Fentanyl versus sufentanil: plasma concentrations during continuous epidural postoperative infusion in children

C. Lejus1,*, D. Schwoerer1, I. Furic1, J.-P. Le Moing2, J.-C. Levron2 and M. Pinaud1

1Department of Anaesthesiology, Hôtel-Dieu, CHR Nantes, France. 2Janssen Research Foundation, Val de Reuil, France

Accepted for publication: March 14, 2000


    Abstract
 Top
 Abstract
 Introduction
 Methods and results
 Comments
 References
 
No pharmacokinetic data are available with respect to the plasma concentrations and fentanyl or sufentanil during epidural administration in children. This double-blind randomized study included 12 children (5–12 yr). Patients in group F were given an epidural loading dose of fentanyl 1.5 µg kg–1 and in group S sufentanil 0.6 µg kg–1. Both groups then received a continuous epidural infusion of bupivacaine 5 mg kg–1 day–1 with either fentanyl 5 µg kg–1 day–1 or sufentanil 2 µg kg–1 day–1. An epidural PCA system was also given to the children (bolus: bupivacaine 0.2 mg kg–1 and fentanyl 0.2 µg kg–1 or sufentanil 0.08 µg kg–1). Maximal median concentrations of plasma (0.117–0.247 ng ml–1 for fentanyl and 0.027–0.074 ng ml–1 for sufentanil) were reached approximately 30 and 20 min respectively after the loading doses. These values were similar to those measured after 48 h.

Br J Anaesth 2000; 85: 615–7

Keywords: analgesia, postoperative; analgesics opioid, fentanyl; analgesics opioid, sufentanil; analgesic techniques, epidural; children


    Introduction
 Top
 Abstract
 Introduction
 Methods and results
 Comments
 References
 
Epidural bupivacaine has been shown to provide effective postoperative analgesia in paediatric patients. Bupivacaine toxicity may cause convulsions and cardiovascular depression. Therefore, it has been recommended that an opioid should be combined with bupivacaine rather than increasing the infusion rate of bupivacaine. The efficacy of a combination of fentanyl with bupivacaine has been reported.1 However, only two studies report the epidural administration of sufentanil in children for postoperative analgesia.2 3 Furthermore, no paediatric data are available about plasma concentrations after continuous and prolonged epidural administration of fentanyl or sufentanil. Therefore, we investigated this in children receiving epidural fentanyl or sufentanil at doses giving similar analgesia.


    Methods and results
 Top
 Abstract
 Introduction
 Methods and results
 Comments
 References
 
After approval of the study by the Ethical Human Studies Committee of our University Hospital and written parental consent had been obtained, 12 children (5–12 yr) scheduled for postoperative epidural analgesia after orthopaedic surgery were enrolled in this prospective, randomized, double-blind clinical trial. Twenty minutes after premedication with midazolam 0.3 mg kg–1, anaesthesia was induced by inhalation of halothane or sevoflurane. Endotracheal intubation was facilitated with atracurium 5 mg kg–1 and anaesthesia was maintained with an expired fraction of 0.8% isoflurane in nitrous oxide/oxygen (FIO2=0.5). Ventilation was controlled in order to maintain normocapnia. Children were placed in the lateral position for insertion of a lumbar epidural catheter before surgery. The epidural test dose consisted of 0.5% bupivacaine 0.1 ml kg–1 with epinephrine (1/200 000). Before surgery, all children received a bolus dose of 0.75 ml kg–1 of a 50/50% mixture of 0.5% bupivacaine and 1% lidocaine, with epinephrine. The patients were allocated randomly to receive either fentanyl (group F) or sufentanil (group S). Patients were given an epidural dose of fentanyl 1.5 µg kg–1 in group F and of sufentanil 0.6 µg kg–1 in group S. Immediately after the epidural loading dose had been given, a continuous epidural infusion was started with bupivacaine 5 mg kg–1 day–1 plus fentanyl 5 µg kg–1 day–1 in group F and sufentanil 2 µg kg–1 day–1 in group S. In the recovery room, after tracheal extubation and once the children were completely awake, an epidural patient-controlled analgesia (PCEA) system was given to the children. They could self-administer boluses of bupivacaine 0.2 mg kg–1 with fentanyl 0.2 µg kg–1 or sufentanil 0.08 µg kg–1 in groups F and S respectively. Lock-out time was 1 h, with a maximal number of two boluses per 4 h. The maximal daily total doses of epidural bupivacaine, fentanyl and sufentanil were 7.4 mg kg–1, 7.4 µg kg–1 and 2.96 µg kg–1 respectively. The continuous and PCEA epidural administration was planned for the 48 h after operation. Randomization was performed by the pharmacist of the hospital, who prepared the vial of opioids for the double-blind procedure.

