Meyhoff, Christian S. MD, PhD*; Lund, Jørgen MD†; Jenstrup, Morten T. MD†; Claudius, Casper MD, PhD*; Sørensen, Anne M. MD, PhD*; Viby-Mogensen, Jørgen MD, DMSc*; Rasmussen, Lars S. MD, PhD, DMSc*
Clinicians may have difficulties with dosage calculations in obese patients. Dosing of neuromuscular blocking drugs according to total body weight (TBW) is simple but carries the risk of prolonged duration of action in obese patients,1,2 because there are important differences in distribution, protein binding, and elimination of drugs between obese and lean patients.3
Therefore, it has been suggested that dosing should be based on ideal body weight (IBW) rather than on TBW,1,2 but this could be inadequate because of prolonged onset time and poor conditions for tracheal intubation.
Pharmacokinetic parameters of drugs with low lipophilicity, such as rocuronium, are not very different in obese and lean patients.4 Two studies performed using objective monitoring of neuromuscular function have, however, included few obese patients (12 in both studies1,2), and clinically relevant end points, such as time to reappearance of the fourth twitch (T4) after train-of-four (TOF) stimulation and time to TOF ratio 0.90, were not reported. These end points are important, because they represent the time when reversal of the block can be initiated5 and the patient can be safely tracheally extubated,6 respectively. In addition, dosing of rocuronium according to IBW could be inadequate because of prolonged onset time and poor conditions for tracheal intubation. Therefore, it is unclear whether rocuronium in morbidly obese patients should be dosed according to IBW or to a dosing scheme based on corrected body weight (CBW), incorporating a percentage of the difference between IBW and TBW.7 We hypothesized that a dosing scheme based on IBW would be most suitable in morbidly obese patients, because duration of action would be shorter, without compromising the conditions for tracheal intubation.
The aim of this study was to compare duration of action, defined as time to reappearance of T4, onset time, and tracheal intubation conditions in three groups of morbidly obese patients in which the intubation doses of rocuronium were based on three different weight corrections.
Danish Medicines Agency and the Local Ethics Committee approved the study (NCT00540085), and written informed consent was obtained from all subjects. Patients aged 18–65 yr, scheduled for laparoscopic gastric bypass or gastric banding were eligible. Exclusion criteria were expected difficult airway, interfering neuromuscular disease, known impaired hepatic or renal function, suspected allergy to the study drugs, and medications known to influence the neuromuscular transmission.
The study adhered to the International Conference on Harmonisation Good Clinical Practice standards. We recorded height, TBW, waist-hip ratio, and body fat percent, using the skinfold technique,8 after which we calculated (in kg):
1. IBW = Height in cm − 106 (for women) or height − 102 (for men),9
2. CBW20% = IBW + 20% × (TBW − IBW),
3. CBW40% = IBW + 40% × (TBW − IBW).
CBW40% was chosen because this correction is proposed for dosage of propofol in obese patients,7 and the CBW20% group was included to increase the possibility of finding an optimal dosage algorithm.
Before arrival to the anesthetic room, patients were randomly allocated 1:1:1 to receive rocuronium (0.6 mg/kg) according to IBW, CBW20%, or CBW40% using a set of computer-generated random numbers kept in sealed, sequentially numbered opaque envelopes. This rocuronium intubation dose was mixed with saline to a total of 10 mL and administered by the study investigators and blinded to the patient, and the anesthetic and surgical staff. Standard monitoring consisted of noninvasive arterial blood pressure, pulse oximetry, capnography, electrocardiography, and state entropy.
Patients received oxycodone (10 mg) and paracetamol (1 g) orally approximately 1 h before anesthesia. Anesthesia was induced with IV infusion of propofol (5 mg · kg−1 · h−1) and remifentanil (1.0 μg · kg−1 · min−1), both according to CBW40%, and 1 min later followed by propofol (200 mg) IV. After loss of the eyelash reflex, the patients were mask ventilated while the neuromuscular monitoring equipment was calibrated. Anesthesia was maintained with infusions of propofol and remifentanil adjusted to a state entropy between 30 and 50.
