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*Division of Anesthesiology and Liver and Multivisceral Transplant Center, University of Modena and Reggio Emilia, Italy
Address correspondence and reprint requests to Lesley De Pietri, c/o Division of Anesthesiology, University of Modena and Reggio Emilia, # 71 via del Pozzo, 41100 Modena, Italy. Address e-mail to lesley.depietri{at}tin.it.
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Abstract |
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Introduction |
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Postoperative coagulation disturbances related to liver surgery, even in patients with normal preoperative coagulation undergoing uncomplicated hepatectomy (3), raise concerns about the safety of postoperative analgesia administered through an epidural catheter. Coagulation changes after liver surgery and the possible increased risk of bleeding complications, including spinal hematoma (4,5), have limited the use of epidural analgesia. The extent of the liver resection may affect the magnitude and duration of the postoperative coagulation disturbances and makes the proper timing of epidural catheter removal important (6,7).
A single dose of intrathecal morphine, administered immediately before surgery, can be a useful alternative method to obtain safe and prolonged postoperative analgesia when an epidural catheter is contraindicated. This prospective, randomized study compared, after liver resection and over a 48-h follow-up period, analgesia and side effects of a single dose of intrathecal morphine combined with morphine patient-controlled analgesia (PCA), with a continuous epidural naropine infusion supported by morphine PCA.
The aim of this study was to evaluate the noninferiority of analgesia (monitored by a visual analog scale [VAS]) of the intrathecal technique compared with the continuous epidural infusion.
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Methods |
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Blood tests, including platelet count, International Normalized Ratio (INR), activated partial thromboplastin time (aPTT), and fibrinogen were determined before surgery, immediately after surgery, and daily until values returned to within the normal range.
Patients with bleeding diathesis (essential thrombocythemia, idiopathic thrombocytopenic purpura, von Willebrand disease, and hemophilia A and B), neurological dysfunction (multiple sclerosis, subacute myelo-opticoneuropathy or preexisting lower limb neurological deficit), significant respiratory diseases, recent systemic or local infections, history of drug use, or treated with opioids because of chronic pain were excluded from the study.
According to institutional policy, we introduced or removed an epidural catheter when INR was <1.5, aPTT was <1.24, and platelet count were more than 100 x 109/L. We treated our patients according to the recommendations based on a small patient series by Schumann et al. (8), although American Society of Regional Anesthesia Guidelines on Coumadin do not apply to the patients on whom we performed a neuroaxial block because our patients' postoperative coagulation derangement may have had multiple etiologies. Patients were randomly allocated to two groups by a computer-generated list: the epidural analgesia group (EP group; n = 25) and the intrathecal analgesia group (IN group; n = 25). All patients had an IV line connected to a PCA device with IV morphine to improve quality of analgesia. A VAS was used for patient pain assessment.
All patients were premedicated with diazepam 0.1 mg/kg orally 1 h before the induction of anesthesia. They were monitored with electrocardiogram, pulse oximetry, capnography, inspired and expired oxygen, anesthetic vapor concentration, systemic (radial) arterial blood pressure, and central venous pressure through the right jugular vein.
In the EP group, an epidural catheter was inserted at the T9-10 or T10-11 level using the loss-of-resistance technique after local anesthesia. Lidocaine 2% 2 mL, plus 2 mL after 5 min, was used to exclude the subarachnoid placement of the catheter. Ropivacaine 0.2% 6–8 mL and morphine 2 mg were injected before the induction of anesthesia.
In the IN group, dural puncture was performed at the L3-4 or L4-5 level with a 27-gauge Whitacre spinal needle after local anesthesia. After return of clear, free-flowing cerebrospinal fluid, morphine 0.2 mg in 0.9% saline solution (2.5 mL) was injected.
Thiopental sodium 3–5 mg/kg, fentanyl 2–3 µg/kg IV, droperidol 2.5 mg, and vecuronium 0.1 mg/kg were used for the induction of anesthesia and tracheal intubation. Anesthesia was maintained with desflurane 4%–5% in a 50% oxygen-air mixture with minimal flow ventilation, and muscle relaxation was obtained with vecuronium 0.05 mg/kg. Whenever the arterial blood pressure or heart rate increased by more than 30% in the IN group, that depth of anesthesia was judged inadequate and hemodynamic control was ensured with incremental doses of IV fentanyl (50–100 µg). Intraoperative analgesia in the EP group was provided with continuous epidural infusion of ropivacaine 0.2% (5–7 mL/h). A decrease in systolic arterial blood pressure by more than 30% less than the preoperative value was corrected with 500 mL of colloid, with IV ephedrine 5 mg, or with both. Decreases in heart rate to less than 50 bpm were treated with IV atropine 0.25 mg. Total duration of the operation, intraoperative consumption of analgesics, and the time of tracheal extubation were also recorded.
