Can late- or two-step administration of neostigmine reduce the reversal time of cisatracurium-induced moderate neuromuscular blockade?

Editor, The use of set doses of neostigmine for reversal of neuromuscular blockade (NMB) has now been replaced with drug administration based on the depth of the blockade. As the fraction of nicotinic receptors occupied by cisatracurium reduces during superficial NMB, it is fair to infer that the required doses of neostigmine are smaller, and the rate of reversal is faster.1 Full reversal doses, however, may cause paradoxical neuromuscular weakness during shallower blocks.2,3 A common scenario in everyday practice is when the surgery is completed but the patient is still suffering from cisatracurium-induced moderate NMB. What would be the ideal method for inducing a faster and more reliable reversal after the emergence of the third response to train-of-four (TOF) stimulation: immediate antagonism of the NMB or waiting for spontaneous reversal to a more superficial NMB before neostigmine administration? We compared the time required for reversal of a moderate NMB from a train-of-four count (TOFc) of 3 to a train-of-four ratio (TOFr) of 1.0 following neostigmine injection (60 μg kg−1) with the time required waiting for a more superficial block (TOFr of 0.4) before giving neostigmine (30 μg kg−1). A Two-step delivery method was also investigated: neostigmine 30 μg kg−1 at a TOFc of 3 and a further 30 μg kg−1 when the TOFr was 0.4. After approval by the Research Ethics Committee of the School of Medical and Health Sciences, the Pontifical Catholic University of São Paulo on March 9, 2021, CAAE 39680120.7.0000.5373 and Trial registration with ClinicalTrials.gov (NCT 04920682, April 28, 2021), patients undergoing general anaesthesia for the nose and ear surgery were enrolled between 15 May and 20 August 2021 in this randomised prospective clinical trial. Patients aged 18 to 65 years and with American Society of Anesthesiologists (ASA). Physical status of I or II were included. Patient exclusion criteria were as follows: refusal to participate in the study; the presence of kidney, liver or neuromuscular disease; contraindication to the use of any of the drugs used in the study; body mass index (BMI) >30 kg m–2. At the end of surgery, we awaited spontaneous recovery of the NMB until the appearance of the third twitch to a TOF. Subjects were randomly allocated to one of four groups: group M (reversal from a moderate NMB by administration of neostigmine 60 μg kg−1 with atropine 30 μg kg−1 when the TOFc was 3 and 0.9% saline when the TOFr was 0.4); group S (reversal from a superficial NMB by administration of 0.9% saline when the TOFc was 3 and neostigmine 30 μg kg−1 with atropine 15 μg kg−1 when the TOFr was 0.4); group N (two-step reversal (neostigmine 30 μg kg−1 with atropine 15 μg kg−1 when the TOFc was 3 and neostigmine 30 μg kg−1 with atropine 15 μg kg−1 when the TOFr was 0.4); group C (control, placebo), 0.9% saline solution when the TOFc was 3 and also when the TOFr was 0.4 (Supplementary figure 1, https://links.lww.com/EJA/A766). For each patient, an opaque envelope was prepared, sealed and numbered sequentially containing the group to which the patient was allocated. A list of random numbers generated by a computer (www.random.org) was used for this purpose. An anaesthesiologist not involved in the study was responsible for preparing the solutions. Anaesthesia induction was performed with remifentanil followed by a propofol bolus and cisatracurium 0.1 mg kg−1. Total intravenous anaesthesia was maintained by infusions of remifentanil and propofol. The NMB was monitored using acceleromyography (TOF Watch SX; Schering-Plow) as recommended for use in clinical research. Calibration (CAL 2) was performed after the patient was anaesthetised. The primary outcome was the time required for reversal of a moderate NMB from a TOFc of 3 to a TOFr of 1.0. Secondary outcomes included the time necessary for reversal of the NMB from a TOFc of 3 to a TOFr of 0.4; from a TOFc of 3 to a TOFr of 0.9; from a TOFr of 0.4 to a TOFr of 1.0 and whether full reversal of a moderate NMB occurred in < 10 min. The sample size was based on a previous study and indicated that 12 patients per group were required to detect a difference across the groups ≥1.3 standard deviations with a power of 