Aging impairs organ function resulting in decreased reserve and ability to endure stress. Advanced age is, therefore, a significant risk factor for increased morbidity. On the other hand, perioperative morbidity in elderly patients has decreased in recent years with the advent of newer surgical, anaesthetic and monitoring techniques . Aging affects all systems of the body, primarily the cardiovascular, renal and respiratory systems. A number of physiological and anatomical changes also occur at the neuromuscular junction  although the implications of these changes to the anaesthetized patient are not fully understood. With aging, there is an adaptive process which occurs and leads to increased neurotransmitter release despite a reduced supply of vesicles. A loss of active synaptic areas leads to deterioration in muscle structure and function .
In this study, we compared vecuronium and cisatracurium with regard to onset time, clinical duration of action, recovery index, spontaneous recovery time, tracheal intubation conditions and haemodynamic variables under sevoflurane-remifentanil anaesthesia in elderly patients.
The study was approved by the Ethics Committee of the Medical School of Celal Bayar University, Manisa, Turkey. Written informed consent was obtained from all patients or from their family. Forty patients over 65-yr old, American Society of Anaesthesiologists (ASA) Grades I-II, within 30% of ideal body weight, undergoing low-to-moderate-risk elective surgery and requiring general anaesthesia were included in this randomized, double-blind study.
Exclusion criteria were personal or family history of malignant hyperthermia, or sensitivity to neuromuscular blocking drugs, history of chronic alcoholism and/or drug abuse, prior exposure to drugs known to alter the patient's response to neuromuscular blocking drugs. Patients were not given preoperative premedication. Oxygen saturation, heart rate (HR) and non-invasive blood pressure (BP) were monitored.
Anaesthesia was induced with thiopental (3-4 mg kg−1) and maintained with 1% sevoflurane, remifentanil (0.05 μg kg−1 min−1) and 50% N2O in oxygen. Ventilation was controlled to maintain an end-tidal partial pressure of carbon dioxide of 30-35 mmHg. Neuromuscular transmission was monitored by accelerometry (TOF-GUARDINMT, Biometer, Belgium). Surface electrodes were applied over the ulnar nerve at the wrist and the piezo-electric device was attached to the corresponding thumb.
The accelerometer was calibrated after loss of consciousness using 0.2 ms supramaximal square wave impulses at 0.10 Hz. The patients were then randomized in two groups. Patients received either 0.15 mg kg−1 cisatracurium or 0.1 mg kg−1 vecuronium injected over 5-10 s. The drugs were prepared by a physician not involved with the study or any of the assessments. Intubation was attempted when neuromuscular block was 95%. Following administration of the neuromuscular drug, onset time (T95: from completion of neuromuscular drug injection to maximum twitch suppression; muscle response 95% T1 suppression) and clinically effective duration (T25: from completion of injection of the bolus dose to 25% twitch recovery), recovery index (T25-75: recovery period of T1 from 25% to 75%), and spontaneous recovery time (T4/T1 ≥ 80%) were compared between two groups. Intubating conditions were graded as 'Excellent', 'Good', 'Poor' or 'Not possible' according to the scale published by Viby-Mogensen and colleagues . In the event of unsuccessful laryngoscopy, ventilation was continued for another 30-45 s until the next attempt.
Single twitch stimulation was changed to train-of-four (TOF) stimulation at 15 s intervals following tracheal intubation. To avoid changes in muscle responsiveness, core temperature was kept above 35°C and peripheral skin temperature of the monitoring hand kept above 32°C by wrapping the arm.
The haemodynamic parameters HR, systolic arterial pressure, diastolic arterial pressure and mean arterial pressure were measured immediately before and 2, 5 and 10 min after the injection of the study drugs. Clinical signs of histamine release (e.g. bronchospasm, hypotension, rash or cutaneous flushing, thorax rigidity), were recorded during the first 10 min after bolus dose injection of the study drug.
Statistical analyses were performed with SPSS 10.0 for windows (SPSS Inc., Chicago, IL, USA). Analysis of variance for repeated measures was used to compare haemodynamic variables. As a post hoc Tukey test was used, U- and t-tests were used to compare independent variables. All data are presented as mean ± standard deviation (SD). The level of significance was set at P < 0.05.
The study groups were comparable with regard to age, weight, sex and ASA distribution (Table 1).
Onset time (T95) was shorter (158 ± 34 s) after vecuronium than after cisatracurium (200 ± 50 s) (P < 0.05). Clinical duration of action was 56.5 ± 14.3 min for cisatracurium and 55.6 ± 19.7 min for vecuronium (P > 0.05). Recovery index (T25-75) was shorter in the cisatracurium group (19.5 ± 7.5 min) than the vecuronium group (33.7 ± 18.6 min) (P = 0.007). Spontaneous recovery time (T4/T1 ≥ 0.8) did not differ significantly between the groups.
Although all patients attained a T4/T1 ratio over 0.8, residual paralysis was detected clinically in two patients in the vecuronium group, which was antagonized with 0.02 mg kg−1 neostigmine at the end of surgery. No other patients required reversal of muscular relaxation and none of the patients required an additional dose of the neuromuscular blocking drug.
All 20 patients receiving cisatracurium, and 18 of those receiving vecuronium had good or excellent intubating conditions (P > 0.4) (Table 2). Two patients in the vecuronium group could not be intubated on the first attempt, but intubating conditions were good 30 s later.
Haemodynamic variables were similar between groups (Table 3). One patient in the cisatracurium group under chronic beta-blocker treatment required atropine during the induction period.
Other side-effects such as histamine release, bronchospasm, flushing, muscle rigidity, etc. were not observed in any patient.