The weight of the resected specimen was measured by weighing scales after liver resection, and correlations among weight of resected liver, platelet count, INR, aPTT, and fibrinogen were also investigated.
After surgery, patients were admitted to the intensive care unit (ICU) for overnight observation or returned to the ward, according to the preoperative condition, the extent of the liver resection, and the occurrence of intraoperative critical events, such as major bleeding, cardiovascular imbalance, and respiratory dysfunction.
In the EP group, epidural analgesia was continued after surgery with an epidural infusion of ropivacaine 0.2% 5–7 mL/h. In both groups, patients were allowed to receive 1-mg boluses of morphine from an IV PCA pump, with a lockout time of 5 min and a 4-h dose limit of 20 mg. No background infusion of morphine was used.
Quality of analgesia was reported by the patient as a pain score on a graded-scale VAS (0–100 mm). Patients with no pain relief or insufficient analgesia (VAS >40) at 30 min after tracheal extubation were excluded from the study, and another analgesic technique was implemented. Patients were taken to the ward or to the ICU when their Aldrete score was 10 and arterial blood gas values were normal (Paco2 <50; pH = 7.35–7.45).
All patients received oxygen via a facemask with 4 L/min of O2 for at least 4 h after surgery. Noninvasive arterial blood pressure, heart rate, respiratory rate, and pain scores were recorded at 4, 8, 12, 24, 36, and 48 h after surgery using VAS at rest and when coughing. Sedation was assessed on a 5-point scale (I = completely awake with the eyes open; II = drowsy, closed eyes; III = asleep but responding to verbal commands; IV = asleep but responding to touch or pain; V = not responding). The postoperative clinical monitoring of the patients and the evaluation of VAS were managed by investigators blinded to the analgesic technique used.
Four hours after surgery, arterial blood gas evaluation was performed to detect any possible respiratory depression (Paco2 >50 mm Hg or respiratory rate <8 breaths/min). Naloxone 0.1 mg IV was administered if the patient was drowsy, respiratory rate was less than 8 breaths/min, or Pco2 >50 mm Hg. Patients were excluded from the study if they required sedatives or opioids other then IV PCA morphine. Morphine consumption was recorded in all patients at 4, 8, 12, 24, 36, and 48 h after surgery. Duration of intrathecal or epidural analgesia was defined as the time from patient randomization in the operating room to the time of the first delivery of a morphine bolus from the PCA device.
Side effects such as nausea, vomiting, psychomimetic effects, neurological disorders, pruritus, sedation, respiratory depression, and hypotension were evaluated. Patients were evaluated for postdural puncture headache and radicular back pain; muscle weakness and sensory deficit, as early signs of spinal cord compression caused by hematoma, were also evaluated.
Where appropriate, results were presented as mean (± sd). Patient characteristics, duration of surgery, intraoperative fentanyl, time to extubation, time to discharge to the ward, and postoperative morphine consumption were analyzed by unpaired Student's t-test. The correlation between variables was assessed by linear regression analysis. The Mann-Whitney rank sum test was used to analyze VAS and sedation score. P < 0.05 was considered significant. The primary aim of this study was the comparison between intrathecal and epidural analgesia after liver resection, according to VAS. Before starting the study, an estimate for expected standard deviation was entered in the calculation for power analysis and sample size. According to GraphPad StatMate (GraphPad Software, San Diego, CA), a sample size of 25 patients in each group has a 80% power to detect a difference between (VAS) mean values of 2.43 (not less) with a significance level (
) of 0.05. With NCSS, Number Cruncher Statistical System, and PASS, Power Analysis and Sample Size Program, (NCSS, Kaysville, UT), a poststudy power analysis was computed, and a noninferiority hypothesis of intrathecal morphine versus epidural naropine was tested using the Mann-Whitney nonparametric adjustment for a uniform distribution. To test noninferiority or equivalence, it is required to define the margin of equivalence (the largest difference that is not of practical significance), and a value of 10 mm was chosen because statistically significant changes of 10 mm in VAS scores are also of clinical significance in a variety of psychophysiological measurements in children (9), adults, and elderly subjects, whereas small differences between VAS scores may be statistically significant but clinically meaningless (10). Therefore, it was accepted that a VAS difference of more than 10 mm between the 2 treatments (mean values) could eliminate the hypothesis of noninferiority of equivalence of intrathecal morphine versus epidural naropine.
