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Low-Dose or High-Dose Rocuronium Reversed with Neostigmine or Sugammadex for Cesarean Delivery Anesthesia: A Randomized Controlled Noninferiority Trial of Time to Tracheal Intubation and Extubation

Stourac, Petr MD, PhD; Adamus, Milan MD, PhD; Seidlova, Dagmar MD, PhD; Pavlik, Tomas MSc, PhD; Janku, Petr MD, PhD; Krikava, Ivo MD, PhD; Mrozek, Zdenek MD, PhD; Prochazka, Martin MD, PhD; Klucka, Jozef MD; Stoudek, Roman MD; Bartikova, Ivana MD; Kosinova, Martina MD; Harazim, Hana MD; Robotkova, Hana MD; Hejduk, Karel MSc; Hodicka, Zuzana MD, PhD; Kirchnerova, Martina MD; Francakova, Jana MD; Obare Pyszkova, Lenka MD; Hlozkova, Jarmila MD; Sevcik, Pavel MD, PhD

doi: 10.1213/ANE.0000000000001197
Obstetric Anesthesiology: Research Report

BACKGROUND: Rocuronium for cesarean delivery under general anesthesia is an alternative to succinylcholine for rapid-sequence induction of anesthesia because of the availability of sugammadex for reversal of neuromuscular blockade. However, there are no large well-controlled studies in women undergoing general anesthesia for cesarean delivery. The aim of this noninferiority trial was to determine whether rocuronium and sugammadex confer benefit in time to tracheal intubation (primary outcome) and other neuromuscular blockade outcomes compared with succinylcholine, rocuronium, and neostigmine in women undergoing general anesthesia for cesarean delivery.

METHODS: We aimed to enroll all women undergoing general anesthesia for cesarean delivery in the 2 participating university hospitals (Brno, Olomouc, Czech Republic) in this single-blinded, randomized, controlled study. Women were randomly assigned to the ROC group (muscle relaxation induced with rocuronium 1 mg/kg and reversed with sugammadex 2–4 mg/kg) or the SUX group (succinylcholine 1 mg/kg for induction, rocuronium 0.3 mg/kg for maintenance, and neostigmine 0.03 mg/kg for reversal of the neuromuscular blockade). The interval from the end of propofol administration to tracheal intubation was the primary end point with a noninferiority margin of 20 seconds. We recorded intubating conditions (modified Viby-Mogensen score), neonatal outcome (Apgar score <7; umbilical artery pH), anesthesia complications, and subjective patient complaints 24 hours after surgery.

RESULTS: We enrolled 240 parturients. The mean time to tracheal intubation was 2.9 seconds longer in the ROC group (95% confidence interval, −5.3 to 11.2 seconds), noninferior compared with the SUX group. Absence of laryngoscopy resistance was greater in the ROC than in the SUX groups (ROC, 87.5%; SUX, 74.2%; P = 0.019), but there were no differences in vocal cord position (P = 0.45) or intubation response (P = 0.31) between groups. No statistically significant differences in incidence of anesthesia complications or in neonatal outcome were found (10-minute Apgar score <7, P = 0.07; umbilical artery pH, P = 0.43). The incidence of postpartum myalgia was greater in the SUX group (ROC 0%; SUX 6.7%; P = 0.007). The incidence of subjective complaints was lower in the ROC group (ROC, 21.4%; SUX, 37.5%; P = 0.007).

CONCLUSIONS: We conclude that rocuronium for rapid-sequence induction is noninferior for time to tracheal intubation and is accompanied by more frequent absence of laryngoscopy resistance and lower incidence of myalgia in comparison with succinylcholine for cesarean delivery under general anesthesia.

