INFLUENCE OF GENDER ON THE ONSET AND DURATION OF ROCURONIUM-INDUCED NEUROMUSCULAR BLOCK

AIMS
To assess the influence of gender on the course of rocuronium-induced neuromuscular block following a single bolus dose of 2 x ED(95) (0.6 mg kg(-1)).


METHODS
Following the ethics committee approval and informed consent, 245 patients (121 men, 124 women) scheduled for elective general surgery under TIVA with muscle relaxation were studied. After rocuronium 0.6 mg kg(-1), the onset time for maximal depression of T(1), clinical duration until 25 % recovery and recovery index (T(1) from 25 to 75 %) were determined with TOF-Watch SX accelerometric monitor. The data for male and female groups were compared with appropriate statistical tests (Student's unpaired t-test, Mann-Whitney Rank Sum Test and Fisher's exact test).


RESULTS
Men were significantly larger (p < 0.001) and heavier (p < 0.05) than women, but the body mass index was comparable (ns). The onset time was shorter in females [92.5 (SD 14.2) vs. 104.7 (12.2) s, p < 0.0001]. Clinical duration was increased in females [43.1 (7.9) vs. 31.3 (5.5) min; p < 0.0001], while the recovery index was identical in both groups [14.7 (5.0) min in females and 14.8 (4.0) min in males; ns].


CONCLUSIONS
Women are more sensitive than men to the dose 0.6 mg kg(-1) of rocuronium. Under the study conditions described, the onset time was shortened and the clinical duration increased in female patients. This suggests that the routine dose of rocuronium should be reduced in women.


INTRODUCTION
Traditionally, body weight (BW), body surface area (BSA) and/or body mass index (BMI) are the usual variables used to calculate the dose of a drug.However, there is increasing evidence for gender diff erences in the pharmacokinetics and pharmacodynamics of anaesthetic and neuromuscular blocking agents 1 .Females may be more susceptible to the eff ect of a drug, while requiring larger doses of another one to achieve the same eff ect as in males.
Rocuronium (ROC) is a modern aminosteroid neuromuscular blocking agent (NMBA) with intermediate duration of action.Introduced into clinical practice in 1992, it is frequently used during general anaesthesia allover the world today.ROC is a non-depolarizer with the fastest onset (45-60 s) and clinical duration of approximately 30-50 minutes 2 .
The purpose of this study was to investigate whether and how gender infl uences the course of rocuronium-induced neuromuscular block following single bolus dose of 2 × ED 95 (0.6 mg kg -1 ).

MATERIAL AND METHODS
After obtaining local Ethics Committee approval and informed consent, 250 adult patients, scheduled for elec-tive general surgery under total intravenous anaesthesia (TIVA) with tracheal intubation, muscle relaxation and mechanical ventilation, were studied.Exclusion criteria were ASA physical status III or more, age under 18 and over 65 years and obesity (BMI > 30 kg m -2 ).Patients using medication known to interfere with NMBAs (anticonvulsants, amino glycosides or polypeptide antibiotics) or who were pregnant or breast feeding and those with severe renal, hepatic, metabolic or neuromuscular diseases were not studied.Patients with anticipated diffi cult intubation (Mallampati score 3 III and more) were also excluded.A pre-anaesthetic questionnaire was used to collect patients' demographic data -gender, age, weight, height, ASA physical status classifi cation; derived parameters (body mass index, body surface area) were computed 4 .

Anaesthesia
The patients were premedicated orally with diazepam 5-10 mg 1 hr before the beginning of surgery.On arrival in the operating room, an intravenous cannula was inserted into a forearm vein.Datex-Ohmeda S/5 ™ Anaesthesia Monitor with relevant modules (ECG, non-invasive blood pressure [NIBP], pulse oxymetry, oxygen inspiratory and exspiratory concentrations, spirometry, core and skin temperature) was used to monitor the patient during anaesthesia and surgery.After 3 min preoxygenation, intravenous premedication with midazolam (Dormicum ® , F. Hoffmann-LaRoche, 0.05 mg kg -1 ) and sufentanil (Sufenta ® forte, Janssen Pharmaceutica, 0.1 μg kg -1 ) was injected into a rapidly running infusion of normal saline.Total intravenous anaesthesia (TIVA) in TCI mode (target controlled infusion) was induced and maintained with a Base Primea ® (Fresenius Vial) infusion device.Target plasmatic concentrations were initially set to 2.0 μg ml -1 for propofol (Propofol Abbott, Abbott Laboratories) in Schnider's model 5 and 1.8 ng ml -1 for sufentanil in Gepts's model 5 , respectively, and adjusted according to clinical response during anaesthesia.To facilitate tracheal intubation, neuromuscular block was induced with single bolus dose of rocuronium (Esmeron ® , Organon) 0.6 mg kg -1 injected intravenously during 5 seconds.Following maximal depression of T 1 (onset time), direct laryngoscopy was initiated followed by tracheal intubation.The endotracheal tube was connected to closed "low-fl ow" anaesthetic breathing circuit with a mixture of 40 % oxygen in air; mechanical ventilation was adjusted to maintain end-tidal partial pressure of carbon dioxide (E T CO 2 ) 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 was discontinued 20 minutes before the end of anaesthesia and tracheal extubation was not performed before full recovery from neuromuscular block (TOF-ratio ≥ 0.90).When required, the recovery was accelerated with neostigmine (Syntostigmin, Hoechst-Biotika, 0.04 mg kg -1 ) given together with atropine (Atropin, Hoechst-Biotika, 0.015 mg kg -1 ).

