Slappendel, Robert MD; Weber, Eric W. G. MD; Dirksen, Ris PhD, MD; Gielen, Mathieu J. M. PhD, MD; van Limbeek, Jacques PhD, MD
Many studies [1-4] have shown that the intrathecal administration of morphine provides excellent postoperative pain relief in major orthopedic surgery. However, the use of spinal morphine was often associated with unpleasant side effects, such as urinary retention, pruritus, and postoperative nausea and vomiting (PONV) . Moreover, early studies reported late respiratory depression in some cases, but intrathecal doses of morphine as large as 2.5 mg were used [4,6,7].
The water-soluble nature of morphine contributes to the longevity of its analgesic effect and allows the rostral ascent [8,9] that underlies the risk of late respiratory depression. The cerebrospinal fluid opioid concentration is dose-dependent , as are both analgesia and respiratory depression . Profound and prolonged respiratory depression was reported by Bailey et al.  after an intrathecal dose of 0.6 mg, and minimal, yet statistically significant, respiratory depression occurred even after the administration of 0.15 mg of morphine .
We hypothesized that even smaller doses might further minimize side effects but were unsure whether these doses would offer the desired analgesic effect. Therefore, we performed a randomized, double-blinded trial to establish the optimal dose of intrathecal morphine that effectively relieves pain after total hip surgery and to evaluate whether the smallest effective dose indeed coincides with minimized side effects.
The study was approved by the ethical committee of our hospital, and written, informed consent was obtained from all patients. One hundred forty-three consecutive patients (ASA physical status I-III) scheduled for total hip surgery during intrathecal anesthesia were included in the study in a prospective, randomized, double-blinded manner.
All patients were premedicated with 5, 7.5, or 10 mg of midazolam (0.1 mg/kg) orally 1 h before spinal anesthesia. Intrathecal anesthesia (27-gauge Quincke needle) was produced by administering 20 mg of bupivacaine plus morphine dissolved in 4 mL. Patients were allocated to four groups: Group I = 0.025 mg, Group II = 0.05 mg, Group III = 0.1 mg and Group IV = 0.2 mg of morphine. The delivered morphine dose was known to the pharmacist in case of an adverse event.
The anesthesiologist administered 1 mg of midazolam at the minimal interval of 5 min until the patient indicated that the desired sedation was achieved. Noninvasive blood pressure, heart rate (electrocardiogram), oxygen saturation (SpO2), and respiratory frequency were continuously monitored during anesthesia and in the intensive care unit during the first 24 h after surgery.
In the postoperative period, all patients were treated with the nonsteroidal antiinflammatory drug nabumeton 1500 or 2000 mg orally (first dose 1 h before surgery), one dose a day (30 mg/kg). If nabumeton was contraindicated, oral paracetamol was given (70 mg/kg six times a day). Pain was evaluated using visual analog scores (VAS). VAS ranges from 0 to 10, with 0 = no pain and 10 = most severe pain. For each individual patient, we assessed the highest VAS score in the 24-h period and total pain VAS scores (area under the curve of VAS scores in the 24-h period). If pain was present, morphine was administered IV by a patient-controlled analgesia (PCA) pump (Braun, Melsungen, Germany). The settings of the PCA pump were baseline 0.0 mg/h, bolus dose 1.0 mg, bolus interval 5 min, maximum 30-mg dose per 4 h.
PONV was treated according to the standard protocol. The first step was 10 mg of metoclopramide IM, followed by 10 mg of metoclopramide IM after 1 h when necessary. If symptoms persisted, 1.25 mg of droperidol was given, and finally 5 mg of tropisetron, both IV. Each step was initiated by patient request. The minimal interval between each step was 1 h. PONV was evaluated from the following data: the patient's subjective feeling (the presence or absence of subjective nausea), the patient's request to be treated with an antiemetic, and the actual consumption of antiemetics.
Other side effects scored in the postoperative period included respiratory depression (defined as <10 breaths/min and arterial blood gas showing acidosis and hypercarbia), itching (by specific inquiry and recording of the antipruritic medication promethazine), urinary retention (defined as absence of spontaneous voiding 7 h after surgery and volume at catheterization of >400 mL), hypotension (>25% reduction of preoperative mean arterial blood pressure), and bradycardia (heart rate <40 bpm). The presence or absence of any of these side effects was noted at 3-h intervals during the 24-h observation period. The medication for treatment of any of these side effects was also registered at the same intervals during the 24-h observation period.
Analysis of interval scored data was performed by using analysis of variance techniques or t-tests (paired or unpaired depending on data structure). Nonparametric techniques (Kruskall-Wallis) were used when necessary. Post hoc analysis was performed by using the Duncan test with significance level of P = 0.05. Proportions were analyzed with chi squared statistics and Fischer's exact test. The alpha level for all analysis was set as P = 0.05. Data are reported as means +/- SD.
Demographic data and intraoperative factors are given in Table 1. The four groups did not differ in age, height, weight, or gender. The patient groups were also not different in any other characteristics, e.g., the preoperative use of beta-blockers, the magnitude of blood loss during surgery, the percentage of patients who required sedation during surgery, use of cementation, and concurrent decrease in arterial blood pressure.
The VAS scores were <3 in the postoperative period in all patients in all four groups (Figure 1). The highest VAS score of each individual patient in the 24-h period and total pain VAS scores area under the curve of VAS scores in the 24-h period were highest for Group I (Figure 2). These higher VAS scores were associated with a significantly higher consumption of systemic morphine in Group I. The mean use of systemic morphine administered by the PCA infusion pump was 23.7, 17.8, 10.9, and 9.9 mg in Groups I-Iv, respectively (Group I different from Groups III and IV; P < 0.01).
