Traditionally, body weight is used to calculate the dose of a drug. However, there is increasing evidence of gender differences in the pharmacokinetics (PK) and pharmacodynamics (PD) of anaesthetic drugs and neuromuscular blocking agents (NMBAs) . While females are more susceptible to the effect of one drug, they may require a larger dose of another to achieve the same effect as in males.
Cisatracurium and rocuronium are modern NMBAs with intermediate duration of action. While the influence of gender on the effect of rocuronium has been determined [2-4], little information is available on cisatracurium in this respect.
Our study was planned to investigate the possible effect of gender on the course of neuromuscular block following a single bolus dose of cisatracurium or rocuronium.
After obtaining the Hospital Ethics Committee approval and written informed consent, 1000 adult patients, scheduled for elective general surgery under total intravenous anaesthesia (TIVA) with tracheal intubation, muscle relaxation with single bolus dose of NMBA and mechanical ventilation, were studied. The patients were randomly assigned to one of two groups with different relaxants administered (cisatracurium (CIS) vs. rocuronium (ROC)). We used a method of computer-generated random numbers with blockwise randomization to obtain balanced sample sizes in all groups (CIS males, CIS females, ROC males, ROC females).
The exclusion criteria were ASA physical status more than III, age under 18 yr and obesity (BMI > 30 kg m−2). Patients using medication known to interfere with NMBAs (anticonvulsants, aminoglycosides or polypeptide antibiotics) or who were pregnant or breastfeeding and those with severe renal, hepatic, metabolic or neuromuscular diseases were not studied. Patients with anticipated difficult intubation (Mallampati score  III and more) were also excluded. The expected duration of the surgery was about 60 min. Patients in whom the initial dose had to be supplemented with one or several top-ups or those with unstable neuromuscular transmission monitoring were also excluded from the study.
A pre-anaesthetic questionnaire was used to collect patients' characteristic data – gender, age, height, weight, ASA physical status classification; derived parameters (body mass index, body surface area) were computed .
The patients were premedicated orally with diazepam 5–10 mg 1 h before the beginning of surgery. On arrival in the operating room, an intravenous cannula was inserted into a forearm vein. Datex-Ohmeda S/5TM Anaesthesia Monitor (Datex-Ohmeda Inc., Louisville, USA) with relevant modules (electrocardiogram (ECG), non-invasive blood pressure (NIBP), pulse oxymetry, oxygen inspiratory and expiratory concentrations, spirometry, core and skin temperature, neuromuscular transmission (NMT)) was used to monitor the patients during anaesthesia and surgery. After 3-min preoxygenation, intravenous premedication with midazolam (0.05 mg kg−1) and sufentanil (0.1 μg kg−1) was injected into a rapidly running infusion of normal saline. TIVA in the target-controlled infusion (TCI) mode was induced and maintained with the Base Primea® (Fresenius Vial, Brezins, France) infusion device. Target plasma concentrations were initially set to 4.0 μg mL−1 for propofol in Schnider model [7,8] and 0.8 ng mL−1 for sufentanil in Gepts model [7,9] and adjusted according to clinical response (BP and/or heart rate (HR) changes) during anaesthesia. To facilitate tracheal intubation, neuromuscular block was induced with a single bolus dose of either cisatracurium (0.1 mg kg−1) or rocuronium (0.6 mg kg−1) injected intravenously within 5 s. The attending anaesthetist was aware of the neuromuscular blocker that was used. Following maximal depression of T1 (onset time), direct laryngoscopy was initiated followed by tracheal intubation. The endotracheal tube was connected to a closed ‘low-flow' anaesthetic breathing circuit with a mixture of 40% oxygen in air; mechanical ventilation was adjusted to maintain end-tidal partial pressure of carbon dioxide (etCO2) between 4.7 and 5.0 kPa. Both oesophageal and skin temperatures were recorded continuously. Thenar skin temperature was monitored using a probe placed on the dorsum of the hand from which the response to ulnar nerve stimulation was recorded. Skin temperature over the thenar muscles was maintained above 34°C throughout the study period by wrapping the arm in cotton wool. Sufentanil and propofol were discontinued at the end of anaesthesia and tracheal extubation was not performed before full recovery from neuromuscular block (train-of-four (TOF) ratio ≥ 0.90). When required, the recovery was accelerated with neostigmine (0.04 mg kg−1) given together with atropine (0.015 mg kg−1).
