Several studies have demonstrated that lipophilic opioids when administered epidurally using a 'continuous' regimen, exert their effect systemically rather than epidurally [1,2]. Many PCA studies, on the other hand, have shown the superiority of the epidural route, mainly in terms of a lower drug than required by the intravenous (i.v.) route [3,4]. It may be expected that as the contribution of the basal infusion in PCEA is increased, the regimen may progressively gain the characteristics of a continuous infusion.
Previous studies have demonstrated the potentiating role of clonidine upon a sufentanil analgesia given in bolus administration and in a PCEA regimen with a background infusion [5,6]. In a double-blind study the effect of a concurrent epidural infusion upon the quality of PCEA with sufentanil was evaluated . The basal rate caused very little decrease in the number of additional demands and resulted in a significantly greater drug consumption and, as a consequence, more side effects.
The aim of this PCEA study with sufentanil and a sufentanil-clonidine combination was to evaluate the effect of a basal infusion upon the quality of analgesia, the total dose and number of bolus demands, the quality of sleep, and the incidence of side-effects within the first 24 h.
The study was approved by the Hospital Ethics Committee. After informed consent, 60 patients scheduled for elective Caesarean section were entered into this study. The evening before and 2 h before operation, 150 mg ranitidine was given orally for pulmonary aspiration prophylaxis.
In all patients the anaesthetic technique was a combined spinal-epidural (CSE) block, which was initiated after an i.v. fluid load of 1000 mL Ringer's Lactate and 500 mL of HAES-steril® 6% (Fresenius, Bad Homburg, Germany).
After penetration of the dura, 6.6 mg isobaric bupivacaine and 3.3 μg sufentanil (i.e. 2 mL of a solution containing 2 mL of bupivacaine 0.5% and 1 mL of sufentanil 5 μg mL−1) were slowly injected intrathecally. After removal of the spinal needle, a 20 g catheter (Perifix®, Braun) was placed epidurally. The upper level of the block, tested with ether swabs, was required to be at least T5 before the surgeon was allowed to start the incision. If after 15 min the upper level of the sensory block appeared to be insufficient, additional increments (lignocaine 2%, 3 mL) were administered via the epidural catheter.
Following termination of surgery, the epidural catheter was connected to a Bard-I® PCA pump. All patients were treated with a solution containing 2 μg mL−1 sufentanil diluted in 0.9% NaCl. Clonidine was added to half of these prepared solutions to obtain a concentration of 3 μg mL−1 (SC groups). Therefore four groups, containing 15 patients each, were compared and treatments were allocated in a randomized fashion. The observer was blinded for the content of the syringe only.
The assessments made were: Visual Analogue Scale Scores for pain at 6, 12, 18 and 24 h, quality of night rest (VAS score 0-10), pruritus and sufentanil consumption with the number of bolus demands during the first 24 h. At 6 h intervals the degree of sedation was assessed as follows; 0: none/1: slight i.e. heavy eyes, feeling of sleep/2: moderate i.e. closing the eyes when left undisturbed/3: marked i.e. difficulty in remaining awake even during visits. Vital parameters were reported by the midwives every 2 h during the first 6 h and thereafter at 6-h intervals.
As soon as patients started to feel pain (VAS > 1.0), an initial bolus of 5 μg sufentanil with or without 7.5 μg clonidine, i.e. 2.5 mL, was administered, after which the pumps were started. The PCA settings were a demand dose of 2.5 mL with (S+ and SC+ group) or without background infusion (S and SC group) at 2.5 mL hr−1, a lock-out interval of 10 min and a maximum hourly dose of 20 μg sufentanil and 30 μg clonidine (i.e. 10 mL).
When patients either complained of insufficient pain relief, despite adequate use of the PCA pump, scored pain higher than 3 or required maximum doses for at least 2 consecutive hours, the infusion was increased to 4 mL hr−1 and 4 mL per demand with a maximum hourly dose of 30 μg sufentanil and 45 μg clonidine (i.e. 15 mL). When patients did not require additional demands for at least 6 consecutive hours, the settings were decreased to 2 mL per hour and per demand dose, allowing identical maximal hourly limits.
PCA pumps remained connected to the patients for 40 to 48 h, after which the epidural catheters were removed. However, only the data from the first 24 h were considered for statistical analysis.
Statistical analysis was performed using the Mann-Whitney U-test and the Fisher's Exact test as appropriate. Pain scores were tested with the ANOVA test. A value of P<0.05 was considered to be significant.
Patient demographics are presented in Table 1. There were no differences between the four groups with regard to age, weight, parity or the duration of pregnancy.
The interval between birth and the start of PCEA was also comparable for all groups (Table 2).
Sufentanil consumption was significantly higher in those patients receiving the plain sufentanil with basal rate (221.0±11.8 μg 24 h−1). In both groups not receiving a basal rate, the requirements decreased whether or not the clonidine was added, although this decrease was more prominent in the plain sufentanil groups (65%) than in those patients treated with the mixture (35%). The addition of clonidine reduced the consumption of sufentanil significantly in those receiving a background infusion (SC+ group). Without a background infusion (SC group) the addition of clonidine did not result in significant reductions in sufentanil requirements.
Pain scores were significantly lower up to 18h after injection in the SC+ group compared with those receiving sufentanil by demand only (S group) (Fig. 1). At 6 h the VAS scores of patients treated with sufentanil-clonidine without basal rate (SC) also differed significantly from the higher score in the S group.
The use of a background infusion reduced the number of demands, although this was far more significant in the sufentanil-clonidine combination. In spite of the lowest number of demands in the SC+ group, sleep scores were comparable among the four groups.