Supplemental Digital Content is available in the text.Published ahead of print March 11, 2016

From the *Department of Pediatric Anesthesiology and Intensive Care Medicine, University Hospital Brno, Faculty of Medicine, Masaryk University, Brno, Czech Republic; Department of Anesthesiology and Intensive Care Medicine, University Hospital Olomouc, and Faculty of Medicine and Dentistry, Palacky University Olomouc, Olomouc, Czech Republic; 2nd Anesthesiological Department, University Hospital Brno, Brno, Czech Republic; §Institute of Biostatistics and Analyses, Faculty of Medicine, Masaryk University, Brno, Czech Republic; Department of Obstetrics and Gynecology, University Hospital Brno, Faculty of Medicine, Masaryk University, Brno, Czech Republic; Department of Anesthesiology and Intensive Care Medicine, University Hospital Brno, Faculty of Medicine, Masaryk University, Brno, Czech Republic; #Department of Obstetrics and Gynecology, University Hospital Olomouc, and Faculty of Medicine and Dentistry, Palacky University Olomouc, Olomouc, Czech Republic; and **Department of Anesthesiology and Intensive Care Medicine, University Hospital Ostrava, and Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic.

Accepted for publication December 29, 2015.

Published ahead of print March 11, 2016

Funding: Financial support from the Czech Ministry of Health Internal Grant Agency (NT 13906-4/2012).

The authors declare no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website.

The preliminary results of this study were presented as conference abstracts and posters at the following congresses: Euroanaesthesia 2013, Barcelona, Spain; Euroanaesthesia 2014, Stockholm, Sweden; Euroanaesthesia 2015, Berlin, Germany; and Anesthesiology 2015, San Diego, CA.

Reprints will not be available from the authors.

Address correspondence to Petr Stourac, MD, PhD, Department of Pediatric Anesthesiology and Intensive Care Medicine, University Hospital Brno, Faculty of Medicine of Masaryk University, Jihlavska 20, 625 00 Brno, Czech Republic. Address e-mail to petr.stourac@gmail.com.

The risk of failed intubation, ventilation, and oxygenation failure remains one of the most serious complications of general anesthesia for cesarean delivery.1 In the general population, the risk of difficult intubation is approximately 1:2500; in term pregnancy, the incidence is 5 to 10 times greater (1:224–1:533).1–3 A 2015 meta-analysis of risk of failed intubation reported an incidence of 1:442 in general anesthesia for cesarean delivery.4 An additional concern is that intubating conditions change during the course of delivery; the Mallampati classification can increase by 1 to 2 grades, often to grades III and IV.5 Development of critical hypoxia can occur in both mother and fetus faster than in nonpregnant patients.6

According to the recent reports of the Confidential Enquiry into Maternal and Child Death registry, an important aspect of safe care for the mother is to achieve adequate muscle strength at the end of general anesthesia to maintain a patent airway.7 Although rocuronium is an accepted alternative for rapid-sequence induction for cesarean delivery,8 most anesthesiologists in the Czech Republic prefer succinylcholine followed by a nondepolarizing muscle relaxant (rocuronium, atracurium, cisatracurium, and vecuronium), although pharmacologically induced intraoperative muscle relaxation is often unnecessary for abdominal wall closure given the abdominal wall distension associated with pregnancy.9,10 A dose of rocuronium 0.6 mg/kg during induction of anesthesia for cesarean delivery, as recommended by the manufacturer, provides inferior intubating conditions and delayed onset of neuromuscular relaxation compared with succinylcholine.11 However, we cannot expect safe recovery from neuromuscular blockade (train-of-four [TOF] ratio of >0.9) at the end of surgery after neuromuscular blockade with rocuronium 0.9 to 1.0 mg/kg, even after reversal with neostigmine.12–14 In contrast, no matter the degree of a rocuronium- or vecuronium-induced neuroblockade, sugammadex can be used in a dose of 2 to 16 mg/kg to reverse blockade. Its feasibility for cesarean delivery has been reported in case series, case reports,12–16 and case studies of high-risk mothers in whom succinylcholine was contraindicated.17–19

To the best of our knowledge, there are few published studies on the benefits to mother and/or newborn of rocuronium administration in a dose of 1 mg/kg compared with succinylcholine 1 mg/kg for rapid-sequence induction of general anesthesia for cesarean delivery, and no published studies report the possible benefit of sugammadex for active reversal of neuromuscular blockade after high-dose rocuronium for cesarean delivery.