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Results |
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Tuohy needle insertion for epidural catheter placement required multiple attempts in 4 (16%) patients compared to 2 (8%) patients when dural puncture was performed. No bleeding was observed during needle or catheter placement. Fourteen patients (28%) were admitted to the ICU: six (24%) from the IN group and eight (32%) from the EP group (P = not significant).
The postoperative mean INR value was 17.4% higher than the mean preoperative value after minor liver resections and 30% higher after major liver resections (P < 0.05).
The daily mean changes in INR value with respect to the mean preoperative value were significant up to postoperative Day (POD) 5 for both types of liver resection (Fig. 1A). The mean INR never reached 1.3 after minor liver resections. INR was highest on POD1 in all patients (P < 0.05) at 1.49 ± 0.26 (close to the accepted threshold value for epidural catheter removal; INR = 1.5) after major resections and at 1.02 ± 0.14 after minor resections. The epidural catheter was never removed before POD4 (when the mean INR value was less than 1.3) after major liver resections.
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The mean platelet count was less than the mean preoperative level up to POD5 (P < 0.05) and was smallest on POD3 both after minor and major liver resection (Fig. 1B). Mean fibrinogen levels and mean aPTT values were in the normal range throughout the observation period, and no significant changes were observed.
Mean INR value and weight of the resected liver parenchyma were positively correlated on POD1 (r = 0.52156) (Fig. 2), but such a correlation was not found with the weight range of the minor liver resections.
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A significantly larger mean dose of fentanyl was used in the in group compared with the Ep group. Tracheal extubation time and recovery room observation time were significantly shorter in the EP group than in the IN group (Table 1).
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Moderate to severe pain (VAS >30 mm) was never observed either at rest or when coughing during the first 48 h after surgery in both groups (Fig. 3, A and B).
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The time to first morphine requirement was significantly longer in EP-group patients. PCA morphine consumption was similar in both groups up to 12 h after surgery; there were significantly more PCA morphine boluses in the IN group (Table 2).
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PCA morphine was required by 14 of 25 (56%) patients in the EP group and 23 of 25 (92%) patients in the IN group (P < 0.05). The mean total amount of morphine used during the first 48 h was larger in the IN group than in the EP group (P < 0.01) (Table 2).
Three patients in the EP group (12%) required increased fluid support to treat hypotension. Five of 25 patients (20%) in the IN group had a sedation score of III after tracheal extubation. No differences in sedation were observed between the 2 groups beyond 30 min after tracheal extubation. No hypercapnia or hypoxia were observed. Vomiting was 4% in both groups, pruritus was 0% in the EP group and 16% in the IN group (P < 0.05), and nausea was 4% in the EP group and 16% in the IN group (P < 0.05). No patient had postdural puncture headache, and no spinal hematoma occurred (95% confidence interval, 0%–13.71%).
According to the poststudy power analysis and the test of noninferiority performed with the NCSS-PASS software package, group sample sizes of 25 and 25 achieved a power >95% at 12, 24, and 48 h, at rest and when coughing, to detect noninferiority of VAS in the IN group versus the EP group, choosing 10 mm to determine a margin of equivalence (10 mm = true difference between the means) and using a one-sided Mann-Whitney test, assuming that the actual distribution is uniform. The significance level () of the test was 0.025. These results can be presented in another way saying that the 95% confidence interval of the treatment effect (the true differences between the means) at rest and when coughing, at 12, 24, and 48 h, lies inside the margin of equivalence.
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Discussion |
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PCA with IV morphine and epidural PCA, with epidural local anesthetic and opioids, are two major advances in management of pain after major abdominal surgery (14). Nevertheless, the possibility of using an alternative technique to the epidural route, which guarantees a relatively long period of analgesia while avoiding the placement of an epidural catheter, seems interesting. Intrathecal morphine has become popular in recent years; its analgesic effect has been proven after most types of surgery (15). From 0.1 to 0.2 mg of intrathecal morphine is regarded as the optimal analgesic amount in laparoscopic abdominal and pelvic surgery, whereas it is recommended to avoid a larger dose because side effects increase and quality of analgesia does not (16). However, Devys et al. (17) used an intrathecal dose of 0.3–0.4 mg of morphine to obtain good postoperative analgesia in abdominal surgical procedures not including liver resections. We chose a smaller dose of intrathecal morphine because large reductions of liver parenchyma may decrease drug clearance and disturb drug metabolism (18). Abnormal drug metabolism may lead to excessive sedation, respiratory depression (19,20), and possibly hepatotoxicity1. This study shows that a small single dose of intrathecal morphine, supported by IV PCA morphine, can provide good postoperative analgesia for the first 48 hours after liver resection. Patients treated with intrathecal morphine had low VAS scores and rarely required any IV PCA morphine in the first 12 hours after surgery. VAS scores on POD2 were low in both groups, but the mean value of the total IV PCA morphine consumption was significantly higher in the IN group compared to the EP group.
