Intrathecal low-dose levobupivacaine and bupivacaine combined with fentanyl in a randomised controlled study for caesarean section: blockade characteristics, maternal and neonatal effects


Hippokratia 2013, 17(3):262-267

Misirlioglu K1, Sivrikaya GU2, Hanci A3, Yalcinkaya A3
Department of Anaesthesiology, Private Medisu Hospital, Antalya, 2Department of Anaesthesiology and Reanimation, Antalya Training and Research Hospital, Antalya, 3Department of 2nd Anaesthesiology and Reanimation, Sisli Etfal Training and Research Hospital, Istanbul, Turkey



Background: Intrathecal combination of local anaesthetics with opioids produces a synergistic effect without intensifying motor and sympathetic blockades. It also enables successful anaesthesia with use of a low dose of local anaesthetic, which also results in more stable haemodynamics. We compared the characteristics of blockade and maternal–neonatal effects of low-dose levobupivacaine and low-dose bupivacaine combined with fentanyl used in spinal anaesthesia for caesarean section.
Methods: Seventy-two patients undergoing caesarean section with spinal anaesthesia received low-dose 0.5% levobupivacaine (7 mg) plus fentanyl 25 µg (group L) or low-dose 0.5% bupivacaine (7 mg) plus fentanyl 25 µg (group B). The time to achieve sensory blockade of T6, the maximum spread of sensory blockade, time to S2 regression, sensorial blockade levels and motor blockade at the beginning and end of surgery were the parameters assessed. Haemodynamic parameters (systolic and diastolic blood pressures, heart rate), neonatal effects (APGAR scores at 1. and 5. min, umblical-cord gas analyses) were recorded, as were side-effects.
Results: The qualities ofsensory blockade were similar and clinically effective in both groups. Significantly more patients had complete motor blockade in group B than in group L at the beginning and end of surgery. Haemodynamic and neonatal parameters were similar between the two groups. Pruritis was a common side-effect in both groups.
Conclusion: In spinal anaesthesia for caesarean section, using low-dose levobupivacaine in combination with fentanyl elicits effective sensorial blockade and less motor blockade with similar haemodynamic and neonatal effects than usage of low-dose bupivacaine in combination with fentanyl

Key words: Local anaesthetics, levobupivacaine, bupivacaine, fentanyl, caesarean section

Corresponding author: G. Ulufer Sivrikaya, Fener Mah. Eski Lara Yolu, No: 110 Muhsin Adiyaman Sitesi, E Blok Daire: 15, Muratpasa, Antalya, Turkey, tel: +905322924173, e-mail:


Spinal anaesthesia for caesarean section (CS) is a widely preferred type of regional anaesthesia because of its ease of placement and rapid onset. Careful prevention of potential complications must be sought to maintain a high safety profile because all procedures affect the mother and newborn. Unwanted cephalad extensions of the blockade occur as a result of physiological changes in epidural veins and cerebrospinal fluid (CSF) in pregnant women1-3. CS is also a relatively short-duration procedure that is often followed by early mobilisation of the patient, which increases the potential for late extension of the blockade.

Levobupivacaine is the pure S(–) enantiomer of racemic bupivacaine. It has a similar clinical profile and a lower potency for motor blockade but an enhanced safety profile when compared with bupivacaine: this is a major advantage in regional anesthesia and analgesia (especially in obstetrics)4-7. Levobupivacaine shows a lower risk of toxicity in the cardiovascular sysytem and central nervous system (CNS) than bupivacaine8,9.

Neuraxial anaesthesia can be undertaken using local anaesthetics at different doses and baricity. Intrathecal opioids added to local anaesthetics produce a well-documented synergistic effect without intensifying motor and sympathetic blockades, and enable successful anaesthesia with the use of a low-dose local anaesthetic which results in more stable haemodynamics10-12.

The aim of the present study was to evaluate the clinical effectiveness and blockade quality of low-dose levobupivacaine and to compare it with low-dose bupivacaine when they are combined with fentanyl in CS. The primary endpoint was the difference in motor blockade between the two groups. Other endpoints were the differences between the two groups with respect to the characteristics of sensory blockade, maternal haemodynamic and neonatal effects, and side effects.