The aim of this study was to determine whether the ability to reverse deep neuromuscular blockade with sugammadex would allow for a sufficiently high dose of rocuronium to achieve comparable intubating conditions with succinylcholine in parturients undergoing general anesthesia for cesarean delivery, while ensuring comparable recovery at the end of surgery. We hypothesized that rocuronium 1 mg/kg would be noninferior to succinylcholine 1 mg/kg for time to tracheal intubation. Secondary outcomes were differences in intubating conditions, incidence of anesthesia perioperative complications, neonatal outcome, and the time from surgical skin closure to tracheal extubation.

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METHODS

Study Oversight

Two university hospitals participated in this randomized, single-blinded (parturient), parallel-group, controlled study to compare the effect of rocuronium and succinylcholine during rapid-sequence induction for cesarean delivery. The trial was designed by the principal academic investigator in cooperation with members of the study group. The study is reported according to the Consolidated Standards of Reporting Trials (http://www.consort-statement.org/) statement.20,21 Before patient enrollment, it was registered in ClinicalTrials.gov database with the identifier: NCT01718236, October 30, 2012. The study was approved by the institutional ethics committees of both centers (University Hospital Brno, Brno, Czech Republic; and University Hospital, Olomouc, Czech Republic).

The University Hospital in Brno is a perinatal center for the region of South Moravia with the population of almost 1.2 million people and >6000 deliveries per year (rate of cesarean delivery 22%; 30% of these under general anesthesia). The University Hospital in Olomouc is a perinatal center for the Olomouc region with an approximate population of 650,000 people and >2600 deliveries per year (rate of cesarean delivery 31%; 55% of these under general anesthesia).

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Inclusion and Exclusion Criteria

All women aged 14 to 60 years admitted to the obstetric ward in Brno or Olomouc University Hospital for delivery were eligible to participate in the study. Inclusion criterion for enrollment was cesarean delivery scheduled under general anesthesia. The exclusion criteria were as follows: indicated and performed neuraxial blockade, anesthesiologist or obstetrician opposition to patient inclusion, allergy or intolerance to ≥1 of the study drugs or known allergies or reactions to iodine, and patient refusal or no written informed consent. Discontinuation criterion was failure of TOF Watch SX (Organon, Oss, The Netherlands) measurements during the induction of general anesthesia.

Each parturient who met the inclusion criteria was approached for study participation on admission to the delivery ward. All participating women provided informed consent on the day of cesarean delivery (intrapartum cesarean delivery) or on the day before (scheduled cesarean delivery). After written informed consent, they were stratified into 8 groups defined by center, type of cesarean delivery, age, and body mass index. Randomization to the intervention (ROC) or control (SUX) group was performed after the decision was made for cesarean delivery by the anesthesiologist according to the study randomization scheme (see below).

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Observed Parameters

Demographic details of the parturient and newborn, medical history, indication for cesarean delivery, preanesthetic examination, important event times, total procedure time (end of administration of the propofol to tracheal extubation), surgery duration time (skin incision to last stitch), intubating conditions assessed using the modified Viby-Mogensen Scale22 (resistance to laryngoscopy, position of vocal cords, laryngoscopic view, and response to intubation attempt; rated by the attending anesthesiologist), and intraoperative complications (including regurgitation, aspiration, vomiting, difficult airways, oxygen desaturation, tachycardia, bradycardia, hypertension, and hypotension, among others) were recorded on the case report form by the 15 anesthesiologists involved in the study (12 fully certified and 3 trainees). Each parturient was also evaluated after 24 hours for subjective complaints (sore throat, impaired phonation, myalgia, inability to expectorate, weakness, awareness, shortness of breath, diplopia, and postoperative pain) during a follow-up interview by the anesthesiologist. Each parturient was directly asked about individual complaints (yes/no) and also asked by the anesthesiologist if she had any other current complaint.

Anonymized data were recorded in electronic case report form of the study database (RocSugIO.registry.cz; TrialDB, Yale University, New Haven, CT).

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Anesthesia Protocol

The anesthesia protocols for both groups are detailed in Figure 1. The standard protocol for airway management consisted of direct laryngoscopy with a Macintosh blade size 3 or 4 and tracheal intubation with an orotracheal tube (7.0–7.5) without a stylet. During anesthesia, electrocardiography, heart rate, SpO2, noninvasive blood pressure, and end tidal carbon dioxide (ETCO2) values were monitored and recorded in the anesthesia record.