Neuromuscular monitoring
Neuromuscular transmission monitoring complied with GCRP (good clinical research practice) 6,7 , using TOF-Watch ® SX (Organon) NMT monitor.After induction, but before administration of the neuromuscular blocking drug, the TOF-Watch ® SX NMT monitor was calibrated using its automatic start-up-procedure, and we then applied 0.1 Hz single twitch stimulation.Following relaxant injection and after maximal neuromuscular block was established, we switched to TOF stimulation assessed at 15 sec intervals by stimulation of ulnar nerve with four rectangular impulses at 2 Hz, duration 0.2 ms and supramaximal current.The evoked muscle response of adductor pollicis muscle was monitored with accelerometry with a sensor attached to the distal phalanx of the pollex.The forearm was immobilized in supination on a splint and original hand adaptor (Organon) was interposed between pollex and index fi nger.All data refl ecting the eff ect of neuromuscular blocker (TOF-ratio, T 1 ) were transferred into PC via optical cable (Organon).TOF-Watch ® SX Monitor software v. 2.2 INT (Organon) was used to display the NMT values on the screen and store for further processing.
The fi rst response (T 1 ) in the TOF stimulation was used as the parameter for pharmacodynamic measure-ments.A spontaneous recovery until 75% of T 1 was allowed and following pharmacodynamic values were determined in all patients:

Statistical support
Statistical calculations were carried out using the software packages InStat v. 3.06 and Prism 4.03 (GraphPad Software, San Diego, California, USA, www.graphpad.com).The sample size was determined by performing a power analysis based on a previous study 8 .From the data, we calculated that 120 patients in each group would be suffi cient to fi nd a signifi cant diff erence of 10 % or more in clinical duration between groups (0.05 two-sided signifi cance level [α = 0.05], 80 % power [β = 0.2]).Depending on the character and distribution of the data, comparisons between groups were made by means of Student's unpaired t-test, Mann-Whitney Rank Sum Test and Fisher's exact test.The results are expressed as means (SD -standard deviation) or frequencies; p values equal to or less than 0.05 were considered statistically significant.

RESULTS
250 patients (125 men, 125 women) were initially enrolled in the study.Due to technical diffi culties with NMT calibration and unstable reference T 1 values, 5 patients (4 men and 1 woman) had to be excluded resulting in a fi nal size of groups 121 (men) and 124 (women), respectively.The patients' demographics are summarized in Table 1.There were no diff erences between male and female patients in age and ASA grades.However, men were signifi cantly larger (p < 0.001) and heavier (p < 0.05) than women, but the body mass index was comparable (ns).The pharmacodynamic data are listed in Table 2.The onset times were shorter and the clinical duration was signifi cantly longer in females (p < 0.0001).In recovery index, no diff erences between males and females could be demonstrated (ns).

