Tufanogullari, MD than the commonly used cholinesterase inhibitors, edrophonium and neostigmine. METHODS: Sixty patients undergoing elective surgery procedures with a standard- ized desflurane–remifentanil–rocuronium anesthetic technique received either Kevin Klein, MD sugammadex, 4 mg/kg IV (n ϭ 20), edrophonium, 1 mg/kg IV and atropine, 10 g/kg IV (n ϭ 20), or neostigmine, 70 g/kg IV and glycopyrrolate, 14 g/kg IV (n ϭ 20) for reversal of neuromuscular blockade at 15 min or longer after the last dose of rocuronium using acceleromyography to record the train-of-four (TOF) responses. Mean arterial blood pressure and heart rate values were recorded immediately before and for 30 min after reversal drug administration. Side effects were noted at discharge from the postanesthesia care unit. RESULTS: The three groups were similar with respect to their demographic character- istics and total dosages of rocuronium prior to administering the study medication. Although the initial twitch heights (T1) at the time of reversal were similar in all three groups, the time to achieve TOF ratios of 0.7 and 0.9 were significantly shorter with sugammadex (71 Ϯ 25 and 107 Ϯ 61 s) than edrophonium (202 Ϯ 171 and 331 Ϯ 27 s) or neostigmine (625 Ϯ 341 and 1044 Ϯ 590 s). All patients in the sugammadex group achieved a TOF ratio of 0.9 Յ5 min after reversal administration compared with none and 5% in the edrophonium and neostigmine groups, respectively. Heart rate values at 2 and 5 min after reversal were significantly higher in the neostigmine- glycopyrrolate group compared with that in sugammadex. Finally, the incidence of dry mouth was significantly reduced in the sugammadex group (5% vs 85% and 95% in the neostigmine and edrophonium groups, respectively). CONCLUSION: Sugammadex, 4 mg/kg IV, more rapidly and effectively reversed residual neuromuscular blockade when compared with neostigmine (70 g/kg IV) and edrophonium (1 mg/kg IV). Use of sugammadex was associated with less frequent dry mouth than that with the currently used reversal drug combinations. (Anesth Analg 2007;104:569–74) The cholinesterase inhibitors, neostigmine and edro- effective for reversing residual blockade when admin- phonium, are commonly used to reverse the residual istered in combination with muscarinic antagonists, effects of nondepolarizing neuromuscular blocking there are a number of limitations to their use (e.g., drugs at the end of surgery. Although cholinesterase incomplete reversal from “deep” residual blockade, inhibitors are generally considered to be safe and tachycardia, bradycardia, dry mouth, emesis) (1,2). Therefore, there is a need for a reversal drug with a rapid onset of action, efficacy irrespective of the From Department of Anesthesiology and Pain Management, degree of residual neuromuscular blockade, and an University of Texas Southwestern Medical Center at Dallas, Dallas, improved side-effect profile (3). Texas. Recent reports have described the use of drug- Accepted for publication September 21, 2006. specific cyclodextrins to reverse rocuronium-induced Supported by Organon USA, Inc., Margaret Milam McDermott Distinguished Chair in Anesthesiology and the White Mountain Insti- neuromuscular block (4–6). In a preliminary dose- tute. ranging study by Sorgenfrei et al. (6), sugammadex Address correspondence and reprint requests to Paul F. White, (Organon USA, Inc, Roseland, NJ), at doses of 2 MD, PhD, Department of Anesthesiology and Pain Management; University of Texas Southwestern Medical Center at Dallas; 5161 mg/kg and larger, decreased median recovery time to Harry Hines Blvd., CS 2. 282, Dallas, TX 75390-9068. Address e-mail achieve a train-of-four (TOF) response of 0.9 from 21 to [email protected]. min to 1.1–1.3 min. However, this initial placebo- Copyright © 2007 International Anesthesia Research Society controlled study did not compare sugammadex with DOI: 10.1213/01.ane.0000248224.42707.48 either of the two standard cholinesterase inhibitors. Vol. 104, No. 3, March 2007 569 Therefore, we performed an open-label, prospective, (at a pulse width of 200 s and a frequency of 2 Hz) parallel study to compare reversal of rocuronium- was repeated every 15 s, and these data were trans- induced neuromuscular blockade with sugammadex to ferred in real-time via an interface to a laptop com- neostigmine–glycopyrrolate and edrophonium–atro- puter in the operating room. pine when administered under standardized balanced After induction of anesthesia and calibration of the anesthetic conditions. We hypothesized that sugamma- TOF-WatchSX, each subject received a standardized dex would be associated with a significantly more rapid dose of rocuronium, 0.6 mg/kg IV, to facilitate tracheal achievement of a TOF ratio of 0.9 compared with the intubation. Additional bolus doses of rocuronium, 0.15 