Figure 1

Figure 1

Neuromuscular blockade depth was measured using TOF Watch SX device (Organon) stimulating the ulnar nerve on the left distal forearm; the response of adductor pollicis muscle was evaluated using accelerometry. The calibration was performed under IV anesthesia before muscle relaxant administration and lasted 10 seconds. The single-twitch (ST) 1-Hz mode was used during induction of neuromuscular blockade with standardized amplitude for both groups. Intubation was attempted when the ST was 10% (ST 10%). The level of deep nondepolarizing neuromuscular blockade was measured by the post-tetanic count (PTC) mode and shallow and recovering nondepolarizing blockade by TOF count or ratio mode. In the ROC group, sugammadex reversal was administered when the PTC was ≥1. Low-dose sugammadex (2 mg/kg) was administered if the TOF count was ≥1 and high-dose (4 mg/kg) was used for deeper neuromuscular blockade (PTC ≥1). We used an Aespire S/5 anesthesia machine (GE Healthcare, Madison, WI). Intraoperative event times were recorded by a nurse by pressing the Snapshot button on Datex Ohmeda S/5 Monitor (Datex Ohmeda, Madison, WI) and then written into the case report form.

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Obstetric Protocol

Pfannenstiel supracervical laparotomy and Geppert uterotomy were used in all cases. Abdominal wall closure was provided in 5 layers, and skin closure was performed with suture.

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Statistical Analysis

Outcome Measures

The primary end point of this study was the time from induction of anesthesia to tracheal intubation. The interval was measured from the end of administration of the propofol (the syringe was emptied) to the first wave of ETCO2 appearance after successful tracheal intubation. All drugs were administered through the catheter hub of the rapidly running 18-gauge IV catheter inserted in the upper arm. The primary hypothesis of this study was that rapid-sequence induction of general anesthesia using propofol and rocuronium for cesarean delivery is noninferior to the combination of propofol and succinylcholine. Secondary outcomes were differences in intubating conditions, incidence of intraoperative anesthesia complications, neonatal outcomes, and the time from the completion of surgical skin closure to tracheal extubation. Intubating conditions were assessed using resistance to laryngoscopy (none, slight, and severe), position of vocal cords (medial, paramedial, partially abducted, and fully abducted), laryngoscopic view (Cormack-Lehane), response to intubation attempt (none, cardiovascular-blood pressure and/or pulse increase of 20% from baseline, and movement of limbs). Complications during anesthesia and the perioperative period (regurgitation, aspiration, vomiting, difficult airway, oxygen desaturation, tachycardia, bradycardia, hypertension, hypotension, pulmonary embolism, amniotic fluid embolism, hysterectomy, bronchospasm, laryngospasm, shortness of breath, pulmonary edema, and others) were recorded. Neonatal outcome was evaluated using Apgar scores at 1, 5, and 10 minutes assessed by an experienced neonatologist and umbilical artery blood gas analysis.

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Randomization

Stratified block randomization was used for generating the subject allocation sequence. Stratification was performed on the basis of participating center, type of cesarean delivery (intrapartum or scheduled), age (<30 or ≥30 years), and body mass index (<30 or ≥30 kg/m2). For each stratum, the statistician generated the random allocation sequence for the 2 treatment groups. A computer random number generator was used to randomly select permuted blocks of 4 patients and an equal allocation ratio. Sequentially numbered containers were used for individual strata and group assignments were concealed in sequentially numbered, opaque, and sealed envelopes. Each envelope was opened immediately before the induction of general anesthesia, and the patient was assigned to either the ROC or the SUX group.

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Statistical Methods

The criterion for noninferiority with respect to time needed to tracheal intubation was considered to have been met if the upper limit of a 2-sided 95% confidence interval (CI) for the absolute difference between groups was not >20 seconds (assumed to be approximately one-third of the expected interval for intubation attempt start after administration of the neuromuscular-blocking agent). For this setting, a population of 214 patients was required for 90% certainty that the higher limit would be below the noninferiority margin of 20 seconds. The sample size estimation was performed according to Julious.23 We decided to include 240 patients to take into account patients who could not be evaluated.

