It is well known that fentanyl induces ventilatory depression, and this effect has been investigated on its own and in combination with other drugs [1,2].
Clonidine is frequently used in combination with other anaesthetic agents because of its sedative action. The parenteral injection of clonidine reduces the intraoperative requirements for opioids and volatile agents, and it also has analgesic properties .
The aim of the present study was to investigate the effects of fentanyl and fentanyl plus clonidine on ventilation and to determine whether this common combination generates a greater depressive effect on ventilation in man than fentanyl given alone.
Following Local Ethics Committee approval and after obtaining informed consent, 12 healthy male volunteers (aged 30.8 ± 4.9 years) were recruited. A cross-over study design was applied and each subject received either 1.5 ≥μg kg−1 of intravenous (i.v.) fentanyl or the same dose of fentanyl (1.5 ≥μg kg−1) plus clonidine (3 ≥μg kg−1) in two separate sessions which took place at least 24 h apart. The sequence of drug administration was randomized, and the subjects and the observer were blinded.
All volunteers were non-smokers with a body weight that was within 15% of the normal range (75.5 ± 8.8 kg) and none took any medication regularly.
No caffeine or alcoholic beverages were consumed during testing or in the 24 h before this period. All subjects received a standardized breakfast after fasting overnight in order to exclude diurnal variations or nutritional influences on breathing patterns. After clinical investigation, control blood samples were collected for blood count and serum electrolytes, and an i.v. canula (20 gauge) was inserted into an arm vein. Lead II of the ECG, blood pressure and pulse oximetry were continuously monitored throughout the study. Then the subjects were allowed to become familiar with trial conditions and the rebreathing system.
The subjects were kept in a supine position in a dark, quiet room and breathed through a mouthpiece with an occluding nose clip in place which was fitted to the closed rebreathing circuit of a modified Dräger Kreissystem 8-ISO™ (Dräger, Lübeck, Germany). The breathing circuit and its CO2 absorbing system, and a 10-L reservoir bag were filled with oxygen and air to supply an oxygen concentration of 40%. When breathing conditions and end expiratory CO2 (PETCO2) values were stabilized, the CO2- absorbing sodalime was removed from the circuit and the subjects rebreathed their expired CO2 from the reservoir bag. Oxygen (70%) was supplied with a flow of 0.3 L min−1 to compensate for loss caused by sampling for gas analysis (see below).
The resistance of the rebreathing system was kept constant in a range between 5 and 7 mmHg. PETCO2 was continuously measured by sampling expired gas at the mouth piece and was analysed with a Datex Capnomac II™ (Dräger). Flow, minute ventilation and tidal volume were measured online by electronic integration of the flow signal with a Dräger Anemone™ system (Dräger). Minute ventilation and tidal volume were controlled via a mechanically operating flow indicator gauge (Dräger Volumeter 3000) placed in the expiratory part of the breathing circuit. The inspiratory volume varied by less than 5% in both breathing modes. Each apparatus was calibrated according to the manufacturer's manual before and at the end of the series of measurements.
All subjects were encouraged to rebreathe as long as possible to a maximum PETCO2 of ≈9.3 kPa, but could stop any time if they became uncomfortable. Ventilatory response to CO2 was recorded until the desired goal of 9.3 kPa CO2 was achieved. If the subject stopped rebreathing before reaching 9.3 kPa, the highest achieved PETCO2 was recorded.
After completion of these base-line data (t0), either fentanyl (1.5 ≥μg kg−1) or fentanyl (1.5 ≥μg kg−1) plus clonidine (3 ≥μg kg−1) in 20 mL of normal saline solution (NaCl 0.9%) was randomly slowly injected i.v. within 5 min.
The rebreathing tests were performed 10 (t10), 60 (t60) and 120 (t120) min after drug administration. Following the last ventilatory measurement, all volunteers received naloxone (0.4 mg) in order to antagonize every possible remaining drug effect.
The response to CO2 challenge was analysed by using linear regression equations or minute ventilation vs. PETCO2 for each CO2 response curve. The linear portion of the response curve was assessed. The slope of the minute ventilation response to CO2 (minute volume/CO2, mm min−1 kPa−1) was defined for each curve obtained.
All values are represented as mean ± SD. Differences between variables at each time interval of the rebreathing responses were statistically evaluated by using Student's t-test for paired samples. The comparison between the fentanyl and the fentanyl plus clonidine group was evaluated using analysis of variance (ANOVA); P<0.05 was considered significant. All statistics were performed with the SPSS for Windows package Version 5.02.