standard neuromuscular reversal drugs. The secondary g/kg, were administered upon reappearance of the objective of the study was to compare the incidences of second twitch in a TOF to maintain the neuromuscular intra- and postoperative side effects. block during surgery. The reversal drugs were admin- istered at least 15 min after the last dose of rocuronium METHODS during steady-state anesthetic conditions. Patients re- After obtaining IRB approval at the University of ceived either IV neostigmine (70 g/kg) with glyco- Texas Southwestern Medical Center and Zale Lipshy pyrrolate (14 g/kg), edrophonium (1 mg/kg) with University Hospital in Dallas, 60 consenting ASA atropine (10 g/kg), or sugammadex (4 mg/kg) alone physical status I–III patients undergoing elective sur- according to an open-parallel study design. Mainte- gical procedures requiring tracheal intubation were nance anesthetic drugs and neuromuscular monitor- enrolled in this open, parallel study design. The ing were continued for a period of 30 min after patients who preferred not to receive an investiga- administering the reversal drugs. Noninvasive MAP tional drug (sugammadex) were randomly assigned to and HR measurements were obtained immediately one of the two anticholinesterase groups. Patients with before the administration of the reversal drugs (“base- a history of a difficult tracheal intubation, a Mallam- line”) and subsequently at 2, 5, 10, and 30 min pati score of III or IV, allergic reactions to opioid intervals after administration of the reversal drugs. analgesics, muscle relaxants, or other medications Before the discontinuation of the anesthetics and ex- commonly used during general anesthesia, a positive tubation of the trachea, all patients were required to pregnancy test (or breast feeding), or a family history manifest a sustained tetanic response to ulnar nerve of malignant hyperthermia were excluded from par- stimulation using a standard neuromuscular stimula- ticipating in this study. tor. Extubation times after discontinuation of the All patients were premedicated with midazolam, 20 maintenance anesthetic drugs were not recorded be- g/kg IV, and fentanyl, 0.5 g/kg IV, at 30–45 min cause the reversal drugs were given at variable times and 5–10 min before induction of anesthesia, respec- before the end of surgery. tively. On arrival in the operating room, routine Clinical signs of recovery were assessed at 1 min monitors were applied for recording heart rate (HR), intervals after extubation including level of conscious- mean arterial blood pressure (MAP), and oxygen ness (i.e., 3 ϭ awake and oriented, 2 ϭ arousable with saturation values. After administration of oxygen, minimal stimulation, 1 ϭ responsive only to tactile anesthesia was induced with propofol, 2–2.5 mg/kg stimulation). Orientation was also assessed at 1 min IV, and maintained with desflurane 4–6% end-tidal, intervals after regaining consciousness by asking their in a 1:1 oxygen:air mixture, in combination with a name, the hospital, and the day of the week. Upon Ϫ Ϫ remifentanil infusion, 0.1 g ⅐ kg 1 ⅐ min 1 IV. The regaining orientation, a clinical assessment of muscle end-tidal concentration of desflurane (4 Ϯ 1%) was not strength was performed using 1) 5-s head lift test, and changed during the assessment of the reversal drugs. 2) by asking the patient if they were experiencing Ventilation was controlled to maintain the end-tidal general muscle weakness (using a 10-point verbal ϭ ϭ CO2 values between 30 and 35 mm Hg. Nasopharyn- rating scale from 0 none to 9 extremely impaired). geal temperatures were maintained between 35–37°C, Adverse events (e.g., cardiac arrhythmias, inability to and the skin surface temperature of the monitored extubate the trachea upon regaining consciousness, extremity was maintained Ͼ32°C, using forced air dizziness, headaches, dry mouth, nausea and vomit- warming. ing) were recorded by a blinded observer in the The neuromuscular function of the adductor polli- operating room and upon discharge from the postan- cis muscle was monitored using the TOF-WatchSX esthesia care unit. acceleromyograph (Organon Ireland Ltd. Co., Dublin, The power analysis used a simulation to estimate Ireland). The TOF tracing was stabilized after induc- the number of subjects per group (n ϭ 20) needed to tion of anesthesia by administering 1 min of repetitive be able to state with 97.5% confidence that 75% or TOF stimulation followed by a 5-s, 50-Hz tetanic more of the patients would return to TOF ratio of 0.9 stimulation, and then another 3–4 min period of within 5 min after receiving sugammadex, compared repetitive TOF stimulation. The CAL 2 mode was used to with 25% or less of the patients receiving either of the determine the supramaximal threshold and to calibrate two cholinesterase inhibitors (6,7).