Standard frequency tables and summary statistics (means, SD, median, minimum, and maximum) were used to describe the baseline demographic and clinical characteristics. The Fisher exact test was used for analysis of intubating conditions and complications during anesthesia, during the perioperative period and for neonatal outcome evaluation. Differences in the procedure times were assessed using the Mann-Whitney test. All analyses were performed according to the intention-to-treat principle. To examine the influence of intrapartum cesarean delivery, the neonatal outcomes of ROC versus SUX groups were evaluated separately in the scheduled cesarean deliveries. For secondary outcomes, a P value <0.05 was considered statistically significant. All statistical analyses were performed with R software for Windows (version 2.13.0; R Development Core Team, Statistics Department, University of Auckland, Auckland, New Zealand, http://www.r-project.org/).

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RESULTS

Table 1

Table 1

Figure 2

Figure 2

We enrolled 240 parturients (ROC, n = 120; SUX, n = 120) during the study period from December 2012 to December 2013. The Consolidated Standards of Reporting Trials diagram for the study is shown in Figure 2. Basic demographic characteristics of parturients are shown in Table 1. There were no significant differences between groups at baseline.

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Outcome Measures Assessment

The primary end point, the time from anesthesia induction to tracheal intubation, and other procedure times are summarized in Table 2. The mean time to tracheal intubation was 2.9 seconds longer in those receiving rocuronium compared with succinylcholine (95% CI, −5.3 to 11.2 seconds). The upper limit of the 95% CI was below the noninferiority margin of 20 seconds and, therefore, propofol and rocuronium can be regarded as noninferior to the combination of propofol and succinylcholine with respect to the time from induction to tracheal intubation.

Table 2

Table 2

Intubating condition data are shown in Table 3. Intubating conditions were comparable although the ROC group had less resistance to laryngoscopy than the SUX group; there were no differences in Cormack-Lehane score, limb movement, or cough. All parturients were successfully intubated.

Table 3

Table 3

There was no desaturation under 90% before ST 10% during induction of anesthesia or absence of visible finger movement during nerve stimulator stimulation, even in cases in which the time to achieve ST 10% was long. No cannot intubate, cannot ventilate scenario was recorded during the study period.

Neonatal outcome characteristics are shown in Table 4. There were no differences between groups in the incidence of 10-minute Apgar score of <7 although the incidence of low Apgar scores was greater in the ROC than in SUX group at 1 and 5 minutes. There were no significant differences in any neonatal outcome among subjects undergoing scheduled cesarean delivery (ROC, n = 59; SUX, n = 62) (Table 4).

Table 4

Table 4

We identified no differences in the incidence of intraoperative anesthesia complications. In contrast, we found a statistically significant difference in the incidence of myalgia in the 24-hour postoperative period (ROC, n = 0; SUX, n = 8; P = 0.007), but no difference in the incidence of sore throat (ROC, n = 18; SUX n = 29; 95% CI for difference: −19.1% to 0.8%; P = 0.10). There were no differences in any other evaluated complications in the 24-hour follow-up. Data are shown in the Supplemental Digital Content (Supplemental Table 1, http://links.lww.com/AA/B366).

There were no significant differences between groups or participating centers in anesthetic dosage (Supplemental Digital Content, Supplemental Table 2, http://links.lww.com/AA/B366) or between participating centers in measured times for either group (data not shown).

A significant difference between the ROC group and the SUX group in the total procedure time (end of propofol administration to tracheal extubation) was found. In patients receiving rocuronium and sugammadex, the total procedure time was approximately 7 minutes longer than that in patients receiving succinylcholine, rocuronium, and neostigmine (P < 0.001; Table 2). Median time from surgical skin closure to extubation was 10 minutes in the ROC group and 8 minutes in the SUX group (P < 0.001; Table 2).

The evaluation of the neuromuscular blockade level at the end of surgery showed no PTC count (PTC 0) in the 56.6% of the ROC group (n = 68) and a TOF count >1 in the 81.6% of the SUX group (n = 98). In the case of PTC 0 (n = 68), the waiting time from surgical skin closure to PTC 1 achievement in the ROC group was a median of 10 minutes.