Breathing abnormalities did not occur during the rebreathing trials and all volunteers were able to complete the study. During the investigations, no subject developed hypotension with a systolic blood pressure lower than 90 mmHg, but mild bradycardia (heart rate 50-60 beats min−1) was found, especially after clonidine administration. Episodes of apnoea, airway obstruction or hypoxaemia (SpO2) were not observed in either group.
Six out of 10 subjects complained of disturbed vision following the clonidine injection which persisted for about 60 min, but disappeared completely after a further 60 min (t-test not significant at t60).
The within-group comparison of the slopes of the CO2 response curves did not show any significant difference between base-line (t0) values (7430 ± 2075 mL min−1 kPa−1) and those obtained 120 min post-drug application (t120) in the fentanyl group (6263 ± 1864 mL kPa−1; P<0106). Fentanyl combined with clonidine induced a longer-lasting decrease of those slopes (Table 1). A significant change in the response to CO2 challenge was found (t0 1011±371 vs. t1205480 ± 2135 mL min−1 kPa−1; P<0035).
The slopes of the fentanyl CO2 ventilatory response curve at base-line and t120 were almost identical in the fentanyl group, but the slope of the t120 response curve after fentanyl and clonidine remained significantly decreased.
A comparison of the slopes and the shifts of the ventilatory response to hypercapnia did not show any significant difference between the two groups at each assessment point (Fig. 1).
Respiratory depression is a well-known side effect of the systemic opiate fentanyl. Clonidine is a potent α2-adrenergic agonist with sedative effect, and in combination, it reduces the required dosage of other anaesthetic and analgesic drugs. Its use during the course of anaesthesia is increasing. The analgesic properties of clonidine and the reduced opioid requirements during anaesthesia have been examined in various studies [3,4]. The effect of clonidine on ventilation in humans has recently been investigated, but conflicting results were reported.
In the present study, the effect of i.v. fentanyl combined with clonidine on ventilation in healthy subjects was compared with fentanyl administered alone to define whether clonidine potentiates the respiratory depression caused by fentanyl. The ventilatory response to CO2 rebreathing is considered to be a sensitive test of drug effects on respiratory function [5,6]. The response to CO2 challenge on ventilation was measured by analysing the slope and the shift of the ventilatory response curve. The slope of the curve reflects the responsiveness of the breathing centre to increased inhaled CO2 concentration.
In healthy subjects an increase less than 0.5 L min−1 0.133 kPa−1 is considered pathological .
The ventilatory response to CO2 challenge decreased significantly 10 min (t10) after the i.v. administration of fentanyl. At t60, the slope remained slightly but significantly decreased, and at t120, the slope indicated the anticipated recovery from fentanyl-induced respiratory depression.
When the combination of fentanyl and clonidine was administered, the ventilatory depression was prolonged. As in the case of the use of fentanyl alone, the ventilatory response slope had its minimum soon after injection (t10). At t60, the decrease was significant, and even at t120, only a moderate recovery could be observed.
Other authors have not reported any enhanced effects on ventilation when clonidine and opioids are used in combination. Sperry  and Bailey  could find no respiratory depression after the administration of oral clonidine alone or in combination with intramuscular (i.m.) morphine. Jarvis  reported that the respiratory depression induced by i.v. alfentanil was not potentiated by oral clonidine.
Ooi , Penon  and Jarvis  found a slight but nevertheless significant depression of the ventilatory response to CO2 challenge after oral, i.v. and epidural administration of clonidine. The mechanisms of the analgesic effects of opioids and α2-agonists are similar , and therefore, the respiratory depressant effect is possibly mediated via α2-adrenoceptor stimulation. The present authors assume that clonidine might have direct respiratory depressive effects.
The respiratory depression is the result of either α2-adrenergic receptor stimulation or a release of endogenous opiates caused by this receptor stimulation , or an interaction between α2-adrenergic-mediated sedation with opioid transmitter systems [15,16]. The difference between the present authors' findings and those of Sperry  and Jarvis  may be caused by the use of fentanyl, which is known to be a far more potent respiratory depressive agent than morphine or alfentanil.
In summary, the present authors observed the prolongation of a fentanyl-induced ventilatory depression in young healthy volunteers when fentanyl and clonidine were administered in combination. This could be the result of the increased threshold of the respiratory centre. The depression of vigilance is also prolonged when clonidine is administered additionally .
The present authors do not agree with the suggestion of Bernard  that clonidine reduces the demand for opioids during anaesthesia and post-operative analgesia, and therefore, lessens the associated respiratory depression. The present authors conclude that, after opioid anaesthesia and analgesia supplemented with clonidine, prolonged respiratory depression should always be anticipated and taken into account, particularly in day-case anaesthetic practice.
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