The infrequent incidence of nausea and vomiting in our study could be explained by preoperative use of droperidol. Nausea and vomiting are the main side effects of intrathecal morphine, reported by other authors (21) in approximately 50% of patients treated with spinal opioids. However, we observed less vomiting. Nausea and pruritus were more frequent in the IN group patients, who had intrathecal morphine and used more IV PCA morphine. We did not use intrathecal local anesthetic in addition to morphine in order to avoid the wide sympathetic block related to the high subarachnoid anesthesia required for a subcostal incision, and also because the intraoperative analgesic benefit of adding bupivacaine intrathecally was not demonstrated by Motamed et al. (22). The larger intraoperative administration of opioids in the IN group may be explained by the slow onset of the morphine action (17) and by the absence of the preemptive analgesic component provided by the anesthetic used in the EP group. The larger intraoperative amount of opioids may also explain the prolonged time to tracheal extubation and the higher sedation scores observed. The anesthesiologist was not blinded to the type of analgesia administered during surgery, and a bias may have been introduced.
Although higher sedation scores were reached in 12% of patients from the IN group 30 minutes after removal of the tracheal tube, the time in the recovery room was not prolonged.
Respiratory rate and Paco2 were not different between groups. All patients received oxygen 35% in air for a few hours in the early postoperative period. Respiratory depression was not observed. A few studies demonstrated that the combined use of intrathecal and IV morphine is safe, and respiratory depression rarely occurs (19,20).
Cirrhotic patients with compromised liver function or patients who may develop postoperative coagulopathy after a liver resection could benefit from the intrathecal administration of morphine, which avoids the need of an epidural catheter and the risk of its removal. In almost all patients who had surgery for major liver resection, an epidural catheter was in situ during the time of coagulation dysfunction. Large clinical trials, which have not been performed (14), are required to guide anesthesiologists in the choice of epidural analgesia or intrathecal morphine. Because complications caused by spinal bleeding are so unusual (1:150,000 and 1:220,000 in epidural anesthesia and intrathecal anesthesia, respectively) (6), it is not an easy task to quantify the risk in patients who need a liver resection. Obviously, the design of this study and the sample size do not allow evaluation of the safety of these techniques. Careful clinical and laboratory monitoring and frequent neurologic testing performed after dural puncture for intrathecal morphine, or after insertion and removal of an epidural catheter, are mandatory in this patient population (23).
This study does not try to prove that one treatment is better than another but, rather, aims to show that any difference is of no practical consequence. The test of noninferiority, a subset of the general approach to equivalence statistical analysis, was chosen because to run a standard statistical test and to conclude that the two treatments are equivalent, if the difference is not statistically significant, is an invalid approach and leads to invalid conclusions (24). The question is not whether the two treatments lead to different outcomes (there will always be some difference when two treatments are used) but whether the outcomes differ enough to be clinically or scientifically relevant. Therefore, to test equivalence or noninferiority, we had to define, based on literature and clinical experience, a range of treatment effects (mean VAS) that may be considered scientifically or clinically trivial (a 10-mm margin of equivalence). This decision is not about statistics and must be made on scientific or clinical grounds.
In conclusion, intrathecal morphine gives effective control of postoperative pain after liver surgery. It can be used as a valid alternative to continuous epidural analgesia, supported by IV PCA morphine, when the insertion or the removal of an epidural catheter may be considered unsafe because of actual or potential coagulopathy. Further studies with large-scale trials are required to assess the safety of the intrathecal technique compared with continuous epidural analgesia in liver surgery.
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Footnotes |
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Accepted for publication November 9, 2005.
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This article has been cited by other articles:
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  A. Rudin, J. F. Lundberg, M. Hammarlund-Udenaes, P. Flisberg, and M. U. Werner Morphine Metabolism After Major Liver Surgery Anesth. Analg., June 1, 2007; 104(6): 1409 - 1414. [Abstract] [Full Text] [PDF]
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