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DISCUSSION

In this study, we present the first randomized controlled trial comparing a combination of rocuronium 1 mg/kg and subsequent reversal by sugammadex to succinylcholine 1 mg/kg, rocuronium, and neostigmine in general anesthesia for cesarean delivery. The most important finding was the noninferiority of rocuronium 1 mg/kg for rapid-sequence induction compared with succinylcholine 1 mg/kg; however, rocuronium was associated with a brief delay in the time from end of surgery to tracheal extubation. The mean time to achieve the first wave on ETCO2 curve was 3 seconds longer in the ROC group, a difference that likely has no clinical significance.

Abouleish et al.11 first described the use of rocuronium for cesarean delivery using a standard dose of 2 times the 50% effective dose (ED95) dose (0.6 mg/kg). These authors reported longer onset time of rocuronium (98 seconds) than succinylcholine (60 seconds). They also reported good intubating conditions in 90% of cases 80 seconds after rocuronium 0.6 mg/kg administration. In another study, Abu-Halaweh et al.8 reported good/excellent intubating conditions in 95% of patients 60 seconds after rocuronium 1 mg/kg and in 97% of patients after succinylcholine 1 mg/kg administration. We opted to use 3 times the ED95 dose (1 mg/kg) to shorten the rocuronium onset time in accordance with the results of the study by Magorian et al.24 We found a shorter mean onset time than that found by Abouleish et al.11 for the ROC group (59 seconds) and good intubating conditions in both groups, comparable to that reported by Abu-Halaweh et al.8 These results support the view that rocuronium 1 mg/kg is superior in this setting to rocuronium 0.6 mg/kg and noninferior to succinylcholine 1 mg/kg. The slightly higher incidence of resistance to laryngoscopy in the SUX group was not significantly higher than that in the study by Abu-Halaweh et al.8 However, this criterion is influenced by the attending anesthesiologist, because evaluation of resistance to laryngoscopy is subjective.

In comparison to the recent study by Sakurai et al.25, we achieved the ST 10% later in the ROC than in the SUX group (59 vs 42 seconds), but there was a substantial difference in the time evaluation. Sakurai et al. measured the time from the administration of rocuronium to loss of visible twitch, whereas we measured time from end of propofol administration to ST 10%, including the time needed for calibration of TOF Watch SX (10 seconds). This contributed to a longer measured onset time. Based on a study by Baraka,6 time to oxygen desaturation <95% during late pregnancy after preoxygenation in the supine position is almost 3 minutes. For this reason, a 10-second delay has limited clinical relevance. This may explain the absence of severe oxygen desaturation <90%, even in cases in which the time to achieve ST 10% was long (maximum was 258 seconds in SUX group).

There was a significant difference in the incidence of low 1- and 5-minute Apgar scores, but not 10-minute scores. However, if intrapartum cesarean deliveries are excluded from the analysis, where nonhomogenous signs of fetal hypoxemia between groups were observed (more frequent in the ROC group), no differences in neonatal outcome (Apgar score, umbilical blood pH) between groups were found. Williamson et al.14 reported a 66% incidence of initial Apgar score <7, whereas, in our ROC group, this was far less frequent (22.9%). Rocuronium has been demonstrated to have a 16% rate of placental transfer, which might be significant if the mother received 3 times the ED95 dose.11 A future study is needed to correlate cord blood concentrations of rocuronium with Apgar scores and neonatal twitch monitoring.

We found a longer total procedure time in the ROC group compared with the SUX group. However, the surgery time was comparable between groups. The explanation for this may be because of the strict study protocol that precluded administration of sugammadex until a PTC count of >0 was detected. More than 56% cases in the ROC group did not achieve a PTC count of >0 at the end of surgery. Another finding was that >85% cases in the ROC group did not achieve a TOF count of >0, that is, the neuromuscular blockade would not be reversible with cholinesterase inhibitors in these cases. Rocuronium administered at 3 times the ED95 produced deep neuromuscular blockade that was longer than the surgery time. This is in agreement with the results by Pühringer et al.13 and Williamson et al.14 case series in which just 1 parturient of 25 had ≥3 twitches on the TOF at the end of the surgical procedure. The clinical implication is that sugammadex may be a necessary part of rocuronium use if 1 mg/kg is used for cesarean delivery.

