Combined spinal and epidural anaesthesia (CSEA) is a technique in which an analgesic is given via an epidural catheter and a subarachnoid analgesic is administered simultaneously. This technique has become popular because the spinal analgesic establishes an intense and reliable block immediately, and the epidural injection of local analgesics or opioids supplements this by extending anaesthesia and enabling the provision of continuous postoperative analgesia [1-4]. However, CSEA has the potential risk that it can be associated with severe adverse effects if the epidurally administered drug(s) diffuse in significant quantities from the epidural space through the meningeal hole into the cerebrospinal fluid (CSF), which resides in the subarachnoid space [5-9].
Our hypothesis was that the epidural injection of morphine for postoperative pain management is an unacceptable risk when used after CSEA because of the possible flux of morphine into the CSF. The aim of the present study was to examine in orthopaedic patients whether the epidural injection of morphine was associated with a higher incidence of adverse events when given after CSEA than when given after epidural anaesthesia.
After institutional approval had been obtained and with the informed consent of each patient, 30 healthy female patients (ASA I-II, aged 50-80 yr) scheduled for orthopaedic surgery on the lower extremity were studied in a prospective, randomized, double-blinded fashion. Patients with significant renal, hepatic, respiratory or nervous system dysfunction did not participate in the study. Each patient was randomly assigned to one of two groups; patients in Group S (n = 15) received CSEA, while those in Group E (n = 15) received only epidural anaesthesia.
All patients were premedicated with oral diazepam 10 mg and famotidine 20 mg, 2 h before their arrival in the operating room. In the operating room, monitoring of the electrocardiogram (ECG), arterial blood pressure (ABP) by sphygmomanometry, and the oxygen saturation of arterial haemoglobin (SpO2) by pulse oximetry were established in each patient after insertion of an intravenous (i.v.) cannula. Lactated Ringer's solution was infused at 10 mL kg−1 h−1 in all patients. An arterial cannula was also placed for the continuous monitor of ABP and for blood sampling. Each patient in Group S had a 19-G epidural catheter inserted through a 17-G Tuohy needle at the L2-3 interspace under local anaesthesia with lidocaine, followed by a spinal block (3% hyperbaric lidocaine solution 2 mL, to which epinephrine 200 μg was added) through a 27-G Whitacre needle at the L3-4 interspace. The epidural space was confirmed in the median approach with the loss of resistance method using saline 2 mL in a 5 mL glass syringe. Each patient in Group E underwent a similar procedure, except that they received an intradermal prick with a 27-G needle instead of a spinal block. Thus, every patient technically felt needle pricks twice on their back, once in each of the two different regions, to be blinded to which anaesthesia was received. The procedures were performed with the patient in a position whereby the contralateral side of their affected leg was dependent. Immediately after the epidural or spinal injection, the patient turned quickly into the supine position. Each patient then received epidural saline 10 mL (Group S) or lidocaine solution 2% 7-12 mL through the epidural catheter (after a 'test' injection of lidocaine 1.5% 3 mL, to which epinephrine 15 μg was added - Group E). In each patient, after confirming the onset and sufficient spread (up to T7 or a higher dermatome level) of the spinal or epidural anaesthesia, morphine hydrochloride 2 mg in saline 3 mL was injected into the epidural space, and a continuous epidural infusion of morphine (morphine hydrochloride 2 mg in lidocaine 0.5% 48 mL) was started using a balloon-infusion device (Infusor®; Baxter Healthcare, Deerfield, IL, USA) at 2 mL h−1.
Throughout surgery, each patient was sedated slightly with an infusion of propofol 3-5 mg kg−1 h−1. Patients spontaneously breathed oxygen 4 L min−1 through a mask. Additional epidural doses of lidocaine 2% were given as and when necessary during the surgery, e.g. if the patient complained of pain or moved because of pain. Hypotension (systolic ABP ≤ 80 mmHg) was treated with ephedrine 5 mg i.v., while bradycardia (heart rate (HR) ≤ 50 beats min−1) was treated with atropine 0.3 mg i.v. The patients were given oxygen 2 L min−1 through a nasal catheter when they had been returned to in the ward.
At the end of the operation and at 4, 8 and 12 h after the bolus injection of epidural morphine and once on the next day, an anaesthesiologist (who was blind to the type of anaesthesia each patient had received) observed and recorded the following variables: ABP, HR, respiratory rate (RR), arterial blood-gas analysis (BGA), sedation score (0: awake and alert; 1: awake but uncommunicative; 2: drowsy; 3: asleep; 4: comatose), 10 cm visual analogue scale pain scores (VAS: 0: pain free; 10: worst pain), nausea/vomiting scores (0: none; 1: moderate/treatment unnecessary; 2: severe/treatment necessary), and pruritus scores (as for nausea/vomiting scores).
Back in the ward, patients were given a diclofenac 50 mg suppository whenever they complained of pain and requested analgesics, and the time was recorded from the injection of epidural morphine to the first request for diclofenac. When the patients complained of nausea and/or vomiting, they were given a domperidone 60 mg suppository. Intravenous naloxone 0.1 mg was given incrementally if treatment with domperidone failed or if other severe adverse effects of morphine, such as respiratory depression or pruritus, were seen. In practice, this was not necessary (see Results).
Statistical analyses comparing those values between the two groups were made using a t-test for patients' characteristics; repeated-measure analysis of variance (ANOVA) for blood-gas analysis, ABP and HR; the U-test for VAS, VDS, nausea/vomiting scores, pruritus scores and sedation scores; and the χ2-test for the ratio of the patients who received diclofenac or domperidone. P < 0.05 was considered as significant.
