Effects of clonidine and midazolam on anaesthetic requirements
Klinika Anestezjologii i Intensywnej Terapii, Uniwersytet Medyczny w Łodzi
Background. Premedication reduces requirement for anaesthestic agents during anaesthesia. There have been few papers published on the effects of clonidine on the MAC of volatile agents. The aim of this study was to assess the effects of premedication with midazolam or clonidine on remifentanil and sevoflurane requirements, necessary to achieve an adequate level of anaesthesia, in patients undergoing laparoscopic cholecystectomy.
Methods. ASA I and II patients were randomly allocated to three groups. Two groups received premedication with either 150 mg of clonidine, or 7.5 – 15 mg of midazolam. The third group received a placebo. All patients were induced with remifentanil and sevoflurane, and intubated after relaxation with rocuronium. The sevoflurane concentration was adjusted to achieve entropy values between 60 and 50. Analgesia was maintained with remifentanil via infusion at a rate of 0.05 – 0.15 µg kg-1 min-1 .
Results. Sixty patients were enrolled to the study. The concentration of sevoflurane necessary to maintain entropy between 55 and 60 was statistically lower in the midazolam group than in the placebo group (p=0.006) or the clonidine group (p=0.02). No statistically significant differences in remifentanil requirements were observed. The recovery time was shortest in the placebo group (p<0.05), slightly longer in the clonidine group (p>0.05), and longest in the midazolam group (p<0.05).
Conclusions. Clonidine did not affect the MAC of sevoflurane and remifentanil requirement. Midazolam decreased the time taken for induction of anaesthesia.
Premedication has become a standard of anaesthetic management to prepare a patient for anaesthesia and surgery. Its basic purposes are to sedate the patient, to prevent undesirable reflexes during the induction of anaesthesia, and to reduce requirements for anaesthetic agents. It is generally thought that premedication reduces the minimal alveolar concentration (MAC) of volatile anaesthetics and prolongs the action of intravenous anaesthetics, opioids and muscle relaxants [1, 2, 3, 4]. Currently, it is possible to assess objectively two of the three basic symptoms of anaesthesia, i.e. sleep, analgesia and relaxation of striated muscles. Neuromuscular conduction is assessed by analyzing the response of the adductor pollicis muscle to electrical stimulation of the ulnar nerve. The depth of sleep (unconsciousness) is monitored by assessing the bioelectrical brain activity (BIS, entropy) or auditory evoked potentials (AEPs). The assessment of analgesia is more difficult. Nociceptive impulsation is manifested by extremely unreliable clinical symptoms (from the autonomic system), i.e. the heart rate, arterial blood pressure, skin moisture and colour, diameter of pupils and lacrimation. In this regard, the surgical stress index (SSI) seems highly promising .
The objective of the present study was to assess the effects of premedication with midazolam and clonidine on remifentanil and sevoflurane requirements necessary to achieve the adequate depth of anaesthesia in patients undergoing laparoscopic cholecystectomy.
The study design was approved by the Bioethics Committee of the Medical University of Łódz. The study involved patients fulfilling ASA I and II criteria undergoing laparoscopic cholecystectomy. All patients gave written informed consent; using Statistica 8.0 PL, patients were randomly allocated to three groups receiving different oral premedication 30-40 min before anaesthesia. The first group received midazolam (MID) in the dose dependent on body weight: <65 kg – 7.5 mg, > 65 kg – 15 mg. The second group was administered clonidine, 0.15 mg (CLO); the third control group (NO) did not receive premedication.
Prior to anaesthesia, patients were transfused 10 mL kg-1 of crystalloids and the infusion was continued at a rate of 3 mL kg-1 h-1 throughout the procedure. The monitoring of vital signs (ECG, HR, SpO2, body temperature) and entropy was started and the induction of anaesthesia was initiated.
Patients received paracetamol 1 g and the infusion of remifentanil 0.05 mg kg-1 min-1 was started. Anaesthesia was induced with incremental concentrations of sevoflurane. The concentration of the anaesthetic was increased by 100% every 8-10 breaths from the value of 0.3% to 2.4 %. Once the ciliary reflex was abolished, the concentration of sevoflurane was increased to 3.6%. The supramaximal stimulus was determined (stimulation of the ulnar nerve), rocuronium was administered and the infusion of remifentanil increased to 0.12 mg kg-1 min-1. Patients were intubated and artificial lung ventilation was started with the flow of fresh gases – 2 L min-1 and FIO2 0.3-0.35. The concentration of sevoflurane in the respiratory mixture (MAC) was determined to achieve the entropy values (state entropy – SE) between 60-50. The muscle relaxant was administered based on the number of responses to TOF stimulation (once ≥3, 1/5 of the initial dose of rocuronium was given). Intraoperative analgesia was provided with the infusion of remifentanil at a rate of 0.05 – 0.15 mg kg-1 min-1 (depending on nociceptive impulsation from the operative field). Sevoflurane was discontinued 10-15 min before the completion of anaesthesia. The O2 flow was increased to 8 L min-1 and the rate of remifentanil infusion reduced to 0.02 – 0.05 mg kg-1 min-1. Patients received pethidine 0.5 mg kg-1 and after extubation (TOFR >0.9) and completion of remifentanil infusion were sent to the recovery room.