The optimal dose of rocuronium and sugammadex has been discussed extensively for the nonpregnant population.26 For simplicity, and also in accordance with manufacturer recommendations, we chose a dose per actual body weight resulting in a median sugammadex dose of 4 mg/kg. An important finding was that sugammadex did not need to be administered in repeated doses because of signs of residual curarization or reoccurrence of muscular blockade in any of the parturients.

Williamson et al.14 reported a prospective noninterventional study (n = 18) with rocuronium administered in a dose of 1.2 mg/kg, which is the dose recommended for rapid-sequence induction in nonpregnant patients. This protocol resulted in deep neuromuscular blockade at the end of the procedure in all parturients, which was therefore reversed by sugammadex 4 mg/kg.

Shibusawa et al.15 presented a series of 13 female patients who were given thiopental 3.5 mg/kg and rocuronium 0.9 mg/kg. The reversal of neuromuscular blockade was achieved with sugammadex 2 mg/kg irrespective of the depth of neuromuscular blockade, followed by repeated administration every 3 minutes until a TOF ratio of >0.9 was reached. Repeated administration was chosen only in 1 patient with renal failure, who did not achieve reversal of muscle power to TOF ratio of >0.9, even after >10 minutes and after repeated doses of sugammadex 2 mg/kg. Štourač et al.12 presented 6 cases of high-risk parturients who received rocuronium and sugammadex. They also reported a single sugammadex dose of 200 mg, despite varying depth of neuromuscular blockade.

There was a significant difference in myalgia incidence between groups; this is not surprising because myalgia is a well-described complication of succinylcholine administration.27 Nauheimer et al.,16 in a case series of 10 female patients, investigated adverse events after rocuronium-induced neuromuscular blockade in a dose of 1.0 mg/kg and subsequent reversal using sugammadex 4 mg/kg. These authors observed only insignificant adverse events, such as sore throat (30%) and myalgia (10%), similar to the results of our study.

An advantage of our study is the randomized design using stratified block randomization. The study groups were homogeneous, and adherence to study protocol was strict, as shown in Figure 1. Another advantage is the inclusion of both intrapartum and scheduled cesarean deliveries. This is important because general anesthesia is reserved mainly for emergency cesarean delivery.

The firm protocol precluding sugammadex administration during deep neuromuscular blockade (PTC 0) is the main limitation of the study; however, this is standard procedure in routine clinical practice. We waited until PTC 1 appearance in >56% of cases (median 10 minutes) in the ROC group. This explains the longer duration of procedure in the ROC group. This limitation can be overcome by using the approach by Shibusawa et al.15 with the administration of sugammadex 2 mg/kg every 3 minutes until adequate reversal of neuromuscular blockade, irrespective of the depth of blockade.

Generalizability may also be limited for practices that do not maintain neuromuscular blockade with a nondepolarizing muscle relaxant after recovery from succinylcholine. But in some countries, such as the Czech Republic, it is common to ensure good conditions for surgical fascia and skin closure.10 An additional major limitation is that the study was not double blinded. This is important for evaluation of subjective complaints after 24 hours. In reality, a double-blinded study design in these settings and real clinical conditions is very difficult to ensure. We aimed to enroll both scheduled and intrapartum cesarean deliveries regardless of time of day. During the night shift, only 1 anesthesia team was in attendance in the delivery suite in both centers. We also considered that the limitations of a double-blinded design in these settings would be visible fasciculation after succinylcholine administration and rapid recovery from succinylcholine-induced neuromuscular blockade. For these reasons, we decided to use a single-blinded design. To mitigate the effect of anesthesia provider awareness of group assignment, all times were recorded by a research nurse, and management followed a strict protocol directed by accelerometry measurement.

In conclusion, rocuronium for rapid-sequence induction was found to be noninferior to succinylcholine with respect to the time to tracheal intubation but was accompanied by more frequent absence of laryngoscopy resistance and lower incidence of myalgia than succinylcholine for cesarean delivery under general anesthesia.

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DISCLOSURES

Name: Petr Stourac, MD, PhD.

Contribution: This author designed and conducted the study, analyzed the data, and wrote the manuscript.

Attestation: Petr Stourac has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.

Name: Milan Adamus, MD, PhD.

