Cholinergic mechanisms are involved in the control of nociceptive input in the central nervous system. Several studies have demonstrated that intrathecal (IT) neostigmine produces analgesia without neurotoxicity in animal and human volunteers (1–4). Chiari et al. (4) reported that nicotinic acetylcholine receptor agonists may provide therapy for neuropathic pain syndromes in women by the noradrenergic interaction from spinal cholinergic activation. However, IT neostigmine is associated with dose-related adverse effects, especially nausea and vomiting, and this restricts its clinical usefulness. Therefore, techniques that potentiate the analgesic effects of IT neostigmine, allowing for a reduction in its subarachnoid dosage without increasing its side effects, are of interest. Previous studies have demonstrated that the combination of IV ketamine or fentanyl and IT neostigmine might provide prolonged postoperative analgesia compared with IT neostigmine alone (5).
Dexamethasone, a corticosteroid with strong antiinflammatory effects, provides postoperative analgesia (6–8), prevents nausea and vomiting in patients undergoing chemotherapy (9–12), and reduces post- operative nausea and vomiting (PONV) (8,13–16). However, prophylaxis with dexamethasone in IT neostigmine-related analgesia, nausea, and vomiting has not been reported.
The aim of the present study was to determine whether a combination of IV dexamethasone and IT neostigmine would enhance the analgesic effect of IT neostigmine and reduce its adverse effects of nausea and vomiting under spinal tetracaine anesthesia.
The study protocol was approved by the medical ethics committee of our hospital. Sixty male ASA I patients scheduled for inguinal herniorrhaphy using spinal anesthesia were included in this study after informed consent was obtained. The exclusion criteria included known allergy or contraindication to any of the test drugs or spinal anesthesia (e.g., coagulation defects, infection at the puncture site, or preexisting neurological deficits in the lower extremities). This study was conducted in a randomized, double-blinded fashion, with randomization being performed by sealed envelope assignment. All drug solutions were prepared by an anesthetist who was not involved in the administration of anesthesia or in the observation of the patients; thus, both the observer and the patients were blinded to the patient group assignment.
None of the patients received any premedication. They were randomly assigned into either the placebo group (Group P) or the dexamethasone group (Group D). The patients in Group P received IV 2 mL saline, and those in Group D received IV 10 mg dexamethasone before spinal anesthesia. After the administration of IV medication, spinal puncture was performed at the L3-4 interspace with a 25-gauge Quincke needle by using a paramedian approach with the patient in the lateral recumbent position. The spinal drugs were given over 30 s. Both groups received 15 mg tetracaine ( Tetracaine lyophilized crystals, 20-mg vial; Kyorin Pharmaceutical Co Ltd, Tokyo, Japan) and neostigmine 100 μg in 1.5 mL D10W (neostigmine methylsulfate, 0.5 mg/mL vial; Sintong Pharmaceutical Co, Taoyuan, Taiwan). Immediately after the administration of the spinal drugs, the patients were placed horizontally in the supine position and were maintained in the same position throughout surgery. All patients were given 500 mL of compound sodium lactate solution as a circulatory preload followed by infusion at 6–10 mL · kg−1 · h−1. Intraoperative IV sedation was provided with midazolam (1–5 mg).
Arterial blood pressure was monitored every 3 min for the first 15 min after the IT drug administration, and then every 5 min thereafter. Patients were also monitored with electrocardiography and pulse oximetry. Incremental doses of ephedrine were given to those patients whose systolic arterial blood pressure decreased to <90 mm Hg. Bradycardia (<50 bpm) was treated with IV atropine (0.5 mg). Nausea and vomiting were treated with metoclopramide (10 mg) supplemented with IV droperidol (1–2.5 mg). Rescue antiemetics were given if vomiting occurred more than once, for nausea lasting more than 10 min, or at the patient’s request. The treatment was repeated if necessary.