Neuromuscular monitoring followed good clinical research practice (GCRP) guidelines for pharmacodynamic neuromuscular studies.10 After careful cleaning of the skin, two pediatric surface electrodes (Neotrode®, ConMed Corporation, NY) were placed over the right ulnar nerve near the wrist with a distance of 3–6 cm. The forearm and four ulnar fingers were immobilized and the acceleration transducer was secured on the thumb using a Hand Adapter® (Organon, Oss, the Netherlands). The response to ulnar nerve stimulation was recorded with a TOF-Watch® SX (Organon), and data were collected on a laptop using the TOF-Watch SX monitor program. The monitor display was blinded to the anesthetic and surgical staff by means of an opaque sticker, and the hand was covered by the sterile surgical covering. All IV infusions were to the left arm veins.
Once the patient was unconscious, a 50-Hz tetanic stimulus was applied for 5 s, and after baseline stabilization (<5% variation in at least 2 min), supramaximal stimulation and calibration was ensured using the built-in calibration function (CAL 2). The allocated rocuronium dose was given over <5 s in a rapidly flowing IV line.
Laryngoscopy was commenced after 80 s, and tracheal intubation conditions were evaluated after 90 s by an experienced anesthesiologist blinded to the dose of rocuronium. The evaluation was based on a standard scheme including ease of laryngoscopy, position and/or movement of the vocal cords, and reaction to intubation.10
An upper body air-warming device was used to maintain a core temperature of more than 35°C and peripheral skin temperature of more than 32°C, as measured on the volar side of the thenar.10 The patients’ lungs were ventilated to normocapnia with 60% oxygen in nitrogen.
If the neuromuscular blockade was insufficient for surgery, boluses of remifentanil (0.5–1.0 μg/kg) or propofol (20–30 mg) were given. Rocuronium (10 mg) was given if the block was still insufficient 5 min later. The surgeons requested intervention if they considered the neuromuscular blockade to be insufficient, and the anesthesiologist administered the intervention in accordance with the protocol. None of them could see the response to TOF stimulation. Neostigmine (2.5 mg) together with atropine (1 mg) or glycopyrrolate (0.5 mg) were given at end of surgery if the patient had not recovered from neuromuscular block, defined as a TOF ratio less than 0.90. The trachea was extubated when the patient was fully awake, and TOF ratio was more than 0.90. In case of supplemental rocuronium or reversal of the block, neuromuscular data after that timepoint were not included in the data analysis.
To evaluate blinding, the anesthesiologist and the surgeon were asked which of the three groups they believed the patients belonged to. We recorded all adverse events occurring within 24 h of surgery.
TOF-Watch data were stored on a computer, and the reliability of the neuromuscular data was reviewed by two blinded assessors based on specific quality variables according to GCRP guidelines (e.g., presence of supramaximal stimulation, baseline drift, and artifacts).10
The primary end point was the duration of action, defined as time from start of rocuronium injection to reappearance of T4. The secondary end point was onset time, defined as the time from the start of rocuronium injection to 95% depression of T1. The pharmacodynamic data obtained were as follows: time to reappearance of the T1, time to T1 recovery to 25% (of the final T1), and time to TOF ratio 0.90 (with and without normalization). Because the acceleromyographic control TOF ratio before administration of a neuromuscular blocking drug most often is more than 1.00, it has been suggested to refer all TOF ratios during recovery to the control value (normalization). If, for instance, the TOF ratio is 1.20 before injection of a neuromuscular blocking drug, a recorded TOF ratio of 0.90 during recovery corresponds to a normalized value of only 0.75 (0.90/1.20).11,12 Surgical conditions were evaluated by the surgeon at the start and the end of surgery as completely satisfactory, satisfactory, slightly unsatisfactory, or unacceptable.
