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Original Article

A double-blind comparison of intrathecal S(+) ketamine and fentanyl combined with bupivacaine 0.5% for Caesarean delivery

Unlugenc, H.*; Ozalevli, M.*; Gunes, Y.*; Olguner, S.*; Evrüke, C.; Ozcengiz, D.*; Akman, H.*

Author Information
European Journal of Anaesthesiology: December 2006 - Volume 23 - Issue 12 - p 1018-1024
doi: 10.1017/S0265021506000950
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Abstract

Introduction

S(+) ketamine, a non-competitive antagonist of N-methyl-d-aspartate (NMDA) receptors, has been in widespread clinical use for over 10 yr [{L-End} 1,{L-End} 2]. It has a fourfold higher affinity for NMDA receptors and therefore possesses approximately two threefold greater analgesic potency than racemic mixture [{L-End} 3–5]. Additionally, S(+) ketamine has a faster disposition half-time, greater clearance rate and faster demethylation [{L-End} 6,{L-End} 7] allowing better control of the anaesthetic procedure. In obstetrics S(+) ketamine has no detrimental effect on uterine blood flow, maternal or fetal haemodynamics when used in clinically relevant doses [{L-End} 7]. Therefore, it might be of interest in the obstetric settings.

In experimental studies, spinally administered NMDA receptor antagonists such as ketamine or magnesium have been shown to inhibit nociception and produce motor dysfunction [{L-End} 8,{L-End} 9]. These affect likely results from antagonism of NMDA receptors on dorsal horn sensory neurons as well as motor neurons in the ventral horn of the spinal cord. Ketamine has been administered epidurally to human beings for pain relief without the side-effects, such as respiratory depression, urinary retention, or pruritus, frequently observed after epidural opioids [{L-End} 10]. Wong and colleagues [{L-End} 11] suggested that the addition of ketamine to epidural morphine significantly improved analgesia and lowered postoperative morphine consumption in patients undergoing major joint replacement.

Although, the addition of opioids to spinal local anaesthetics has been reported to potentiate the effect of local anaesthetics, it is unknown whether the addition of S(+) ketamine to spinal bupivacaine could result in similar potentiation and lower side-effects, compared with spinal fentanyl/bupivacaine combination.

This prospective, randomized, double-blind, controlled study was designed to investigate the sensory, motor and analgesic block characteristics of intrathecal (IT) S(+) ketamine (0.05 mg kg−1) compared with fentanyl (25 μg) and saline when added to 0.5% plain bupivacaine (10 mg). The hypothesis was that, in parturients undergoing Caesarean section with spinal analgesia, S(+) ketamine (0.05 mg kg−1), administered immediately after spinal bupivacaine, would enhance both the duration of spinal analgesia and postoperative pain relief to the same degree as IT fentanyl (25 μg), but with fewer side-effects.

Methods

Following Ethics Committee approval and informed parturient consent, 90 ASA I or II parturients at full-term gestation presenting for elective Caesarean delivery were included in this prospective, randomized, double-blinded study. Exclusion criteria included significant coexisting disease such as pre-eclampsia and hepato-renal disease, any contraindication to regional anaesthesia such as local infection or bleeding disorders, allergy against the applied drugs, long-term opioid use or a history of chronic pain. Parturients were instructed preoperatively on the use of the numerical rating scale (NRS) for pain assessment. All were fasted for 6 h preoperatively and no premedication were given. Intraoperative monitoring included pulse oximetry, automated blood pressure (BP) cuff, and lead II electrocardiogram. Before subarachnoid block, intravenous (i.v.) access was established and each parturient was administered i.v. 15 mL kg−1 of a lactated Ringer's solution for hydration. An observer blinded to the treatment group performed all pre-block assessments.

The parturients were allocated to one of three groups of 30 each. Parturients were allocated to the study groups by computer-generated random number assignment, kept in sealed envelopes, before the start of the study. The envelopes were opened just before entry in the study.

Preservative-free 0.9% sodium chloride (1.0 mL) plus plain bupivacaine 0.5% (2 mL), 10 mg (Marcaine 0.5%; Astra Zeneca PLC, UK), was administered IT in Group S. S(+) ketamine (0.05 mg kg−1) (1.0 mL) (Ketanest S; Parke-Davis, Karlsruhe, Germany) plus plain bupivacaine 0.5% (2 mL), 10 mg was administered IT in Group K. Fentanyl (25 μg) (1.0 mL) (Fentanyl citrate; Abbott Laboratories, Chicago, USA) plus plain bupivacaine 0.5% (2 mL), 10 mg was administered IT in Group F. Both patients and anaesthesia providers were blinded to the treatment.