Neuromuscular transmission monitoring complied with good clinical research practice [10,11] using the NMT module of the Datex-Ohmeda S/5TM Anaesthesia Monitor (Datex-Ohmeda Inc.). After induction, but before administration of the NMBA, the NMT monitor was calibrated using the automatic start-up-procedure and then 0.1 Hz single-twitch stimulation was applied allowing for a 5-min stabilization period. Following relaxant injection and after maximal neuromuscular block was established, we switched to TOF stimulation assessed at 12-s intervals by stimulation of the ulnar nerve with four rectangular impulses at 2 Hz, duration 0.2 ms and supramaximal current. The forearm was immobilized in supination on a splint and the evoked electromyographic response of the adductor pollicis muscle was monitored. All data reflecting the effect of neuromuscular blocker (TOF ratio, T1) were wirelessly transferred to a PC , displayed on the screen and stored for further processing. The first response (T1) in the TOF stimulation pattern was used as the parameter for PD measurements. A spontaneous recovery until 75% of T1 was allowed and following PD values were determined in all patients:
- Onset time (s) = time interval from the completion of the intravenous injection of the relaxant to maximal T1 depression.
- Clinical duration (min) = time interval from the completion of the intravenous injection of the relaxant to spontaneous recovery of T1 to 25% of the control.
- Recovery index (min) = time interval from the end of clinical duration (T1 = 25%) to 75% recovery of T1 (T1 = 75%).
Statistical calculations were carried out using the InStat v. 3.06 and StatMate v. 1.01i software packages (GraphPad Software, San Diego, CA, USA; www.graphpad.com). The sample size was determined by performing a power analysis based on a previous study . From the data (clinical duration 36 ± 11 min for rocuronium 0.6 mg kg−1), we calculated that 198 patients in each group would be required to find a significant difference of 10% or more in clinical duration between the groups (0.05 two-sided significance level (α = 0.05), 90% power (β = 0.1)). Depending on the character and distribution of the data, comparisons between the respective groups (males vs. females) were made by unpaired t-test, Mann–Whitney rank sum test and Fisher's exact test, as appropriate. The results are expressed as mean ± SD or frequencies; P value equal to or less than 0.05 was considered statistically significant.
A total of 1000 patients were initially enrolled in the study. In all, 80 patients (29 males, 51 females) in the CIS group and 72 patients (48 males, 24 females) in the ROC group were eliminated from the data analysis. Either the requirement to supplement the initial bolus dose of relaxant during surgery or the failure to set up the reliable NMT monitoring was the reason for exclusion (Fig. 1). The resulting groups consisted of 420 patients (221 males, 199 females) and 428 patients (202 males, 226 females) in the CIS and ROC groups, respectively.
The patient data are summarized in Table 1. Compared to females, males were significantly taller, heavier and larger and more frequently were assigned to ASA III grade.
The consumption of propofol and sufentanil was similar in all groups.
The PD data are listed in Table 2. In the ROC group, the onset times were shorter and the clinical duration was significantly longer in females (P < 0.001). In the CIS group, the onset times in females were only slightly longer (n.s.) than in males and the clinical duration was comparable in both sexes. In recovery index, no differences between males and females could be demonstrated for both the CIS and ROC groups.
The aim of the study was to determine if there was any difference between the sexes in the sensitivity to a 2 × ED95 dose of cisatracurium and rocuronium. A large set of patients were enrolled in the study with the aim to discover even small differences in PD parameters between the groups. We used strict exclusion criteria and controlled other factors known to interfere with neuromuscular transmission. In all patients, the depth of anaesthesia was computer-controlled (TCI) with identical target levels of respective anaesthetic agents (propofol and sufentanil). TIVA was preferred to inhalation anaesthesia; our goal was to eliminate the influence of a volatile agent on the depth of muscle relaxation. Only one person (MA) was responsible for the anaesthetic management of all cases and a standardized technique was used for neuromuscular monitoring throughout the study.
Until now, the gender aspect in PK and PD of anaesthetic drugs has attracted little attention. However, ongoing research in order to further optimize treatment in anaesthesia shows that gender should be taken into account as a factor that may be predictive for the dosage of several anaesthetic drugs  and there is increasing evidence for gender differences in the PK and PD of anaesthetic drugs and NMBAs . Females have 20–30% greater sensitivity to the effects of aminosteroid muscle relaxants . When rapid onset or short duration of action is very important, gender-modified dosing may be considered. Males are more sensitive to propofol than females. It may therefore be necessary to decrease the propofol dose by 30–40% in males compared with females in order to achieve similar recovery times . Females are more sensitive than males to opioid receptor agonists, as shown for morphine as well as for a number of κ-receptor agonists. On this basis, males will be expected to require 30–40% higher doses of opioid analgesics than females to achieve similar pain relief . On the other hand, females may experience respiratory depression more often and other adverse effects more easily if they are given the same opioid doses as males. Though not associated with adverse clinical consequences for the patient's outcome, the incidence and the degree of pain and withdrawal reactions in response to the injection of rocuronium is significantly higher in females than in males . The same implies for precurarization dose of rocuronium .