Since sedation is only an instant feature, the scores measured at the four time-points were cumulated. The highest sedation score was noticed in those patients consuming the highest dose of sufentanil (S+). The lowest scores were registered in patients not receiving a basal rate, and the sufentanil-clonidine mixture with basal rate revealed intermediary values (Table 3). Two patients in the SC+ group asked for deletion of the basal rate after 24h because of excessive sedation.
Vital parameters remained stable throughout the study period, although two patients receiving the mixture with basal rate had a short episode of hypotension, which was treated with a fluid load and lasted less than 1 h. Pruritis was equally present in all groups and did not require treatment.
The settings were decreased in two patients receiving the mixture with the background infusion and increased in one patient in each group receiving a sufentanil only.
Urinary retention was not evaluated as the majority of patients had an indwelling bladder catheter in place. However, no problems were noticed after 24 h, when the catheters were removed, and epidural pain relief was continued.
Clonidine, the most frequently used alpha-2-adrenergic agonist drug has antinociceptive properties, but when used alone by epidural application, controversial results have been published with regard to its analgesic effects. Moderate analgesia has been described after minor surgery  while for thoracic surgery no pain relief was found . Mendez et al. found that, after Caesarean section, a bolus of 800 μg followed by an infusion of 20 μg per hour was superior compared with a halved regimen .
With regard to combinations of opioids with clonidine for post-operative pain relief, a synergistic effect was demonstrated when clonidine was added to morphine .
As compared to sufentanil 50 μg alone, a combination of 25 μg with clonidine 1 μg kg−1 appeared to offer superior pain relief with less oxygen desaturation but at the expense of more arterial hypotension .
In a previous study it was demonstrated in PCEA that clonidine, when combined with sufentanil, reduces the 24h requirements of the opioid by 30% compared with 20% when adrenaline, also having alpha-2-adrenergic properties was added . Retrospective pain scores measured at only 10 and 24h did not differ among groups. Quality of sleep and degree of sedation, measured as a single score after the first 24h period, using a three-point verbal rating scale, favoured the regimen using adrenaline whereas no differences were found between the plain sufentanil and sufentanil-clonidine groups. In this previous PCEA study, patients also received a concurrent infusion.
The value of a background infusion has been questioned in many studies. The presence of a concurrent or at least nighttime infusion was expected to improve the quality of sleep and analgesia. However, most studies, mainly using the i.v. route, found increased dose consumption with no or only a small decrease in the need for additional demands [12,13]. In double-blind epidural PCEA-study with sufentanil, a comparison was made between a basal rate of either saline or 4 μg sufentanil . With a sufentanil basal rate, increased dose requirements were registered and as a consequence sedation was significantly more pronounced. In these subjects the number of demands was also lower, though not significantly so, and pain scores tended to be lower at 6 h only.
The superiority of the epidural route has been put into question for continuous infusions of lipophilic opioids [1,2]. As opposed to continuous infusion, PCEA studies with lipophilic opioids were more in favour of the epidural route [3,4]. Therefore, if the background infusion becomes more important, the PCEA regimen may theoretically receive the properties of a continuous infusion. This assumption may provide an additional argument to omit the basal infusion in PCEA.
Supposing that, based upon several studies, the number of PCEA demands increases very little if at all, while deleting the background infusion, then, in the present study, the 24 h consumption of sufentanil in its combination with clonidine would be expected to decrease to extremely low values (≈35-40 μg).
This study partly confirmed previous findings, but for the clonidine-sufentanil combination omission of the basal rate resulted in a three-fold increase in demand dosing. Despite this increase, the absence of the basal rate significantly reduced the consumption of sufentanil but not to the same extent as for plain sufentanil. Obviously sufficient pain relief required at least 100 μg sufentanil during the first 24h following surgery. As a consequence, only when the base rate was used, was there potentiation by clonidine in terms of drug consumption. However, when pain scores were considered in both modalities without basal rate, the quality of analgesia was significantly better at 6 h with the sufentanil-clonidine combination.
The better pain scores with the sufentanil-clonidine combination demonstrate that the use of PCEA does not necessarily mean that patients will obtain an identical quality of analgesia. In the two groups treated with sufentanil alone, the settings needed to be increased for one subject in each. Therefore it may be premature to assume that the PCEA settings in the plain sufentanil groups might have been inappropriate since one demand per hour in both these groups was far below the allowed 1h limits.
Despite the lowest number of additional demands in the clonidine group with the basal rate, the quality of sleep was not improved. This may put into question the hypothesis that a background or night-time infusion would improve the quality of sleep. Insufficient night rest is not always because of an inferior quality of analgesia but may also be attributed to other factors such as temperature, clinical observations, breast feeding, alarms etc.
No correlation could be found either between quality of sleep or degree of sedation. Although the sedative properties of clonidine are beyond any doubt, the cumulative score for sedation in this study seemed to depend largely upon the 24h dose requirements of sufentanil.
The most frequently reported side effect of clonidine is arterial hypotension. Even combined in low doses with opioids, this complication may occur after bolus administration, continuous infusion and PCEA with concurrent infusion [5,6,14]. Although the differences between the two groups receiving the mixture were not statistically different, the low incidence of hypotension with the amounts of clonidine used in this study, is very encouraging.
It may be concluded that regardless of the drug or combination, a concurrent infusion may significantly increase the requirements and decrease the number of demands, without improving the quality of analgesia or sleep but at the expense of more side effects. This confirms the findings obtained in a majority of studies which have suggested that the concurrent infusion during PCA should be abandoned. The addition of clonidine to sufentanil improved the quality of analgesia, while opioid consumption decreased though only significantly so when a basal rate was used. Despite the lowest pain scores when both drugs were combined in PCEA with a background infusion, the regimen without the basal rate offered the best compromise in terms of sufentanil requirements, quality of analgesia, degree of sedation and cardiovascular stability.
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