Measurements of plasma fentanyl and sufentanil plasma were performed on venous samples withdrawn 5, 10, 20, 30 and 60 min and 2, 6, 24 and 48 h after the loading dose in six patients from each group, using a radioimmunological method. The limit of quantification was 0.020 ng ml–1 for sufentanil and 0.05 ng ml–1 for fentanyl. Pain was evaluated every 3 h with a standard visual analogue pain scale graded from 0 to 100, except when the child was asleep. The first evaluation was performed by the child on arrival in the surgical ward. The number of PCEA-satisfied demands for the 48 h after operation was recorded.

Patient characteristics are presented in Table 1. Epidural analgesia was interrupted prematurely in children 6 and 8 at the 15 and 20th hour respectively because of accidental removal of the epidural catheter. In one other child (number 12), the study was stopped at the 30th hour because of a surgical complication. Among the 52 plasma determinations performed in group F and the 51 performed in group S, 1 and 14 respectively were below the limit of quantification (P<0.001). The maximum concentrations (0.117–0.247 ng ml–1 for fentanyl and 0.027 and 0.074 ng ml–1 for sufentanil) had been reached by approximately 30 min after the loading dose for fentanyl and by 20 min for sufentanil. Analgesia was excellent in both groups. The median (25–75%) number of self-administered boluses was similar in the two groups: 8.5 (5–11) in group F and 6.5 (4–7.25) in group S.


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Table 1 Plasma concentrations (ng ml–1) of fentanyl (children 1–6) and sufentanil (children 7–12) during epidural administration. ND=not determined
 

    Comments
 Top
 Abstract
 Introduction
 Methods and results
 Comments
 References
 
The initial systemic absorption of sufentanil is very rapid. The relative delay of the peak plasma concentration of sufentanil observed in our patients was similar to that reported previously in adults.4 The plasma concentrations of fentanyl or sufentanil reached with our epidural regimens were very low, with little suggestion of accumulation at 24 and 48 h. The excellent quality of analgesia associated with very low plasma concentrations of sufentanil suggest a spinal action of sufentanil. Other investigators have reported plasma concentrations of sufentanil or fentanyl below the minimal effective concentration necessary for systemic analgesia after epidural injection.5 With intravenous infusion, a serum sufentanil concentration above 0.03 ng ml–1 seems to be necessary for analgesia.6 7 However, it has been suggested that the epidural and i.v. doses of sufentanil required for analgesia are similar.8

The plasma concentrations of sufentanil and fentanyl that are not associated with risk of respiratory depression are not well established. The target concentration of fentanyl for analgesia is considered to be above 1.5 ng ml–1 and thus induces significant alteration in the carbon dioxide response.9 A 38% decrease in the carbon dioxide response slope has been reported in association with a mean plasma concentration of 0.95 (SD 0.2) ng ml–1.10 Respiratory depression has been described in one adult despite a plasma concentration below 1 ng ml–1, whereas infants and children in the same study had respiratory depression only when the fentanyl concentration exceeded 1 ng ml–1.11 For sufentanil, a plasma concentration >0.25 ng ml–1 is considered to be efficacious with self-spontaneous ventilation when administered i.v.