90% and an alpha error of 5%.1 Nominal categorical variables were expressed as number (%) and evaluated using Fisher's exact tests (for expected values <5) or the χ2 test followed by Bonferroni correction for multiple comparisons. The Kolmogorov–Smirnov and Shapiro–Wilk tests were used to determine whether data were normally distributed. The Kruskal–Wallis test was used to compare numerical variables between the different groups, followed by Dunn's test for multiple comparisons. All statistical analyses were conducted using SAS System for Windows (Statistical Analysis System, version 9.2, SAS Institute Inc., 2002–2008, Cary, NC, USA) and P < 0.05 indicated a statistical significant difference. There were no significant differences between groups in terms of age, gender, BMI or ASA physical status (Supplementary table 2, https://links.lww.com/EJA/A767). The time for reversal from a TOFc 3 to TOFr 1 was significantly shorter in groups M and N: median 7.2 [95% confidence interval (CI), 6.3 to 9.4] minutes and 8.8 (95% CI, 7.8 to 19.5) min, respectively. The time for reversal in group C was 29.3 (95% CI, 25.9 to 33.5) min, for group S it was 18.5 (95% CI, 14.9 to 28.5) min. The time for reversal in this later group was shorter when compared with group C. There was no distinction between groups M and N. (Fig. 1). Secondary outcomes are described in Table 1.Fig. 1: Groups were compared using the Kruskal–Wallis test. P < 0.001—Group M versus group S; Group M versus Group C and Group N versus Group C. P = 0.03 Group N versus Group S; Group S versus Group C. P = 0.09—Group M versus group N. Table 1 - Secondary outcomes Group M Group N Group S Group C TOFc 3–TOFr 0.4a 2.3 (1 to 4.3) 4.2 (2.2 to 15) 13.1 (3 to 24) 12.3 (3 to 16) TOFr 0,4–TOFr 1.0b 5.4 (3.9 to 6.9) 4.7 (3.3 to 13.9) 5.8 (3.6 to 13.7) 20.5 (4.7 to 21.7) TOFc 3–TOFr 0.9c 4.8 (3.4 to 9.5) 7.3 (3.8 to 30.4) 18.1 (6 to 35) 25.2 (11.3 to 33.2) Data are median (95% CI) minutes. Groups were compared using the Kruskal–Wallis test.aGroup C versus groups M and N: P < 0.001; Group S versus groups M and N: P < 0.001; Group M versus group N: P = 0.019.bGroup C versus groups M, N, and S: P < 0.001.cGroup C versus groups M and N: P < 0.001; Group S versus group M and N: P < 0.001. The probabilities for reversal of a NMB from the return of the third response to TOF stimulation to a TOFr of 0.9 or 1.0 within 10 min were considerably lower in groups C (0%, 0%) and S (6.7%, 6.7%) compared with groups M (100%, 71.4%) and N (71.4%, 64.2%). It is not known whether any studies have been conducted to evaluate the reversal time of moderate NMB following neostigmine administration at different periods using the presently suggested doses to avoid the occurrence of paradoxical muscular weakness. There is widespread agreement that acetylcholinesterase inhibitors cannot successfully and safely reverse deep NMB. As a result, the emergence of at least three responses to the TOF stimulation is required for the reversal to be effective.4 Even if neostigmine is administered during the shallower end of moderate block (TOFc 3), the potential for residual NMB remains.5,6 Our research has several limitations. Firstly, the results presented are for patients who were given an intravenous anaesthetic. Inhalation anaesthetics have been shown to considerably prolong the time for NMB reversal.7 Secondly, the incidence of adverse events associated with the administration of neostigmine and atropine was not assessed. Thirdly, the study's single-institutional design restricts the broad importance of our findings. Given the limitations of this study, more research is needed to validate our findings. In conclusion, neostigmine administered as a single full does at the time of reappearance of the third response to TOF stimulation or given in two half doses at a TOFc of 3 and at a TOFr of 0.4 (two step administration) can reverse moderate NMB safely and effectively in a relatively short time. In addition, there is a greater likelihood of a TOFr of 1.0 in less than 10 min compared to a half-dose of neostigmine administered during superficial NMB (TOFr of 0.4). In clinical practice, if a patient presents moderate NMB at the end of surgery, reversing the NMB at this time is faster and safer than waiting for a shallower degree of the blockade before administering a half-dose of neostigmine.