The severity of postoperative pain was measured with a 10-cm visual analog scale (VAS) (0 = no pain, 10 = the worst possible pain) during coughing or movement, at 4-h intervals, or whenever the patient requested analgesia. The 24-h VAS score reflected the patient’s assessment of the total pain experience for the previous 24 h after the IT drug administration. Postoperative analgesia was provided by IM diclofenac 75 mg ( Voltaren®; Roche, Basel, Switzerland) if the VAS score was 4 or more. If necessary, diclofenac administration was repeated 12 h after the previous injection.
The duration of complete analgesia was measured from the time of drug administration to the time when the VAS pain score was more than 0. The time of the administration of the first dose of diclofenac for postoperative pain and the number of diclofenac administrations were also recorded. The duration of motor block was recorded from the time of drug administration to the time when patients were able to lift their legs above the bed. The incidence of adverse effects such as nausea, vomiting, dizziness, anxiety, and pruritus was evaluated by a “yes” or “no” survey. Nausea was defined as a subjectively unpleasant sensation associated with the awareness of the urge to vomit; vomiting was defined as the forceful expulsion of liquid gastric contents. Retching (defined as vomiting movements without expulsion of gastric content) was considered vomiting. Respiratory depression was defined as a respiratory rate <10 breaths/min. All evaluations were performed and recorded at 4-h intervals (except during sleep) for 24 h after IT drug administration.
The sample size (30 patients in each group) was calculated to detect a prolongation of postoperative analgesia of about 160 min compared with placebo, with a statistical power of 0.8 and a P value of 0.05. Parametric data were analyzed with unpaired t-test; the incidence of adverse effects was analyzed with Fisher’s exact test. The VAS data were analyzed with the Mann-Whitney U-test. A value of P < 0.05 was considered statistically significant. Data were expressed as mean ± sd of the mean.
Sixty-three patients were included in the study. Three patients were excluded because of failure of spinal anesthesia, which was then changed to general anesthesia. The two groups of patients did not differ significantly with respect to age, weight, or height (Table 1). Duration of absolute analgesia, the time to first rescue analgesic, number of IM injections of 75 mg diclofenac in the first 24 h after the operation, the overall VAS pain score in the first 24 h after the operation, and the postoperative duration of motor block were similar in the two groups (Table 1). The VAS pain scores at 4-h intervals showed no significant difference between the two groups at any time during the postoperative period (Fig. 1).
There was no significant difference in the incidence of nausea, vomiting, dizziness, and anxiety between the two groups (Table 2). Pruritus and respiratory depression were not observed in any of the patients (Table 2).
Previous studies have demonstrated the analgesic and antiemetic effects of corticosteroids (6–16). In this study, the duration of absolute analgesia, time to first demand, number of administrations of IM diclofenac, VAS pain score at four-hour intervals and 24 hours, and the incidence of nausea and vomiting were similar between the two groups. Thus, this study does not support the enhancement of analgesia and reduction of nausea and vomiting after IT neostigmine by IV dexamethasone. This result is in conflict with several previous studies (6–16).
Several possible explanations may account for the discrepancies between our results and previous studies. The type of injury and the degree of inflammation seem to be an important issue in the antinociceptive actions of IV dexamethasone (16). A previous study (6) demonstrated that dexamethasone administered orally could decrease wound pain after tooth extraction. In contrast, inguinal herniorrhaphy is a more extensive surgical trauma compared with tooth extraction and therefore generates more postoperative inflammation and pain. For mild pain such as tooth extraction, dexamethasone can reduce the pain to an extent that most patients can perceive a significant change in pain intensity. However, for more extensive surgical trauma pain such as after inguinal herniorrhaphy, dexamethasone administration may not be able to provide effective analgesia. However, the number of patients in this study was relatively small, and the lack of significant difference in the analgesic effect between the two groups and even the incidence of nausea and vomiting may have been caused by the low statistical power.
Dexamethasone IV is an effective antiemetic for chemotherapy-associated emesis (9–12). Dexamethasone also reduced PONV in patients undergoing tonsillectomy (13,15) and major gynecologic surgery (8,16). Because dexamethasone reduces chemotherapy-associated emesis and PONV, it seems reasonable that it may also be effective in the prevention of IT neostigmine-associated emesis. However, in this study, IV dexamethasone did not reduce the incidence of the emesis induced by IT neostigmine.