There were no significant differences between the two groups in terms of patients' demographic data. The duration and type of surgery, the amounts of blood loss, crystalloid fluid infusion, and blood transfusion were also comparable (Table 1). ABP and HR did not show significant intergroup differences throughout the study. RR and arterial oxygen (PaO2) and carbon dioxide tension (PaCO2) were similar between the two groups (Fig. 1).
There were no significant intergroup differences in VAS (Fig. 2). The number of patients requiring diclofenac was five in Group S and one in Group E (Table 1), but there was no significant difference between the groups in the requirement for diclofenac (number of doses or time before the first dose). Nausea/vomiting scores and pruritus scores were also comparable (Fig. 3). Four patients in Group S and five patients in Group E were given domperidone (Table 1, not significantly different). No patient required naloxone to antagonize any severe adverse effects of morphine.
One patient in Group S was excluded from the study because a misplacement of the epidural catheter was suspected. Although the analgesia provided by spinal anaesthesia was sufficient enough to start the surgery, the patient complained of severe pain and could move her legs in the middle of her surgical operation, and several incremental epidural injections of lidocaine 2% failed to reduce the pain. It was impossible intraoperatively to detect catheter misplacement by giving an epidural 'test dose' after establishment of the spinal anaesthesia. The patient received an intramuscular injection of pentazocine 15 mg, which relieved the pain.
Since a drug flux through the meninges has been found to increase after the meningeal puncture in both in vitro and in vivo animal studies, we became concerned that the incidence of adverse effects due to epidural morphine, such as respiratory depression, nausea/vomiting and pruritus, might be raised in patients undergo CSEA when meningeal puncture is present. However, in contrast to our hypothesis, in this study population the patients receiving epidural morphine after meningeal puncture for spinal anaesthesia did not show any increased incidence of adverse events in comparison with those receiving it after epidural anaesthesia.
Epidural morphine mainly acts by penetration across the meninges and partly by systemic absorption through the vascular tissues . Subarachnoid pressure is considered to be higher than epidural pressure, so that fluid flux from the epidural space to the subarachnoid space is normally minimal, and 2-4% of epidurally administered morphine appears in the CSF in the absence of meningeal puncture [10,11]. In fact, the minimal effective dose of intrathecal morphine has been reported to be 2-4% of the minimal effective dose of epidural morphine [12,13]. From the reported data of morphine flux through a meningeal hole in a CSEA model , Eldor and colleagues  calculated the spinal: epidural ratios of morphine amounts as: 0.4, 2.0 or 11.1% when a 27-G Whitacre, 24-G Sprotte or 18-G Tuohy needle, respectively, was used to puncture the meninges of monkeys. There is also a report with consistent results in sheep . While extrapolation of such results obtained from animal studies can be criticized, we suppose that the diffusion of morphine across intact meninges was so much greater than the morphine flux through the meningeal hole. That is, the influence of the small meningeal hole on the morphine concentration in the CSF was rather trivial because we used a 27-G Whitacre needle to puncture the patients' meninges.
The main limitation of the present study was that we did not obtain CSF samples to enable us to compare the concentrations of morphine between Groups S and E. Obtaining samples of CSF in the current study nevertheless would have been beset with technical difficulties. A lumbar tap, for instance, would make a hole in the meninges, which would almost certainly increase the morphine influx into the CSF in both groups. Moreover, puncture of the meninges at a higher spinal level away from the site of drug administration carries greater risks to cause, for example, spinal injuries in clinical practice. However, the CSF analysis seems unlikely to a great necessity at least clinically, since no significant intergroup differences in the incidence of adverse events were seen in the present study. Another flaw of this study is the small number of patients who participated. Power analyses (SamplePower®; SPSS, Inc., Chicago, IL, USA) revealed that a Type II error would occur over 58% given the likelihood of a Type I error was 5% as adopted in the statistical analyses of the present data, and that a population of several hundred times greater would be needed to precipitate the occurrence of Type II error into an acceptable range. Nevertheless, this issue should not diminish the value of the current study, because it is the first systematic clinical study to have examined the effect of a meningeal hole on epidural morphine, particularly with regard to the incidence of post-operative adverse events.
Recently, CSEA has gained widespread acceptance because the spinal anaesthesia provides an intense and reliable block with a rapid onset, and the succeeding epidural anaesthesia both increases the level of anaesthesia and prolongs its duration. In addition, the epidural catheter offers an effective route for the provision of postoperative pain relief using local analgesics and opioids. However, there have been several reports of respiratory depression caused by epidural narcotics or local analgesics [7-9]. In those cases, a 'needle-through-needle' technique was used. The technique is considered to increase the possible migration of the epidural catheter  because the meningeal hole is right at the tip of the Tuohy needle. Moreover, the presence of established spinal anaesthesia makes the epidural test dose useless as a way of detecting intrathecal migration of the epidural catheter. In the present study, we did not use the needle-through-needle technique, making it unlikely that intrathecal migration of the epidural catheter would occur.
In conclusion, the incidence of adverse events caused by epidurally administered morphine was no higher after CSEA than after epidural anaesthesia alone. We thus consider that the concentration of morphine in the CSF was largely determined by the extent of diffusion across the intact meninges, with the morphine flux through the meningeal hole being trivial in comparison.
This work was supported in part by a Grant-in-Aid for Scientific Research (11307027) from the Ministry of Education, Science, Sport and Culture, Japan.
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Keywords:© 2002 European Academy of Anaesthesiology
ANAESTHESIA, anaesthesia conduction, anaesthesia spinal, anaesthesia epidural; CENTRAL NERVOUS SYSTEM, meninges; INJECTIONS, injections spinal; injections epidural; OPIOIDS, morphine; PUNCTURES, SPINAL PUNCTURE