Patient characteristics are reported with median and interquartile range. Groups are compared with Wilcoxon’s unpaired rank sum test using SAS for Windows, version 9.1. P <0.05 was considered statistically significant. We estimated a 10 min sd for time to reappearance of T4 based on two previous studies.1,13 We considered a difference in time to reappearance of T4 of 10 min between the IBW and CBW40% groups to be clinically relevant. We calculated that a sample size of 17 patients in each group would allow us to detect this difference, with 5% Type 1 error risk, 80% power, and 10% dropout.
There were 59 eligible patients in the study period, of which two refused to participate, one had an expected difficult airway, one was not included because no research staff was available, and four had surgery postponed. The characteristics of the 51 enrolled patients are presented in Table 1.
Rocuronium was administered 6.5 (sd 1.4), 6.6 (sd1.4), and 6.1 (sd1.1) min after start of propofol-remifentanil infusion in the IBW, CBW20%, and CBW40% groups, respectively. Onset time was not significantly different among the groups (P = 0.16 for comparison of the IBW and CBW40% group; Table 2; Fig. 1). The trachea was intubated at first attempt in all but three patients (two in the IBW group and one in the CBW40% group), in whom a second or third attempt was necessary. Conditions for tracheal intubation were similar in the three groups (Table 2).
Time to reappearance of T4 was significantly longer in the CBW40% group than in the IBW group (P = 0.001).
The surgeon requested intervention for insufficient neuromuscular blockade leading to a supplemental dose of rocuronium in three patients in the IBW group (at TOF ratio 0.18, 0.50, and 1.10) and in two patients in the CBW40% group (at TOF ratio 0.28 and 0.85; Table 2). Surgical conditions were satisfactory or completely satisfactory at start as well as during surgery in 14, 15, and 15 of the patients in the IBW, CBW20%, and CBW40% groups, respectively.
One serious adverse event occurred for a patient in the CBW20% group. This patient had convulsions and transient respiratory failure 6 h after surgery and underwent second surgery because of intestinal bleeding. All other adverse events are reported in Table 2.
Anesthesiologists and surgeons correctly identified 16 of the 51 patients’ allocation. In their answers, there were no indications of unblinding.
Our results showed that in obese patients who were given propofol-remifentanil anesthesia, a dosing scheme for rocuronium (0.6 mg/kg) based on IBW was preferred to other CBWs. When dosing was based on IBW, the duration of action of rocuronium was significantly shorter, without compromising the conditions for tracheal intubation or for surgery. The mean difference in time to reappearance of T4 between the IBW and CBW40% group was 12 min (95% confidence interval (CI): 6–19 min).
The primary strength of our study was the objective neuromuscular monitoring with blinded assessment of quality variables performed in accordance with the GCRP guidelines.10 We studied an obese population with little comorbidity in a highly standardized anesthetic and surgical setting, and the study groups were well balanced with respect to age and body composition. Furthermore, we report two useful end points, representing the time when reversal of the block can be initiated (reappearance of T4)5 and when the patient can be safely tracheally extubated (TOF ratio 0.90),6 respectively. However, we used a relatively high remifentanil infusion rate at induction as per our usual clinical practice, and tracheal intubation was only attempted after the neuromuscular monitoring was setup. The propofol and remifentanil would have facilitated the conditions for tracheal intubation, which were excellent in more than two-thirds of the patients.14
The IBW group had a higher proportion of men than the CBW20% and CBW40% groups. This could be a confounding factor, because the duration of action of a neuromuscular blocking drug may be shorter in males than in females.15 All measurements of body composition were, however, comparable, and within the IBW group, time to reappearance of T4 was median 31 and 37 min for female and male patients, respectively. Thus, we do not believe that this potential confounder has contributed significantly to the results of our study.