Materials and Methods

The Ethics Committee of Sisli Etfal Training and Research Hospital (Approval date: 27.10.2008, number: 63) approved this prospective randomised, double-blind study. All patients provided written informed consent to participate in this study.

We studied 72 women (age, 18–42 years) of American Society of Anesthesiologists (ASA) physical status I–II who required elective CS at gestation >36 weeks for delivery of a singleton baby at term. The exclusion criteria were patients who would not accept spinal anaesthesia and those with: abnormal coagulation profiles; known hypersensitivity to amide local anaesthetics and/or opioids; skin infections; cardiac disease; hypertension; diabetes mellitus.

All patients were premedicated with intravenous (i.v.) 50 mg of ranitidine and 10 mg of metoclopyramide 2 h before surgery. Thirty minutes before the induction of spinal anaesthesia, we started the intravenous infusion of 10–1 of crystalloid solution (Isolyte S™) to provide volume preload. Patients were randomised into two groups via a sealed-envelope method. A wedge was placed under the right hip of the women during the spinal anaesthesia procedure. In both groups, spinal anesthesia was performed by one anaesthesiologist using the same technique with the patient in the lateral position using a midline approach at L3–L4 or L4–L5 with a 25-G Quincke needle. After free flow of CSF was observed, patients in the levobupivacaine group (group L) received 7 mg (1.2 ml) 0.5% levobupivacaine + 25 μg fentanyl (0.5 ml), and the bupivacaine group (group B) received 7 mg 0.5% bupivacaine (1.2 ml) + 25 μg fentanyl (0.5 ml) at an injection interval of ≈30 s. Patients were moved to the supine lateral tilt position immediately after administration of the spinal blockade. The anaesthesiologist who performed spinal anaesthesia was blinded to the study groups. The study solutions used in the present study were prepared by another anaesthesiologist and used at room temperature (23°C).

All patients underwent non-invasive monitoring of systolic blood pressure (SBP) and diastolic blood pressure (DBP), measurement of blood oxygen saturation (SpO2) using pulse oximetry, and electrocardiography for heart rate (HR) with a PETAS KMA-175 Monitor (PETAS, Istanbul, Turkey). A dedicated observer recorded these parameters before spinal anaesthesia, every 1 min for 15 min after spinal anaesthesia, every 3 min thereafter for 30 min, and every 5 min until the end of surgery. Supplementary oxygen (2 ml.min-1) was given to all patients via a face mask.

Blockade characteristics were assessed by testing for sensory and motor blockade. Sensory blockade was monitored with the pin-prick test at 1-min intervals for the first 5 min, then every 2 min for 20 min, until the end of surgery. Surgery was allowed if the upper dermatome to the level of the loss of discrimination to a pin-prick was at least T6. The time to achieve sensory blockade of T6, maximum spread of sensory blockade, and time to S2 regression (as well as sensorial blockade levels at the beginning and end of surgery) were recorded. Motor blockade was assessed based on a modified Bromage scale (0 = no paralysis, able to flex hips/knees/ankles; 1 = able to move knees, unable to raise extended legs; 2 = able to flex ankles, unable to flex knees; 3 = unable to move any part of the lower limbs) at 1-min intervals for the first 5 min, then every 2 min for 20 min, until the end of surgery. Bromage scores at the beginning and end of surgery were noted.

Perioperative maternal hypotension (SBP <20% of baseline or 90 mmHg) or episodes of bradycardia (heart rate <50 beats/min) were recorded and treated with boluses of fluid, or 5 mg ephedrine or 0.5 mg atropine given via the intravenous route. Any other side-effects (e.g. respiratory depression, nausea, vomiting and pruritus) were recorded.

Newborns were evaluated with APGAR scores at 1 min and 5 min by the same neonatologist and with umblical-cord blood gas values.

Statistical analyses

Sample size was calculated to provide 80% power and α = 0.05 to detect a 30-min difference according to the duration of motor blockade between the two groups. Statistical analyses were conducted using the Number Cruncher Statistical System 2007 (NCSS, Kaysville, UT, USA). Independent-sample t-tests for parametric data, Mann-Whitney U test for non-parametric data, Fisher’s exact test and chi-square tests for frequency data were undertaken. p<0.05 was considered significant. Data are the mean ± standard deviation (SD), median (range), or the number of patients (n).