In the first report of epidural administration of sufentanil in children, the slope of the carbon dioxide ventilatory response curve decreased significantly from 1.1 before sufentanil to 0.68 litre min–1 mm Hg–1 30 min after epidural administration.2 A higher dose (0.75 µg kg–1) than that used in our study was administered, and the plasma concentrations were low (0.1 ng ml–1).

The low concentrations of sufentanil and fentanyl measured in our study do not eliminate completely the possibility of respiratory depression, and monitoring the sedation score and respiratory rate remains absolutely necessary. Nevertheless, fentanyl and sufentanil are highly lipid-soluble opioids and migrate less than morphine in the cerebral spinal fluid. They are less likely to cause delayed respiratory depression after epidural administration.


    Acknowledgements
 
The work was supported by Janssen-Cilag France.


    Footnotes
 
* Corresponding author: Service d’Anesthésie et de Réanimation Chirurgicale, Hôtel-Dieu, F-44093 Nantes cedex 01, France Back


    References
 Top
 Abstract
 Introduction
 Methods and results
 Comments
 References
 
1 Løvstad RZ, Halvorsen P, Raeder JC, Steen PA. Post-operative epidural analgesia with low dose fentanyl, adrenaline and bupivacaine in children after major orthopaedic surgery. A prospective evaluation of efficacy and side effects. Eur J Anaesth 1997; 14: 583–9[ISI][Medline]

2 Benlabed M, Ecoffey C, Levron JC, Flaisler B, Gross JB. Analgesia and ventilatory response to CO2 following epidural sufentanil in children. Anesthesiology 1987; 67: 948–51[ISI][Medline]

3 Kokki H, Tuovinen K, Hendolin H. The effect of intravenous ketoprofen on postoperative epidural sufentanil analgesia in children. Anesth Analg 1999; 88: 1036–41[Abstract/Free Full Text]

4 Ionescu TI, Taverne RHT, Houveling PL, Drost RH, Nuijten S, Van Rossum J. Pharmacokinetic study of extradural and intrathecal sufentanil anaesthesia for major surgery. Br J Anaesth 1991; 66: 458–64[Abstract]

5 Geller E, Chrubasik J, Graf R, Chrubasik S, Schulte-Mönting J. A randomized double-blind comparison of epidural sufentanil versus intravenous sufentanil of epidural fentanyl analgesia after major abdominal surgery. Anesth Analg 1993; 76: 1243–50[Abstract]

6 Scott JC, Cooke JE, Stanski DR. Electroencephalographic quantification of opioid effect: comparative pharmacodynamic of fentanyl and sufentanil. Anesthesiology 1991; 74: 34–42[ISI][Medline]

7 Lehmann KA, Gerhard A, Horrichs-Haermayer G, Grond S, Zech D. Postoperative patient-controlled analgesia with sufentanil: analgesic efficacy and minimum effective concentrations. Acta Anaesthesiol Scand 1991; 35: 221–6[ISI][Medline]

8 Cohen SE, Tan S, White PF. Sufentanil analgesia following cesarean section: epidural versus intravenous administration. Anesthesiology 1988; 68: 129–34[ISI][Medline]

9 Cartwright P, Prys-Roberts C, Gill K, Dye A, Staffort M, Gray A. Ventilatory depression related to plasma fentanyl concentrations during and after anesthesia in humans. Anesth Analg 1983; 62: 966–74[Abstract]

10 Renaud B, Brichant JF, Clergue F, Chauvin M, Levron JC, Viars P. Ventilatory effects of continuous epidural infusion of fentanyl. Anesth Analg 1988; 67: 971–5[Abstract]

11 Hertzka R, Gaunlett IS, Fischer DM, Spellman MJ. Fentanyl induced ventilatory depression: effect of age. Anesthesiology 1989; 70: 213–8[ISI][Medline]





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