Every parturient received a combined spinal–epidural in the sitting position at the L2–3 or L3–4 vertebral level. After infiltrating the skin with 1% lidocaine 2 mL, a 17-G Tuohy needle was introduced into the epidural space at the L2–3 or L3–4 vertebral level via a midline approach using the loss of resistance technique. After the epidural space was identified, a 27-G, Whitacre tip spinal needle was placed through the Tuohy needle into the subarachnoid space. After return of clear cerebrospinal fluid, 10 mg of plain bupivacaine 0.5% (2 mL) was injected followed immediately by either 0.9% sodium chloride (1.0 mL), 0.05 mg kg−1 of S(+) ketamine (1.0 mL), or 25 μg of fentanyl (1.0 mL), IT. After the IT injection, the spinal needle was withdrawn, and a 19-G, single-orifice, epidural catheter was inserted 3–4 cm into the epidural space and secured with a sterile drape. Immediately after the completion of the blocks the parturients were placed supine with a 15–20° left lateral tilt for the prevention of aortocaval compression. Oxygen 2–4L min−1 was delivered routinely via nasal cannula until delivery. No additional analgesic was administered unless requested by the patient.

Surgery was started when sensory block was established above the T5 dermatome. After delivery, neonatal Apgar scores were recorded at 1 and 5 min by an attending paediatrician. Patient characteristics data were recorded by an observer blinded to the treatment group. Pain and sedation scores, systolic and diastolic BP (SBP, DBP), heart rate (HR) and peripheral oxygen saturation (SpO2) were recorded by an anaesthetist blinded to the patient group, 5 min before the IT injection, and at 5, 10, 15, 20 and 25 min after the injection, and subsequently every 15 min until the patient complained of pain. Pain was assessed using a NRS from 0 to 10 (0 =no pain at all, 10 =maximum imaginable pain). Sedation was assessed using a 5-point scale (0 =alert and 4 =deep sleep).

The onset of sensory and motor block was recorded, immediately after the IT injection as baseline and at 5, 10, 15, 20 and 25 min after the injection, and subsequently every 15 min until the patient complained of pain. The duration of sensory and motor block, maximal dermatomal level of sensory block, time to reach the maximal dermatomal level of sensory block, duration of spinal analgesia, time to first request for analgesics and quality of spinal analgesia were also recorded.

The level of sensory block, defined as the loss of sharp sensation by using a pinprick test, was recorded bilaterally at the midclavicular line. The onset of sensory block was defined as the time from injection of the IT anaesthetic to the absence of pain at the T10 dermatome; the duration of sensory block was defined as the time for regression of two segments from the maximum block height evaluated by pinprick. The maximal dermatomal level of sensory block was evaluated by pinprick every 5 min for 25 min after completed injection. Motor block was assessed by modified Bromage score (0: no motor loss; 1: inability to flex the hip; 2: inability to flex the knee; 3: inability to flex the ankle); the onset of motor block, defined as time from IT injection to Bromage 1 block, whereas duration of motor block was assumed when the modified Bromage score was zero.

The duration of spinal analgesia was defined as the period from spinal injection to the first occasion when the patient complained of pain in the postoperative period. The quality of spinal analgesia during surgery was judged by the investigator at the end of surgery as excellent – no pain or sensation and patient comfortable, good – mild pain or discomfort, no need for additional analgesics, patient had only the sensation of motion, fair – mild discomfort and required analgesia, poor – patient in agony, moderate or severe pain that required general anaesthesia.

It was also planned that if NRS exceeded three,a mixture of 20 mg of plain bupivacaine 0.5% plus 50 μg; of fentanyl plus 5 mL of saline would be given as a rescue analgesic medication.

