Wiederholter Zusatz von Fentanyl zur peripartalen Bupivacain-Periduralanalgesie Klinische Wirkung und Fentanyl-Plasmaspiegel

Zusammenfassung

Der Zusatz von Fentanyl (F) zur geburtshilflichen Periduralanästhesie mit Bupivacain bewirkt eine Vertiefung der Analgesie. Aus Furcht vor opioidvermittelten Nebenwirkungen wurde F meist nur in der frühen Eröffnungsphase injiziert. Eine Nachinjektion von F erscheint gerechtfertigt, da die mütterlichen und umbilikalen F-Spiegel bei Geburt nach einmaliger Injektion niedrig sind. Wir untersuchten deshalb Pharmakodynamik und Plasmaspiegel nach repetitiver periduraler F-Injektion. 46 Patientinnen erhielten peridural 8 ml Bupivacain 0,25%+2 ml NaCl 0,9% (Bup; n=22) oder 8 ml Bupivacain 0,25%+2 ml (0,1 mg) Fentanyl (B+F; n=24). Auf Anforderung wurde die jeweils gleiche Dosis nachinjiziert. Vor, 20 und 40 min nach Injektion wurde mütterliches, bei Geburt auch umbilikales Blut entnommen. Pro Patientin wurde bis zu viermal nachinjiziert. Die Analgesie in der B+F-Gruppe war vor allem während der Austreibung tiefer als in der Bup-Gruppe. Mittlere maximale mütterliche F-Spiegel stiegen mit der Injektionsfrequenz und betrugen nach einer, zwei oder drei Injektionen 0,54 ng/ml (±0,32; ±SD); 0,88 ng/ml (±0,62) und 1,06 ng/ml (±0,4), (Spannweite 0,18–2,76 ng/ml). Umbilikalvenöse und -arterielle F-Spiegel betrugen 0,72 ng/ml (±1,16) bzw. 0,62 ng/ml (±0,52). Mütterliche Atemfrequenz, Apgar- und umbilikale Blutgaswerte waren gruppengleich. Der wiederholte peridurale Fentanylzusatz verbessert die Analgesie in der Eröffnungs- und besonders in der schmerzhaften Austreibungsphase. Die mit zunehmender Injektionshäufigkeit nur geringgradig ansteigenden mütterlichen und umbilikalen F-Plasmaspiegel verursachten keine bedeutsamen Nebenwirkungen.

Abstract

A combination of epidural opioids with local anaesthetics has been used to improve pain relief during labor and to reduce side effects, such as muscle weakness, usually seen when local anaesthetics are used alone. The addition of epidural fentanyl (F) produces highly effective analgesia, the only side effect being mild itching. Initial trials investigated the improvement in analgesia after a single administration of F during first- but not during second-stage labor. Even though pain perception during second-stage labor under epidural analgesia with local anaesthetics can be severe, the addition of opioids was avoided for fear of neonatal or maternal depression. A recent report found maternal and umbilical plasma concentrations following injection of 100 μg F to be safe and the investigators speculated that repeated addition of epidural/F to injections of local anaesthetic may prove beneficial for the parturient without exposing the mother or fetus to risk. We therefore studied maternal analgesia, maternal and umbilical plasma levels and associated side effects following repeated addition of 100 μg F to bupivacaine epidural analgesia during labor. Methods. Following institutional and governmental approval 53 parturients were randomly assigned to receive either 8 ml bupivacaine 0.25%+0.1 mg fentanyl (B+F group; n=28) or 8 ml bupivacaine 0.25%+2 ml saline (BUP group; n=25) in an epidural catheter at L2/3. The same dose was reinjected upon the patients' request regardless of the degree of cervical dilatation. Blood pressure, heart rate, respiratory rate and the incidence of side effects were recorded before and following each epidural injection. Pain relief was determined at each injection and following cord clamping using the visual analogue pain scale (VAS; 0–100 mm). Maternal venous blood samples were collected to measure plasma F concentrations before and 20 and 40 min after each injection and at birth when umbilical venous and arterial blood was obtained. After centrifugation the samples were maintained at −20° C and then analyzed by radioimmunoassay. At delivery, Apgar scores and umbilical venous and arterial blood gas values were determined. Results. Both groups were comparable for age, weight, height, gestational age and parity. A total of 48 epidural injections were evaluated in the B+F group, 43 in the BUP group. No statistically significant group difference was found between the frequency of injections per delivery (B+F: 2.2; BUP: 1.8); regarding the time between the initial and the first top-up dose (B+F: 144 min; BUP: 140 min) or regarding the interval between the last injection and birth (B+F: 94 min; BUP; 90 min). However, the quality of pain relief during labor and particularly at birth was significantly improved by F (mean VAS in B+F group: 6 mm; mean VAS in BUP group: 42 mm). Mild itching was observed in 43% of patients receiving F, moderate shivering in 13% versus 40% in patients not receiving F. At control mean maternal F plasma levels were not zero but 0.25 ng/ml. After the initial injection and following the first and second top-up dose mean maximum maternal F plasma concentrations were 0.54 ng/ml (±0.32; ±SD), 0.88 ng/ml (±0.62) and 1.06 ng/ml (±0.4) (range 0.18–2.76 ng/ml), respectively. The increase in maternal F concentrations with increasing injection frequency was statistically significant (P<0.02). Mean umbilical venous and arterial F concentrations at birth were 0.72 ng/ml (±1.16) and 0.62 ng/ml (±0.52). No significant group differences were found regarding Apgar scores or umbilical blood gas analyses. In one newborn, radioimmunoassay resulted in unexplainably high umbilical F concentrations without any clinical signs of sedation, depressed vigilance and without any sequellae. Discussion. Repeated addition of 100 μg F to epidural anaesthesia with bupivacaine significantly improves analgesia and provides pain relief not only during the first but also through the very painful second stage of labor. In this study, F did not affect the onset or the duration of analgesia, probably due to the fact that bupivacaine was used at a fixed and (compared to other studies) relatively high concentration. We did not observe clinically relevant side effects in the mother or the newborn. Although epidural injections of 100 μg F were repeatedly administered, the mild dose-dependent increases of maternal and of umbilical plasma F concentrations had no effect and caused no clinical signs of depression. The specificity of radioimmunoassay for fentanyl in parturients is questioned.