Our results show that females were significantly more sensitive to rocuronium than males. The onset time was shorter (91.7 vs. 108.0 s, respectively; P < 0.001) and the clinical duration was longer (43.3 vs. 31.3 min, respectively; P < 0.001) in females. Studying rocuronium-induced block after 0.45 mg kg−1, Mencke and colleagues  demonstrated slower onset by 26% and shorter clinical duration by 35% in males. Xue and colleagues  showed that the dose–response curve of rocuronium in males was shifted to the right, indicating a decrease in the sensitivity to rocuronium-induced neuromuscular block in comparison with females. After the intravenous administration of a total dose of 0.4 mg kg−1 rocuronium, neuromuscular block was significantly longer in females than in males (clinical duration 18.5 vs. 12.5 min). To analyse the typical course of neuromuscular block following relaxant injection, we used the most usual dose of rocuronium (2 × ED95) that is larger than the doses used in the above-mentioned studies. The lower difference in onset times in our study may be due to the larger dose of rocuronium administered, resulting in more uniformity and less scatter in onset times.
Vecuronium is a non-depolarizer most widely studied for gender differences in its effect. Following administration of 0.1 mg kg−1 vecuronium, male patients had significantly less satisfactory intubation conditions at 60 s than female patients. It was suggested that differences in response to vecuronium could be explained by differences in distribution volume and muscle mass between sexes . Semple and colleagues  demonstrated that females were significantly more sensitive to vecuronium than males, requiring 22% less drug to achieve the same degree of neuromuscular block. Xue and colleagues  showed that following vecuronium the average depression of T1 in TOF monitoring was 43% greater in females. The dose–response curve for females was shifted to the left and the clinical duration of vecuronium was longer in females. In another study, the same authors  found that compared to females, due to a larger volume of distribution, males had lower plasma concentrations of vecuronium. Thus, the observed differences in the sensitivity to vecuronium between genders were likely to be caused by PK differences.
Data about gender differences in atracurium effect are contradictory. In a study dealing with the PK of atracurium , the clearance was greater and elimination half-time was shorter in males than in females, but the volume of distribution was not affected by sex. It was concluded that the above-mentioned PK differences were of no clinical significance. On the contrary, Xue and colleagues  showed that the dose–response and duration of effect of atracurium differed with gender. The effective doses of atracurium were greater and its duration of action was shorter approximately by 25% in males than in females. It is difficult to compare our data to this study. We can only speculate that in addition to a different muscle relaxant used (cisatracurium vs. atracurium), the dissimilarity of the conclusions may also be due to the different populations of patients studied (Chinese vs. Caucasian). Direct comparison of atracurium and cisatracurium effect in a homogeneous patients group would be more conclusive.
For cisatracurium, clinical data addressing gender differences are scarce. The population PK/PD approach was used prospectively to determine the PD/PK parameters of cisatracurium . The results revealed that gender, as one of the variables, was associated with some effects on the PK/PD parameters of cisatracurium. Although statistically significant, these differences were not associated with any clinically relevant changes during onset and recovery from the block. Cisatracurium undergoes Hofmann elimination (a chemical process dependent on pH and temperature). Thus, tight physiologic control of pH and temperature results in little variability in this biodegradation pathway without significant gender differences .
In our study, the recovery index was similar in males and females for both cisatracurium and rocuronium. It means that when the muscle strength recovered to 25%, further course and subsiding of the block was uniform in all groups. This is in agreement with earlier studies [11,23,24].
What is the implication for clinical anaesthesia? An easiness of intravenous injection of muscle relaxant, resulting in neuromuscular block, contrasts with clinically serious consequences following its application and with considerable interindividual variability of the effect. Particularly at the end of anaesthesia, this may present a problem; in one patient, the effect of a single bolus dose of NMBA may have fully subsided, while in another one, there is significant degree of block still present [11,25-28]. This expected variability of action may be further accentuated by gender differences. Alkhazrajy and colleagues  assessed the residual muscle weakness after general anaesthesia either without muscle relaxant or with rocuronium or vecuronium. They compared the handgrip strength preoperatively and 1 h postoperatively with a hand dynamometer. The degree of weakness for the relaxant groups was unrelated to age but was strongly influenced by the patients' sex. One hour postoperatively, female patients showed a marked decrease in handgrip strength after both vecuronium and rocuronium (32% and 34%, respectively) compared to males (14% for vecuronium and 19% for rocuronium). These results suggest that female patients are more likely to have residual weakness after anaesthesia with muscle relaxants and therefore may be more predisposed to postoperative pulmonary complications . This constitutes strong evidence that patients undergoing surgery benefit from perioperative neuromuscular monitoring .
In summary, this study confirms significant gender differences in the rocuronium effect. Females are more susceptible than males; therefore, the dose should be reduced for the same onset and duration of the block. The PD parameters of cisatracurium are similar for both females and males. Based on these findings, no dosage adjustments are necessary in this respect.
This study was supported by the Czech Ministry of Health Internal Grant Agency – project ND7665-3/2003.
Conflict of interest statement: Dr Adamus works as a consultant for the Organon, Czech Republic. Organon did not participate in either generation of hypothesis, data collection, analysis or writing up the manuscript.
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