SBP 20% below baseline (prenatal) or <100 mmHg was treated with i.v. ephedrine 5 mg followed by an i.v. fluid bolus of 500 mL of lactated Ringer's solution. If HR was less than 50 beats min−1, 0.5 mg of atropine sulphate was administered i.v. Ephedrine requirements, the incidence of hypotension, bradycardia (HR < 50 beats min−1), hypoxaemia (SpO2 < 95) and excessive sedation, pruritus, dizziness, nausea and vomiting were recorded. The discharge criteria for the ward were resolved motor block, stable vital signs, no nausea or vomiting, and no severe pain. Patients were also assessed for the presence of motor or sensory complications, headache or backache on the 3rd day after surgery by a blinded observer.

To calculate the power and define the primary end-point, data from a previous study was taken into consideration [{L-End} 12]. The primary end-point was defined as a 25-min difference in the median duration of spinal analgesia between groups. Power analysis showed that with a power of 0.9 and significance level of 0.05, 30 subjects per study group were required.

Normality was checked for each continuous variable, and normally distributed values were expressed as mean (95% confidence interval, CI), or (SD), number (%), others as median (range) where appropriate. Patient characteristics (gestational age, maternal age, height and weight) data were analysed using one-way analysis of variance (ANOVA). Clinical data were analysed using the Kruskal–Wallis test. If there were significant differences among the three groups, the analysis was continued with post hoc comparisons of differences between pairs of groups by using U-test. Bonferroni's correction was applied (P < 0.05/n; where n = number of comparisons) when multiple comparison were made and P < 0.017 considered statistically significant. Haemodynamic data were analysed by using repeated measure analyses. The incidence of intra- and postoperative adverse events were analysed using χ2 tests. Values of P < 0.05 were considered statistically significant. Statistical analyses were performed using the statistical package SPSS v 11.5 (SPSS Inc, Chicago, USA).

Results

All patients completed the study protocol, n =30 in each group. The patient characteristics variables of patients are shown in Table 1. There were no significant differences between groups in patient characteristics or the duration of surgery. Neonatal Apgar scores after 1 and 5 min were similar between the groups (Table 1).

Table 1
Table 1:
Patient characteristics. Data presented as mean (95% CI) or number of patients, except for gravid status, Apgar scores and the dose of ephedrine used, which are given as median (range).

The onset time of sensory block was significantly shorter in Groups K (2.8 ± 0.9 min) and F (3.0 ± 0.5) than in Group S (3.6 ± 1.1 min; P < 0.014) (Table 2). The mean duration of sensory blockade was significantly shorter in Groups K (95.7 ± 20.4 min) and S (94.6 ± 21.6 min) than in Group F (11.5 ± 31.8 min; P < 0.009) (Table 2).

Table 2
Table 2:
Characteristics of spinal block. Data are shown as mean ± SD, or number of patients except for maximal sensory block height which is given as median (range).

The onset time of motor block was significantly shorter in Groups K (3.7 ± 1.2 min) and F (4.6 ± 1.5 min) than in Group S (6.9 ± 2.4 min; P < 0.001). However, there were no significant difference in the onset of motor blockade between Groups K and F (Table 2). Duration of motor blockade was significantly longer in Group F (103.3 ± 31.6 min) than in Groups K (80.3 ± 16 min) and S (84.2 ± 18.5 min) (P < 0.001).

The maximal dermatomal levels of sensory block achieved were T4 (T2–T5), T3 (T1–T4) and T3 (T1–T4) in Groups S, K and F, respectively. There was no significant difference in maximal dermatomal level of sensory block between groups as was shown in Table 2. The time to reach maximal dermatomal level of sensory block was significantly faster in Groups K (5.0 ± 1.6 min) and F (5.1 ± 1.6 min) than in Group S (6.6 ± 1.4 min) (P < 0.001) (Table 2).

Parturients who were given fentanyl 25 μg had significantly prolonged duration of spinal analgesia (126.8 ± 29.8 min) compared with S(+) ketamine (102.1 ± 20.6 min) and saline (99.5 ± 21.1 min) (P < 0.001; Table 2). The time to first analgesic request (epidurally given mixture of bupivacaine, fentanyl and saline) was also significantly longer in Group F (153.3 ± 37.6 min) than in Groups K (110 ± 22.3 min) and S (112.6 ± 19.9 min) (P < 0.001; Table 2).