The results of the study indicate that although the haemodynamic effects of cisatracurium and vecuronium were comparable in treated elderly patients under sevoflurane-remifentanil anaesthesia, recovery index was shorter in the cisatracurium group. On the other hand, onset time was shorter in the vecuronium group. It is concluded that both drugs are safe in elderly patients in combination with sevoflurane-remifentanil, and that the relaxant should be selected according to the requirements of the intervention and the patient.
Volatile anaesthetics augment the relaxant effects of non-depolarizing neuromuscular blocking drugs in a dose-dependent fashion [5,6] which may also depend on the duration of anaesthesia . Vanlinthout and colleagues  concluded that 1.7% sevoflurane augmented and prolonged the neuromuscular block produced by vecuronium. We used a 1% concentration of sevoflurane in this study. Interestingly, the results of previous studies indicate that the effects of volatile anaesthetics were not the same with all neuromuscular blocking drugs [9-11]. The reason for this may be partly due to differences in experimental design. However, atracurium and vecuronium seem to be less affected by the choice of general anaesthetics than other agents .
By the seventh or eighth decade of life, maximal voluntary contractile strength of proximal and distal muscles is decreased by an average of 20-40% in both male and female . Time and rate of relaxation are slowed due to decreased rates of maximal sarcoplasmic reticulum calcium uptake and sarcoplasmic reticulum Ca2+ ATPase activity. Furthermore, there is a reduction in total fibre numbers, especially of the fast glycolytic type II fibres, as well as reduction in the number of alpha motor neurons in adults over 60 yr of age .
The results of this study showed that onset time was significantly shorter after vecuronium than after cisatracurium. This was consistent with the slower blocking effect of cisatracurium on neurotransmission, which can be clinically more important in elderly. Sealing the mask may be particularly difficult in these patients because of the sagging cheeks. When prolonged mask ventilation is required, complications such as risk of aspiration of gastric content and pressure damage to the eyes can occur in addition to the difficulties in ventilating the patient.
Intubating conditions depend on the patient's anatomy and the anaesthetic drug doses given at induction of anaesthesia. When cisatracurium was compared with vecuronium in regard to intubation conditions, all 20 patients had good or excellent intubation conditions in the cisatracurium group vs. 18 in the vecuronium group, but the difference is not statistically significant. De Wolf and colleagues  concluded that cisatracurium 0.15 mg kg−1 (3 × ED95) suppressed twitch response by 99-100% within 2.4-3.7 min. The time to maximum effect was approximately 1 min longer in elderly patients and in those with renal failure than in healthy young adults [15-17]. Although our study population was elderly, our results were similar to those of De Wolf and colleagues in young patients . Despite the fact that twitch response was suppressed by 95%, the vocal cords were not completely open in two patients in the vecuronium group, but intubation of these two patients was performed successfully after a further 30 s.
Sorooshran and colleagues  found an onset time of 4 min after cisatracurium in elderly patients under isoflurane anaesthesia, which was longer than in younger patients. In a different study, vecuronium had an onset time of 3.5 min in elderly patients under sevoflurane anaesthesia, which was also longer than in younger patients . Clinical duration of action was similar in both studies.
In our study, clinical duration of action was similar in both groups, but the recovery index was significantly shorter after cisatracurium. Compared with previous studies [15,19] this is a prominent finding. We conclude that the longer action of vecuronium in elderly patients is due to reduced vecuronium metabolism and disposition  secondary to decreases in hepatic and renal blood flows with increasing age. The volume of distribution for cisatracurium is large in the elderly despite age-associated decreases in extracellular fluid space . This might also be attributed to a decrease in plasma protein binding.
Onset time depends primarily on cardiac output, but changes in plasma binding and alterations in the volume of distribution in the elderly may also play an important role . In this study, none of the patients had serious systemic diseases. Thirty patients had hypertension controlled by medication. All laboratory and clinical examination results were normal in both groups. There were no other confounding factors, such as liver or renal disease, that might have influenced the parameters under study, and the only factor taken into consideration in both groups was age (over 65-yr old). We believe that the different elimination pathways might be the cause of difference in recovery index, but cardiac output and organ perfusion might also have affected these results.
There is only one report of a direct comparison of cisatracurium and vecuronium in the elderly, but the study design differed from ours . In that multicentre study, total intravenous (i.v.) anaesthesia was used instead of a volatile-opioid combination. The results were similar to ours, but the recovery index after vecuronium was shorter in our study than in theirs. This difference might be related to use of sevoflurane-remifentanil vs. total i.v. anaesthesia or the ASA status of the patients. Our study population consisted of ASA I or II patients, with clinically normal physical status and undergoing elective surgery.
The results of this study suggest that cisatracurium and vecuronium do not affect haemodynamic stability, and do not cause any side-effects in elderly patients under sevoflurane-remifentanil anaesthesia.
In addition, we consider the remifentanil dose to be very important, especially in elderly patients. We administered 0.05 μg kg−1 min−1 remifentanil, and this dose provided optimal haemodynamic responses without adverse reactions such as thorax rigidity.
We observed a shorter spontaneous recovery index after cisatracurium in elderly patients. Furthermore, cisatracurium showed less variability in its offset than vecuronium.
Residual paralysis was detected clinically in two patients in the vecuronium group. Residual neuromuscular blockade remains a problem even after short surgical procedures. It is suggested that the TOF ratio at the adductor pollicis muscle should be at least 0.9 to avoid residual paralysis . We agree with this, especially in elderly patients.
In this study, both drugs provided good intubating conditions. For rapid intubation in elderly patients, we recommend vecuronium. But, if recovery time has priority, we suggest that cisatracurium as a good alternative. In addition, sevoflurane-remifentanil combination is a good anaesthetic choice to provide haemodynamic stability in elderly patients.
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