There were no significant differences with regard to mean values of age, weight and gestational age among women as well as the duration of surgery in the two groups (Table 1). Values of SBP, DBP and heart rates were comparable and almost stable during surgery in both groups (Table 2).

The sensory and motor blockades characteristics’ are shown in Tables 3 and 4. The qualities of sensory blockade were similar and clinically effective in both groups (Tables 3 and 4). At the onset of surgery, 10 patients in group B and 3 patients in group L had a Bromage score of 3. At the end of surgery, 6 patients in group B had a Bromage score of 3, but none of the patients had a Bromage score of 3 in group L. These differences were significant (p=0.032 and p=0.014, respectively) (Table 4).

The number of patients having episodes of hypotension and bradycardia were comparable between the two groups. The prevalence of hypotension was 30,5% in group L and 25% in group B. Three patients in group L and 5 patients in group B had an episode of bradycardia. Patients responded to intravenous boluses of fluid and ephedrine treatment. Atropine was used in 1 patient in group B. A total of 11.1% of patients in group L and 13.8% of patients in group B had pruritis.

Neither APGAR scores at 1 min and 5 min (Table 5) nor umblical-cord gas analyses (Table 5) had any significant changes between the two groups. These data were within physiological ranges in group L and group B.


In this present study, low-dose levobupivacaine and low-dose bupivacaine combined with fentanyl produced a similar quality of sensorial blockade as well as maternal haemodynamic and neonatal effects in CS under spinal anaesthesia. Combination of fentanyl with low-dose levobupivacaine induced less motor blockade than low-dose bupivacaine when administered via the intrathecal route.

The efficacy of neuraxial local anaesthetics is enhanced by the addition of intrathecal opioids. Such combinations are usually associated with improved anaesthesia and analgesia. It also allows the use of very low doses of local anaesthetic, which contributes to more stable haemodynamics13-15. In the study by Parpaglioni et al16, the addition of sufentanil via the intrathecal route reduced the minimum local anaesthetic dose (MLAD) of spinal levobupivacaine and ropivacaine. It did not affect their potency ratio significantly, and resulted in enhanced spinal anaesthesia. Intrathecal fentanyl added to low-dose local anaesthetics produces a synergistic effect without increasing sympathetic blockade or delaying discharge from hospital17.

Lee et al study18 was published as the first study on the intrathecal use of 0.5% levobupivacaine with fentanyl. They concluded that 2.3 ml of 0.5% levobupivacaine with fentanyl (15 µg) was as effective as 2.6 ml of 0.5% levobupivacaine alone in spinal anaesthesia for urological surgery. Significant differences were not observed between the two groups with respect to haemodynamic changes and the quality of sensory and motor blockades. In a recent study by Cuvas et al19, addition of fentanyl 15 µg (0.3 ml) to 0.5% levobupivacaine (2.2 ml) produced a shorter duration of motor blockade than pure 0.5% levobupivacaine (2.5 ml solution) in spinal anaesthesia, whereas both regimens were effective for transurethral resections. Akcaboy et al20 and Erbay et al21 compared the effectiveness of low doses of 0.5% levobupivacaine and 0.5% bupivacaine (5 mg and 7.5 mg, respectively) when combined with fentanyl (25 µg). These regimens were shown to be effective in spinal anaesthesia for transurethral resection of the prostate (TURP) if used in higher doses. In both studies, levobupivacaine plus fentanyl resulted in effective sensorial blockade with less motor blockade than bupivacaine plus fentanyl.