Median NRS scores were significantly higher in Groups K and S at 45, 60, 75, 90, 105 and 120 min than in Group F (P < 0.001) (Fig. 1). Median sedation scores were significantly higher in Group K at 25, 30, 45 and 60 min than in Group S (P < 0.001). However, there was no significant difference in sedation scores between Groups K and F at any study period (Fig. 2). The quality of spinal analgesia was excellent in 93.3% of patients in Group F and 90% of patients in Group K as compared to 76.6% in Group S (P < 0.002). However, none of the patients in the groups had fair or poor quality of analgesia (Table 2).

Figure 1.
Figure 1.:
Relationship between time and pain scores. *P < 0.001; between Group F and Groups K and S by U-test.
Figure 2.
Figure 2.:
Relationship between time and sedation scores. *P < 0.001; between Group K and Groups F and S by U-test.

There were no statistically significant differences in SpO2 values between groups. Values remained within the normal range throughout the study period. Although transient hypotension occurred at various time points in each group, no significant difference was found in the incidence of hypotension episodes. Ephedrine requirements were also similar in all groups (data not presented).

The side-effects and complications were shown in Table 3. The overall side-effects seen during the study period was significantly higher in Groups K and F than in Group S (P < 0.017). No major complication was reported and mostly (hypotension, sedation) were minor. Patients who received IT S(+) ketamine did not indicate any psychological event. No postdural puncture headache was reported after surgery, but five patients (one in Group S, two in Group K and two in Group F) had moderate backache with minor local tenderness at the injection site.

Table 3
Table 3:
Side-effects and complications of spinal block.

Discussion

The main finding of this study is that, in patients undergoing Caesarean section with spinal analgesia, the addition of S(+) ketamine (0.05 mg kg−1) IT to 10 mg of spinal plain bupivacaine (0.5%), led to rapid onset of both sensory and motor blockade, and enhanced the segmental spread of spinal block, although it did not prolong the duration of spinal analgesia and reduce the incidence of side-effects, frequently observed with opioids.

In the literature, results regarding analgesic benefit of IT ketamine as an adjuvant are conflicting. Klimscha and colleagues [{L-End} 13] demonstrated that IT S(+) ketamine did effectively treat inflammatory pain. Togal and colleagues [{L-End} 1] reported that the addition of IT S(+) ketamine to spinal bupivacaine provided shorter motor and sensory block onset time, shorter duration of action and less motor blockade in patients undergoing transurethral prostate surgery. Yanli and Eren [{L-End} 14] showed that IT racemic ketamine did shorten the onset time and increase the level of bupivacaine block by two segments. However, Weir and Fee [{L-End} 15] demonstrated that racemic ketamine combined with bupivacaine alone did not produce any improved analgesia. In our study, S(+) ketamine addition to spinal bupivacaine although improved the spinal analgesia and enhanced the segmental spread of spinal block, it did not prolong the duration of spinal analgesia. Possible reasons for improvement in spinal analgesia include local anaesthetic effect of S(+) ketamine [{L-End} 1], additive analgesic effect [{L-End} 16] and possible inhibiting effect of S(+) ketamine on the metabolism of bupivacaine [{L-End} 17].

In 1984, Bion [{L-End} 18] evaluated the effect of spinal ketamine, as a sole agent, for lower limb surgery. He reported that IT ketamine (50 mg) produced significant analgesia without interfering with cardiovascular and respiratory function. However, its use, as a sole agent, was limited because of the short duration of surgical analgesia and psychomimetic side-effects.

As IT S(+) ketamine itself can produce signifi-cant analgesia, we expected a synergistic interaction between it and local anaesthetics, leading to a more rapid and widespread block. Indeed, we observed a rapid onset of both sensory and motor blockade, and improved the segmental spread of spinal block possibly due to the high lipid-soluble properties of the S(+) ketamine. The onset of action mainly depends on the relative concentrations of the non-ionized lipid-soluble form [{L-End} 19]. A higher concentration of non-ionized bupivacaine will result in more rapid onset of action, since only this lipid-soluble form diffuses across the neural sheath and nerve membrane [{L-End} 19]. This property of the S(+) ketamine could increase the concentration of non-ionized bupivacaine by providing more acidic environment, which results in extensive and rapid absorption from the subarachnoid space.