The analysis involved: HR, MAP, response entropy (RE), state entropy (SE), the mean rate of remifentanil infusion, time for induction of anaesthesia, i.e. the time from the beginning of sevoflurane administration to ciliary reflex abolition and time from discontinuation of sevoflurane to extubation.
The determinations were performed at seven stages of anaesthesia: 1 – before induction, 2 – after ciliary reflex abolition, 3 – immediately after intubation, 4 – after setting the respiratory mixture composition, 5, 6, 7 – 30, 45 and 60 min after the onset of anaesthesia, respectively.
The data were analysed statistically. Due to small sizes of groups and distributions different from normal – the time of ciliary reflex abolition was analysed using the Shapiro-Wilk test of normality. For the remaining results, the non-parametric Kruskal-Wallis test was applied; when significant differences for at least one group were found, the Newman-Keuls test was used. The statistical hypotheses were verified at p<0.05.
Each study group consisted of 20 patients. The sleep induction was quickest in the MID group and slowest in the CLO group (p<0.05). The recovery time was shortest in the NO group (p<0.05), slightly longer in the CLO group and longest in the MID group (p<0.05) (Table 1).
No significant differences in remifentanil requirements were observed. The highest demands were found in patients without premedication.
At stage 5 of anaesthesia, the lowest values of MAP were observed in the MID group and the differences were significant compared to the CLO (p<0.02) and NO (p<0.004) groups (Fig. 1). Likewise, HR values in the MID group were significantly lower than in the NO group (p=0.03) (Fig. 2). Despite the differences found, values of MAP and HR in individual groups were within normal levels .
Moreover, significantly lower MAC values were observed in the MID group compared to the CLO (p=0.02) and NO (p=0.006) groups (Fig. 3).
Clonidine is an agonist of a2-adrenergic receptors. It intensifies the action of sympaticolytic agents and autonomic nervous system reactions . Used in premedication, clonidine reduces intraoperative consumption of isoflurane [8, 9] and halothane , simultaneously decreasing the arterial blood pressure. In inhalation induction with sevoflurane, recommended for haemodynamically unstable patients, or in anaesthesias with the spontaneous respiration preserved, clonidine premedication (also in children) reduces the MAC and provides fast recovery after surgery [11, 12, 13].
The results did not confirm the findings of most other similar studies [3, 9, 10, 11, 12], which is likely to be associated with the small dose of clonidine used for premedication (2.5-3 mg kg-1)  compared to the dose used by other authors (5 mg kg-1). The dose used in the present study was smaller to avoid possible side effects of clonidine – vasodilation and reduced arterial blood pressure.
It was found that 0.15 mg of clonidine did not affect the MAC of sevoflurane, the time of induction of anaesthesia or the recovery time. Different findings were reported by Inomata and colleagues  who studied the effects of clonidine premedication (4.5 mg kg-1) on the time of induction and MAC-awake in the group of patients in whom general anaesthesia was induced with volatile sevoflurane using the “one-breath” method. In their study, earlier administration of clonidine (30-40 min before anaesthesia) markedly shortened the induction time. According to some other authors, clonidine premedication reduced the MAC of sevoflurane from 33% to 45%  and decreased the dose of propofol . Thanks to that, intubation was feasible or the laryngeal mask could be used without the necessity to induce deep anaesthesia, which was associated with the risk of circulatory depression.
1. Premedication with clonidine in the dose of 0.15 mg does not reduce the MAC of sevoflurane and requirements for opioid analgesics.
2. Premedication with midazolam shortens the time of volatile induction of anaesthesia, reduces the dose of opioids yet is associated with longer awakening.
The author is grateful to dr Michał Orczykowski, Department of Anaesthesiology and Intensive Therapy, Medical University of Lódz for technical assistance in collecting data.
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Klinika Anestezjologii i Intensywnej Terapii
Uniwersytetu Medycznego w Łodzi
ul. Żeromskiego 113, 90-569 Łódź