It is well known that co-administration of low doses of opioids potentiates the analgesic effect of epidurally applied local anaesthetics. The advantage of these mixtures lies in the concomitant reduction of possible side-effects of both the opioid and the local anaesthetic, while excellent postoperative pain relief is maintained. To date, bupivacaine has been preferred for epidural pain therapy postoperation. However, with the introduction of ropivacaine - a new amide-type local anaesthetic that seems to reduce the incidence of motor blockade - increasingly more anaesthetists are administering mixtures of ropivacaine with sufentanil for epidural postoperative pain therapy.
One very effective method of providing optimal postoperative pain relief uses portable infusion pump systems for patient-controlled epidural analgesia (PCEA). These systems can be used with a mixture of sufentanil and ropivacaine . However, little is known about potential interactions between epidural drug-delivery systems and the drugs being administered with regard to the adsorption and stability of the drug mixtures. The epidural drug solution is typically infused for 96 h after surgery. It is prepared by the pharmacist and is intended for storage in a refrigerator for up to 4 weeks at 8°C.
Although PCEA devices are considered a reasonable method of drug delivery, it has been argued that a sufentanil-local anaesthetic mixture may be unstable in polyvinylchloride (PVC)-containing medical reservoirs owing to absorption of the highly lipophilic opioid [2,3]. Resulting alterations in the sufentanil concentration are thought to affect postoperative pain management. The present study, therefore, assessed the stability and compatibility of sufentanil citrate at 0.5, 0.75 and 1.0 μg mL−1 with ropivacaine 0.2%, stored in quantities of 750 mL in reservoirs consisting of either PVC or glass. Assessments were also carried out for storage >4 weeks.
Sufentanil citrate (Sufenta®; Janssen-Cilag GmbH, Neuss, Germany; 250 μg 5 mL−1) was reconstituted under aseptic conditions with sodium chloride 0.9% and ropivacaine (Naropin®; AstraZeneca Deutschland, Wedel, Germany) to obtain three different final concentrations: sufentanil 0.5, 0.75 and 1.0 μg mL−1 in 750 mL ropivacaine 0.2%. The samples were stored either in a Baxter® polyvinyl chloride bag (Baxter Deutschland GmbH, München-Unterschleißeim, Germany) or in a glass reservoir under ambient light conditions at 25°C. For each assay, the pump reservoir was filled with 750 mL of the desired concentration.
Samples (3 mL) were then removed from each container as well as from the distal end of the epidural catheter at distinct time points: immediately after preparation, and after 24, 48, 72 and 96 h. A mixture of ropivacaine 0.2% and sufentanil 1.0 μg mL−1 that had been stored for 4 weeks at 8°C in a PVC reservoir was also analysed in the same manner.
Pharmacia Deltec (SIMS Deltec, Inc, Kirchseon, Germany) Ambulatory Infusion Pumps®, CADD-PCA® model 5800R, and Portex® epidural catheters and filters (Portex Ltd, Hythe, UK) initiated epidural infusions. The drug containers were attached to the pumps, and the extension sets were connected to the reservoir on the one side and to the epidural filter on the opposite side. The distal part of the epidural catheter was coupled to the filter, while the proximal part was guided into a 50 mL glass container using a 16-gauge cannula. During the simulated epidural infusions, the pumps ran for 96 h at 5 mL h−1.
All specimens were inspected against light and dark backgrounds to detect any colour changes or macroscopic impurities. The various concentrations of sufentanil were measured using a radioimmunoassay procedure. ANOVA calculated differences between the sufentanil concentrations. The stability of the concentrations within the reservoir and at the catheter tip was analysed using Pearson correlation coefficients.
It was demonstrated that sufentanil citrate at 0.5, 0.75 and 1.0 μg mL−1 in an admixture of ropivacaine 0.2% remained stable in PVC as well as in glass reservoirs for 4 days, which can be regarded as the usual duration of postoperative epidural analgesia (Fig. 1). The sufentanil concentration in the sample collected from the end of the epidural catheter also remained stable for 4 days (Fig. 2). In addition, no changes with regard to colour, clarity or concentration were observed, even after storage of the mixture for 4 weeks at 8°C. No significant differences were observed between glass reservoirs, PVC reservoirs and PVC reservoirs stored for 4 weeks.
The correlation coefficients within the concentrations at the different measurement time points were high both for the reservoir (rmin = 0.98, rmax = 1.00) and for the catheter (rmin = 0.86, rmax = 1.00). However, in the catheter group, the data showed an initial decrease (P = 0.006) in the sufentanil concentrations, although no significant differences were observed in the drug-reservoir materials.
At 0.5, 0.75 and 1.0 μg mL−1 in a mixture with ropivacaine 0.2% (in sodium chloride 0.9% to a total volume of 750 mL), sufentanil can be stored for 96 h at 25°C and also for 4 weeks at 8°C. The solutions remain stable in both PVC and glass reservoirs.
In contrast to the results of Roos and colleagues , the substantial initial reductions in sufentanil concentrations measured in the present study were not due to adsorption by the PVC container. The most likely explanation appears to be that the drug-delivery system, i.e. the catheter and filter material, caused a reduction in the concentrations - as was suggested by De Vogel and colleagues . Unfortunately, no specific studies concerning epidural filters acting as absorbers of drug exist. With regard to administration via an epidural Portex® catheter, the results suggest that it is reasonable to flush the epidural catheter system with sufentanil before connecting it to the patient.
As the major goal was to guarantee that the patient receives optimal postoperative pain relief, it is necessary to deliver stable drug concentrations that can be calculated in advance, especially during the first 24h after surgery. However, priming the delivery system with an initial bolus of sufentanil can easily be put into practice and, hence, it is advisable. The eligible quantity and quality remain to be investigated. Further studies will therefore be needed to clarify whether a single flushing of the filter and catheter with the specific drug mixtures can ensure the delivery of stable concentrations.
The study was supported in part by Janssen-Cilag Ltd, Germany.
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