Although, the maximal dermatomal levels of sensory block achieved were higher in Groups K and F than in Group S, there was no significant difference in maximal dermatomal level of sensory block between groups. Fentanyl exerts its spinal effect on the dorsal horn of the spinal cord, where it binds to opioid receptors [{L-End} 20]. It may also exert a supraspinal action by IT cephalad spread [{L-End} 21]. Our findings suggest that S(+) ketamine not only acts at spinal level but also at supraspinal level, as evidenced by similar enhance in the segmental spread of sensory block and increased sedation scores. Analgesic effect of ketamine at spinal and supraspinal level has previously been demonstrated [{L-End} 1,{L-End} 22,{L-End} 23].

The prolongation of spinal analgesia by opioids such as fentanyl has been shown in many studies and in different patient groups [{L-End} 24,{L-End} 25]. We expected such prolongation with S(+) ketamine–bupivacaine combination, because of the ketamine's analgesic effect on opioid receptors [{L-End} 26]. Instead, the duration of spinal analgesia was shorter in Group K than in Group F about 17.5 min, and the time to the first request for analgesia was also shorter in Group K than in Group F about 35 min. These results are suggesting that IT S(+) ketamine might have a shorter duration of action than IT fentanyl and consistent with previous studies that IT S(+) ketamine provides shorter motor and sensory block onset time without prolonging the duration of analgesia [{L-End} 1,{L-End} 27].

Median NRS scores were significantly higher in Groups K and S at 45, 60, 75, 90, 105 and 120 min than in Group F. We believe that these differences might be of any clinical relevance because higher NRS scores reduce the time to first analgesic request and allow us to use higher doses of bupivacaine mixture in postoperative period. Evidently, in the present study, the time to first analgesic request was also significantly shorter in Groups K and S than in Group F.

In this study, the addition of S(+) ketamine to spinal bupivacaine did not result in lower side-effects, compared with spinal fentanyl–bupivacaine combination. The incidence of pruritus, although, was higher in Group F than in the other groups, no significant difference was found between Groups F and K. IT S(+) ketamine, even at small dose (0.05 mg kg−1), produced sedation. Sedation can only be caused by S(+) ketamine if this drug reaches the brain. In contrast to water-soluble agents like morphine, highly lipid-soluble agents like ketamine, fentanyl and sufentanil bind to the spinal cord to a major extend with only minor fractions reaching the brain. Supraspinal spread of ketamine hydrochloride has previously been demonstrated [{L-End} 23]. In rats, IT ketamine has been shown to produce short-lasting hypotension and bradycardia, which may be due to inhibition of sympathetic outflow from the thoracolumbar region [{L-End} 28]. Although, the maximal dermatomal levels of sensory block achieved were higher in Groups K and F than in Group S, the incidence of hypotension and the dose of ephedrine used were similar between the groups.

As an adjuvant, the ideal dose or concentration of IT S(+) ketamine for satisfactory analgesia and longer duration of action during Caesarean section under spinal analgesia has not yet been confirmed. Our dose was based on data from Kathirvel and colleagues, who showed that 25 mg of IT S(+) ketamine spared the local anaesthetic effect of bupivacaine [{L-End} 27]. In that study, it has been stated that higher doses of IT ketamine alone did not produce adequate analgesia, but did produce more side-effects at a higher dosage (0.75–1 mg kg−1). On the other hand, the endogenous opioid analgesic system is activated by pregnancy during labour and the early postpartum period, leading to less analgesic requirement and consumption [{L-End} 29]. In our study, as the patient groups were pregnant, we studied a relatively low dose of S(+) ketamine (0.05 mg kg−1) in combination with plain bupivacaine 10 mg.

In conclusion, in patients undergoing Caesarean section with spinal analgesia, the addition of S(+) ketamine (0.05 mg kg−1) IT to 10 mg of spinal plain bupivacaine (0.5%) led to rapid onset of both sensory and motor blockade and enhanced the segmental spread of spinal block, although it did not prolong the duration of spinal analgesia and reduce the incidence of side-effects, frequently observed with opioids. There is thus no strong rationale for using IT S(+) ketamine as an adjuvant to spinal bupivacaine and it cannot be recommended at the present time.

Acknowledgement

The authors gratefully acknowledge the assistance of nursing staff and would like to thank G. Seydaoglu, PhD, for expert statistical advice. The study was not supported by external funds.

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Keywords:

ANAESTHETICS, INTRAVENOUS, ketamine; LOCAL ANAESTHETICS, bupivacaine; ANALGESICS, OPIOID, fentanyl; SPINAL ANAESTHESIA

© 2006 European Society of Anaesthesiology