The incidences of PONV and urinary retention and consumption of antiemetics were not different among the groups (Figure 2). The mean number of antiemetics used in all patients was 1.2 +/- 1.1, 1.2 +/- 1.3, 1.1 +/- 1.2, and 1.3 +/- 1.2 in Groups I-IV, respectively. PONV occurred at a higher overall incidence during the first 24 h after surgery in women than in men (77% vs 44%; P < 0.05).
No patient had a respiratory rate <10 breaths/min. Arterial oxygen saturation was monitored continuously. The SpO2 of all patients increased when oxygen was administered (3 L/min by nasal catheter) (Figure 3). Arterial blood gases sampled at such desaturations <90% did not show acidosis.
The incidence of itching was dose-related, as was the incidence of request for antipruritic medication.
Heart rates decreased 6%-16% in all groups after anesthesia, returning to baseline levels 12 h postoperatively. The incidence of hypotension was 48.6%, 56.8%, 54.0%, and 73.5% in Groups I-IV, respectively (significantly different for Group III and IV; P < 0.05).
The major finding of this study is that the optimal dose of intrathecal morphine after total hip surgery is as low as 0.1 mg (Group III). This dose resulted in excellent pain relief and a low demand for systemic morphine in the first 24 h after surgery. The larger dose of 0.2 mg of intrathecal morphine did not produce better analgesia; moreover, the incidence of itching was higher and the degree of hypotension more profound and longer lasting. Intrathecal morphine doses <0.1 mg were less effective.
Many studies have evaluated the effects of intrathecal morphine for postoperative pain relief after surgery [1-4]. These studies [3,4,6] used larger doses of morphine (up to 2.5 mg) or included patients undergoing different types of surgery . In our study, the site and type of surgery was restricted to total hip replacement. Adequacy of morphine is reflected by VAS scores and systemic morphine demand from a PCA pump. After the 0.1-mg intrathecal morphine dose, postoperative pain was effectively relieved during the first 24 h.
PONV showed similar overall incidences in all groups. In this study, we confirm the high incidence of PONV after orthopedic surgery [13,14]. PONV was not induced by these small doses of intrathecal morphine, as found in our earlier study .
A major concern with intrathecal morphine is respiratory depression. Intrathecal morphine has been shown to cause significant dose-related decreases in SpO2 in human volunteers after doses of 0.2-0.6 mg . The time to depression of the slope of the ventilatory response to carbon dioxide curve show peak respiratory depressant effects after lumbar intrathecal morphine administration that concur with the moment of highest cervical cerebrospinal fluid concentrations found in another study [8,9]: i.e., approximately 4-5 h after injection. After the smallest dose evaluated in this study (0.2 mg), mild respiratory depression effects were found under laboratory conditions . Whether similar changes in respiration were present in our clinical study is unclear. Likewise, others have failed to identify signs of respiratory depression in clinical conditions, provided that the intrathecal dose of morphine is restricted to <0.15 mg . The inability to correlate such mild respiratory depressant effects with small intrathecal doses of morphine may well relate to the fact that a decrease in SpO2 is a common phenomenon in elderly patients after both general and intrathecal anesthesia . Not only intrathecal morphine, but also a whole array of anesthetic drugs, can contribute to respiratory depression. In a recent study, eight cases of serious respiratory depression were detected from the charts of approximately 1600 patients who had received systemic morphine by PCA . Our elderly patients were premedicated and sedated with midazolam, IV morphine was administered by PCA pump, and systemic antiemetic drugs (droperidol and/or metoclopramide) were used in the postoperative period. Yet, the magnitude and incidence of decreases in oxygen saturation were similar to those reported in another postoperative study in elderly patients not exposed to intrathecal morphine . The key question is whether respiration after a total hip procedure is more affected when intrathecal morphine is used than when it is not. We show that the mild respiratory depressant effects after the administration of 0.2 mg of morphine intrathecally represent an effect at a dose twice as large as that we defined as optimal. Any anesthesia technique affects respiration, and one can always argue that very large numbers of patients must be studied to be sure that there is no respiratory depression after an intrathecal dose of 0.1 mg of morphine. Monitoring in intensive care units is not required because of the administration of 0.1 mg of intrathecal morphine, even in the opiate-naive, elderly patient. Another dose-related intrathecal morphine side effect is itching, but it is easy to manage with a single dose of promethazine when necessary.
Patients in all groups showed, as expected, a decrease of heart rate and blood pressure after intrathecal anesthesia with bupivacaine and morphine . Only one patient in Group I (the smallest dose of intrathecal morphine) had bradycardia. The decrease in blood pressure after the administration of .2 mg of intrathecal morphine was more profound and longer lasting. In our earlier study , we found that 16% of patients developed bradycardia when the effect of intrathecal bupivacaine without morphine subsided in the postoperative period.
In summary, the intrathecal dose of 0.1 mg of morphine added to bupivacaine provides excellent postoperative analgesia for total hip surgery. The larger doses of intrathecal morphine used earlier [2,4,6] (>0.2-2.5 mg) were more effective and can cause unnecessary and dangerous side effects. We believe that 0.1 mg of intrathecal morphine added to bupivacaine provides excellent postoperative analgesia in the first 24-h, assists in hemodynamic stability, and does not cause significant respiratory depression. Finally, after this intrathecal morphine dose, there seems to be no need for routine intensive care-based recovery, even in elderly patients.
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