The antiemetic mechanism of corticosteroids is unknown. Dexamethasone may inhibit the synthesis of prostaglandin, which is related to the triggering of emesis (10). Previous studies suggested that decreased serotonin release in the central nervous system and changes in the permeability of the blood cerebrospinal fluid barrier to serum proteins (14) may also play a role in the antiemetic effects of corticosteroids. Emesis induced by IT neostigmine is probably caused by the cephalad migration of neostigmine to the brainstem, and both droperidol and metoclopramide were ineffective in stopping the vomiting (1). The complex act of vomiting is controlled by the emetic center, which can be affected by stimuli from several areas, including the chemoreceptor trigger zone (CTZ) in the area postrema (17). The CTZ is rich in dopamine, opioid, serotonin, histamine, and muscarinic cholinergic receptors; these may play an important role in the transmission of impulses to the emetic center (17). It has been suggested that different cholinergic (muscarinic) receptor sites are present in the cerebral cortex and the pons and that compounds with specific activity at these receptors could form the basis for effective antiemetic drugs (18). Thus, controlling of emesis induced by IT neostigmine should be more effective with the use of anticholinergic drugs such as atropine or scopolamine.
The specific role of the CTZ in emesis is controversial. The concept of chemosensory activation of the CTZ by a parallel array of independent receptor sites has been questioned, and a sequential activation model with linkages between effect nuclei has been suggested (19). In this model, the control of emesis does not depend on a discrete groups of neurons in an emetic center but is the expression of a local circuit involving sequential stimulation of separate effector nuclei (19). However, no currently available drug will antagonize all receptor sites involved in the emetic response. Hence, a combination of anticholinergic drugs and other antiemetic drugs will probably have greater antiemetic action than a single drug for the IT neostigmine-related emesis.
Hursti et al. (20) demonstrated an antiemetic effect of exogenous corticosteroid only in patients with low endogenous corticosteroids. In addition, dexamethasone 8 mg alone did not reduce PONV (21), although the reported dose of dexamethasone for prevention of PONV ranges from 0.15 mg/kg, up to a maximum of 10 mg IV, 8 mg orally (6,16). A similar dose in this study had little antiemetic effect in the patients having the absence of low endogenous corticosteroids. Dexamethasone has a biological half-life of 36 to 72 hours (22), and in chemotherapy, there is some evidence that delayed emesis (e.g., beyond 24 hours) is better controlled with dexamethasone compared with classic antiemetics (11,12). The late antiemetic efficacy of dexamethasone may be a result of favorable pharmacokinetics and could partially explain the lack of antiemetic effect in the 24-hour period of observation in this study.
The possible adverse effects associated with the administration of corticosteroids, such as retardation of wound healing, increased susceptibility to infection, and gastrointestinal hemorrhage, were not found in this study because no prolonged hospital stay occurred because of wound infection or delayed healing and no hematemesis or melena happened in the patients. Previous studies (8,13,15,21) also have demonstrated that short-term (<24 hours) use of corticosteroids was safe. However, the precise dose of corticosteroid or duration of therapy with a corticosteroid that may cause corticosteroid-related adverse effects is unclear, particularly in patients at risk for such adverse effects. It is also unclear whether a single dose of dexamethasone can suppress adrenal function in patients during surgery. In addition, studies have reported conflicting results on analgesia (23,24) and PONV (21) after IV corticosteroid. The levels of dizziness and anxiety observed in this study were relatively mild, and there was no difference in the incidence between groups. Pruritus and respiratory depression were not observed in any of the patients.
In conclusion, we found that prophylactic administration of IV dexamethasone 10 mg did not enhance the analgesia or reduce the incidence of emesis in patients receiving spinal anesthesia with tetracaine plus neostigmine 100 μg during inguinal herniorrhaphy.
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© 2001 International Anesthesia Research Society
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