Studies have demonstrated the effect of a combination of local anaesthetic and opioid for regional anaesthesia in CS5,22-25: different results with regard to the characteristics of sensorial blockade between levobupivacaine and bupivacaine have been observed. However, most of these studies have concluded that there was less motor blockade with levobupivacaine than with bupivacaine. The only study comparing the combination of fentanyl and low-dose levobupivacaine versus bupivacaine in CS is that of Bremerich et al7. They compared fixed doses of intrathecal hypertonic 0.5% levobupivacaine (10 mg) and 0.5% bupivacaine (10 mg) combined with intrathecal fentanyl (10 and 20 µg), or sufentanil (5 µg) in terms of the characteristics of sensory and motor blockade in parturients undergoing elective CS with spinal anaesthesia. In that study, levobupivacaine produced a significantly shorter and less pronounced motor blockade than racemic bupivacaine regardless of the type and dose of opioid added. In the present study, we preferred to use 7 mg of 0.5% levobupivacaine and 0.5% bupivacaine as a low dose in combination with 25 μg fentanyl for spinal anaesthesia for patients undergoing CS. Levobupivacaine produced adequate and comparable sensorial blockade with bupivacaine but induced less motor blockade than bupivacaine, a result consistent with previous studies.

Gunusen et al24, concluded that levobupivacaine (7.5 mg) combined with fentanyl (15 μg) was suitable for combined spinal-epidural anaesthesia in elective CS. In other studies focusing on the optimal dose of levobupivacaine in combination with opioids, the median effective dose (ED50)was 6.2 mg and the dose required for the desired effect in 95% of the population exposed to it (ED95) was 12.9 mg in the study by Bouvet et al25. The MLAD was 4.73 mg in the study by Parpaglioni et al16 for CS. In the present study, a low-dose of levobupivacaine (7 mg), which was in-between the doses mentioned above, combined with fentanyl produced effective anaesthesia for CS.

In the present study, decreases in SBP and DBP as well as changes in heart rate were in acceptable ranges. Erdil et al26 noted, in spinal anaesthesia, better haemodynamic stability associated with low-dose levobupivacaine plus fentanyl compared with that seen with low-dose bupivacaine plus fentanyl. Coppejans et al22 compared equipotent doses of bupivacaine, levobupivacaine and ropivacaine combined with sufentanil in patients undergoing elective CS with combined spinal–epidural anaesthesia. They found that haemodynamic values were comparable between the three groups (although a trend towards better SBPs and a lower prevalence of severe hypotension were noticed with levobupivacaine). In the present study (and not in accordance with the studies above), maternal haemodynamic changes were comparable between levobupivacaine and bupivacaine.

Hypotension is a frequent side-effect that can be seen in 18-84% in parturients during spinal anaesthesia27-29. In pregnant women, engorgement of epidural veins from aortocaval compression with displacement of CSF may contribute to unwanted cephalad extensions of the blockade, which can be associated with an increased risk of hypotension. In the present study, the relatively lower prevalence of hypotension in both groups was thought to be a result of volume preloading before spinal anaesthesia and lowering of the local anaesthetic dose in combination with an opioid. Pruritis was also recorded in both groups in the present study. Pruritis is a common adverse effect of intrathecal use of fentanyl which has been reported by other investigators20,30.

In the present study, the neonatal effects of levobupivacaine and bupivacaine in combination with fentanyl were similar. In a study by Lirk et al31, intrathecal bupivacaine, ropivacaine and levobupivacaine used for CS produced similar effects on neonates (as evaluated by APGAR scores and the pH of arteries in the umbilical cord). In another study22, after combination of sufentanil with bupivacaine, ropivacaine and levobupivacaine, Apgar scores and the pH of arteries in the umbilical cord in neonates did not differ: our results are consistent with that study.

One limitation of our study is that not evaluating the time to full recovery of sensory block, which can also be related with analgesia time or time to first analgesic request. In the literature there is conflicting results of this data showing shorter time to full recovery of sensory block21 or longer time to first analgesic request5 with intrathecal bupivacaine compared to levobupivacaine in combination with opioids. This can be assess in a future study.

In conclusion: in CS, spinal anaesthesia with 7 mg levobupivacaine plus 25 μg fentanyl provided less motor blockade with effective sensorial blockade compared with that seen with 7 mg bupivacaine plus 25 μg fentanyl. Such induced motor blockade offers the advantage of early mobilisation. Both agents produced similar maternal and neonatal effects with a negligible side-effects.

Conflict of interest



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