DISCUSSION
The aim of the study was to determine if there was any diff erence between the sexes in the sensitivity to a standard intubation dose of rocuronium (2 × ED 95 , 0.6 mg kg -1 ).We used rigorous exclusion criteria and controlled other factors known to interfere with neuromuscular transmis-Infl uence of gender on the onset and duration of rocuronium-induced neuromuscular block Data are means (SD -standard deviation), ***p < 0.0001 sion.In all patients, the depth of anaesthesia was computer-controlled (TCI, TIVA) with identical target level of respective anaesthetic agents (propofol, sufentanil).Total intravenous anaesthesia was preferred to inhalation anaesthesia; our goal was to eliminate the infl uence of a volatile agent on the depth of muscle relaxation.Only one person (MA) was responsible for the anaesthetic management of all cases and standardized technique was used for neuromuscular monitoring throughout the study.Until now, the gender aspect in pharmacokinetics and pharmacodynamics 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 1 .There is increasing evidence for gender diff erences in the pharmacokinetics and pharmacodynamics of anaesthetic drugs and neuromuscular blocking agents 1,9 .Females have 20-30 % greater sensitivity to the eff ects of aminosteroid muscle relaxants 10 .When rapid onset or short duration of action is very important, gender-modifi ed dosing may be considered.Males are more sensitive than females to propofol.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 1 .Females are more sensitive than males to opioid receptor agonists, as shown for morphine as well as for a number of kappa 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 1 .On the other hand, females may experience respiratory depression more often and other adverse eff ects 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 women than in men 11 .The same implies for precurarization dose of rocuronium 12 .
Our results showed that women were signifi cantly more sensitive to rocuronium than men.The onset times were decreased [92.5 (SD 14.2) vs. 104.7 (SD 12.2) s, respectively; p < 0.0001] and the clinical duration was longer [43.1 (SD 7.9) vs. 31.3(SD 5.5) min, respectively; p < 0.0001] in women.Studying rocuronium-induced block after 0.45 mg kg -1 , Mencke et al. 10 demonstrated slower onset by 26 % and shorter clinical duration by 35 % in men.Xue et al. 13 showed that the dose-response curve of rocuronium in the men was shifted to the right, indicating a decrease in the sensitivity to rocuronium-induced neuromuscular block versus the women.After an intravenous administration of total dose of 0.4 mg kg -1 rocuronium, neuromuscular block was signifi cantly longer in the women than in the men [clinical duration 18.5 (SD 5.3) vs. 12.5 (SD 4.9) min].To mimic the typical course of neuromuscular block following relaxant injection, we used the most usual dose of rocuronium (2 × ED 95 , 0.6 mg kg -1 ) that is larger than the doses used in the above-mentioned studies.From the data, we hypothesize that the lower difference in onset times in our study is due to larger dose of rocuronium administered, resulting in more uniformity and less scatter in onset times.
Vecuronium is a nondepolarizer most widely studied for gender diff erences in its eff ect.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 diff erences in response to vecuronium could be explained by diff erences in distribution volume and muscle mass between sexes 14 .In another study, Xue et al. 15 found that, compared to women, after intravenous administration, men had lower plasma concentrations of vecuronium and a larger volume of distribution of vecuronium.The pharmacokinetic differences may be related to the diff erences in the sensitivity to vecuronium between genders.Semple et al. 16 demonstrated that females were signifi cantly more sensitive to vecuronium than males, requiring 22 % less drug to achieve the same degree of neuromuscular block.
In our study, no diff erence in recovery index could be demonstrated between men and women.In other words, when the muscle strength recovered to 25 %, the further course and subsiding of the block was fairly uniform both in men and women 8,17,18 .
What is the implication for clinical anaesthesia?The easiness of intravenous injection of muscle relaxant, resulting in neuromuscular block, contrasts with the potential clinically serious consequences following its application and with considerable interindividual variability of eff ect.Particularly at the end of anaesthesia, this may present a problem; in one patient, the eff ect of a single bolus dose of NMBA may have fully subsided, while in the other one, there is a signifi cant degree of block still present 8,[19][20][21][22] .This variability of action may be further accentuated by gender diff erences.Alkhazrajy et al. 23 assessed the residual muscle weakness after general anaesthesia either without muscle relaxant or with rocuronium or vecuronium, respectively.They compared handgrip strength preoperatively and one hour postoperatively with hand dynamometer.The degree of weakness for the relaxant groups was unrelated to age but was strongly infl uenced by the patient's sex.One hour postoperatively, female patients showed a marked decrease in handgrip strength after both vecuronium and rocuronium (32 % and 34 %, respectively).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 24 .This constitutes evidence that patient undergoing surgery benefi t from perioperative neuromuscular monitoring 22 .

CONCLUSION
This study confi rmed the gender diff erences in the myorelaxant eff ect of 0.6 mg kg -1 rocuronium.Under the conditions described, women were more sensitive to rocuronium than men.The onset times were shorter by 12 % and the clinical duration was prolonged by 38 %.The recovery index was not infl uenced by gender.
This suggests that the routine dose of rocuronium should be reduced in women compared with men.

1 .
ONSET TIME (seconds) = time interval from the completion of the intravenous injection of the relaxant to maximal T 1 depression 2. CLINICAL DURATION (minutes) = time interval from the completion of the intravenous injection of the relaxant to spontaneous recovery of T 1 to 25 % of the control 3. RECOVERY INDEX (minutes) = time interval from the end of clinical duration (T 1 = 25 %) to 75 % recovery of T 1 (T 1 = 75 %)