Contribution: This author designed and conducted the study, analyzed the data, and wrote the manuscript.

Attestation: Milan Adamus has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Dagmar Seidlova, MD, PhD.

Contribution: This author designed and conducted the study, analyzed the data, and wrote the manuscript.

Attestation: Dagmar Seidlova has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Tomas Pavlik, MSc, PhD.

Contribution: This author designed and conducted the study, analyzed the data, and wrote the manuscript.

Attestation: Tomas Pavlik has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.

Name: Petr Janku, MD, PhD.

Contribution: This author designed and conducted the study, analyzed the data, and wrote the manuscript.

Attestation: Petr Janku has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Ivo Krikava, MD, PhD.

Contribution: This author designed and conducted the study, analyzed the data, and wrote the manuscript.

Attestation: Ivo Krikava has seen the original study data, reviewed the analysis of the data and approved the final manuscript.

Name: Zdenek Mrozek, MD, PhD.

Contribution: This author designed and conducted the study, analyzed the data, and wrote the manuscript.

Attestation: Zdenek Mrozek has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Martin Prochazka, MD, PhD.

Contribution: This author designed and conducted the study, analyzed the data, and wrote the manuscript.

Attestation: Martin Prochazka has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Jozef Klucka, MD.

Contribution: This author designed and conducted the study, analyzed the data, processed ClinicalTrials.gov record, and wrote the manuscript.

Attestation: Jozef Klucka has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Roman Stoudek, MD.

Contribution: This author designed and conducted the study, analyzed the data, and wrote the manuscript.

Attestation: Roman Stoudek has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Ivana Bartikova, MD.

Contribution: This author designed and conducted the study, analyzed the data, and wrote the manuscript.

Attestation: Ivana Bartikova has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Martina Kosinova, MD.

Contribution: This author designed and conducted the study, analyzed the data, and wrote the manuscript.

Attestation: Martina Kosinova has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Hana Harazim, MD.

Contribution: This author designed and conducted the study, analyzed the data, processed Ethics Committee Approval, and wrote the manuscript.

Attestation: Hana Harazim has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Hana Robotkova, MD.

Contribution: This author designed and conducted the study, analyzed the data, and wrote the manuscript.

Attestation: Hana Robotkova has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Karel Hejduk, MSc.

Contribution: This author designed the study and wrote the manuscript.

Attestation: Karel Hejduk has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Zuzana Hodicka, MD, PhD.

Contribution: This author designed and conducted the study, analyzed the data, and wrote the manuscript.

Attestation: Zuzana Hodicka has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Martina Kirchnerova, MD.

Contribution: This author designed and conducted the study, analyzed the data, and wrote the manuscript.

Attestation: Martina Kirchnerova has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Jana Francakova, MD.

Contribution: This author designed and conducted the study, analyzed the data, and wrote the manuscript.

Attestation: Jana Francakova has seen the original study data, reviewed the analysis of the data and approved the final manuscript.

Name: Lenka Obare Pyszkova, MD.

Contribution: This author designed and conducted the study, analyzed the data, and wrote the manuscript.

Attestation: Lenka Obare Pyszkova has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Jarmila Hlozkova, MD.

Contribution: This author designed and conducted the study, analyzed the data, and wrote the manuscript.

Attestation: Jarmila Hlozkova has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Pavel Sevcik, MD, PhD.

Contribution: This author designed and conducted the study, analyzed the data, and wrote the manuscript.

Attestation: Pavel Sevcik has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

This manuscript was handled by: Cynthia Wong, MD.

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ACKNOWLEDGMENTS

The authors thank Bosakova Kamila, Fialova Martina, Gal Roman, MD, PhD, Hanounova Katerina, MD, Jonasek Martin, MD, Popkova Jana, Ruzickova Aranka, Toukalkova Michaela, MD, Vranova Olga, Vyplelova Yvona, and Zemanova Jitka, MD (University Hospital Brno, Brno, Czech Republic), for data collection and support; and appreciate Dusek Ladislav, MSc, PhD, Schwarz Daniel, MSc, PhD, and Zelinkova Hana, MSc (Institute of Biostatistics and Analyses, Faculty of Medicine of Masaryk University Brno, Czech Republic).

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