In lean patients receiving rocuronium (0.6 mg/kg) according to TBW, the time to reappearance of T1 is around 20 min,16 and time to T1 recovery to 25% of control (duration 25%) ranged from 23 to 36 min.16–18 Our data in the IBW group approach this upper range, recognizing that duration 25% and reappearance of T4 occur approximately at the same time.19
We found the 75th percentile for duration of action in the CBW40% group to be 55 min. Accordingly, reversal of the block may not be initiated in 25% of the patients for almost 1 h after an intubation dose of rocuronium based on CBW40%. In contrast, the 75th percentile for duration of action in the IBW group was only 37 min. This general difference may be clinically important in morbidly obese patients, and in addition, duration of action can be prolonged in individual patients.20
Time to TOF ratio 0.90 with and without normalization was nearly 70 min in the IBW group, and this is longer than that reported in lean patients, i.e., 43 min after receiving 0.6 mg/kg of rocuronium according to TBW, but this was assessed using mechanomyography.18 We evaluated time to TOF ratio 0.90 only in patients who did not receive supplementary rocuronium or reversal of the neuromuscular blockade before TOF ratio 0.90 was documented with certainty. It must be acknowledged that this approach tends to underestimate the median time to TOF ratio 0.90.
Onset time was almost the same as in previous studies of obese patients when rocuronium was given according to IBW1 but longer than in patients given rocuronium according to TBW, in which onset time was only 60 s.2 In lean patients, onset time is reported to range from 80 to 120 s.16–18 We did not find any significant differences in onset time among the three groups, and the mean difference between the IBW and CBW40% group was only 15 s (95% CI: −3; 33 s). Thus, considering the confidence interval, we cannot exclude that onset time can be reduced by approximately 30 s by dosing rocuronium according to CBW40%. However, we do not consider this possibility to be of major clinical importance in elective patients.
The conditions for tracheal intubation appeared better than those previously reported when rocuronium was administered to lean patients. Excellent conditions were obtained only in 15%–45% of the patients in these studies.16,21 This difference may be caused primarily by the high remifentanil infusion rate used in our study, although another study found excellent conditions in 25 of 30 lean patients using alfentanil.22 The statistical power is, however, limited in these relatively small studies, and the required sample size to detect a difference of 2% in the incidence of difficult intubation conditions would be approximately 750 patients with 80% power.
The rocuronium dose per actual body weight was 0.31 mg/kg in the IBW group and 0.42 mg/kg in the CBW40% group. It is interesting to note similarities between this and reports of the use of low-dose rocuronium where good conditions for tracheal intubation can still be obtained, depending on the use of adjuvant drugs and the time that tracheal intubation is attempted. For example, 0.3 mg/kg given to lean patients resulted in optimal conditions for tracheal intubation in 18 of 20 patients.23
Our data indicate that in obese patients given rocuronium according to IBW, onset time is similar to lean patients given rocuronium according to TBW, whereas duration of action may be longer. The observed onset time around 80 s was clinically acceptable, and reversal of the neuromuscular blockade (reappearance of T4) was possible after a median of 32 min in the IBW group.
The observed excellent conditions for tracheal intubation may not be generalizable to obese patients in other settings where lower doses of propofol and remifentanil are used at induction. Surgical conditions in bariatric laparoscopy were not impeded by earlier reappearance of T4 in our study. Surgical conditions were good and comparable among the three groups (satisfactory or completely satisfactory in 14, 15, and 15 of the patients in the IBW, CBW20%, and CBW40% groups, respectively). Our findings concern bariatric surgery and may not be generalizable to laparotomies, surgical procedures of considerably different duration, settings using less remifentanil at induction, or patients with significant hepatic or renal dysfunction. Also, special precautions are warranted in patients with expected difficult airway.
We conclude that, in our patients undergoing gastric banding or gastric bypass under propofol-remifentanil anesthesia, the intubation dose of rocuronium should be calculated according to IBW. The duration of action was shorter, and this was achieved without a significantly prolonged onset time or compromised conditions for tracheal intubation or surgery.
The authors thank Susanne Schiang, Research Nurse, Department of Anesthesia, The Juliane Marie Center, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark as well as the anesthetic and surgical staff at Hamlet Hospital, Søborg, Denmark for their contribution to data collection.
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