| JOURNAL HOME | CME HOME | THIS MONTH | PAST ISSUES | ETOC | COLLECTIONS |
| AUTHORS | REVIEWERS | EDITORIAL BOARD | FEEDBACK | RSS | HELP |
| ||||||||||||||
| ||||||||||||||
|
|
|
|
||||||||||||
|
||||||||||||||
*Psychiatric Service, Hospital Materno Infantil Presidente Vargas; Anesthesia Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Universidade Federal do Rio Grande do Sul; and Pharmacology Department, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
Address correspondence and reprint requests to Wolnei Caumo, MD, PhD, Rua Monsenhor Veras, 725/306, Bairro Santana, 90610-010, Porto Alegre, RS, Brazil. Address e-mail to caumo{at}cpovo.net.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The 
2-agonist clonidine has shown properties that are potentially beneficial for premedication to reduce sympathetic activity, the incidence of shivering, and oxygen consumption during recovery from anesthesia (5); to dry secretions; to minimize fluctuations in the hemodynamic profile during anesthetic induction (6); and to decrease anesthetic requirements for both opioid and volatile anesthetics (7). Although clonidine has been used perioperatively, its clinical effect on pain and anxiety has not been sufficiently explored.
Clonidine provides significant benefits for preoperative anxiety (8) and analgesia, although it occasionally fails to produce this effect (9,10). Thus, additional studies are necessary to quantify this effect on perioperative outcomes and to assess whether the therapeutic effects that have been reported as statistically significant are clinically relevant. Therefore, this study was designed to evaluate the effect of small oral clonidine doses on perioperative outcomes assessed by anxiolysis, analgesia, and hemodynamic stability.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Patients were allocated in a double-blind manner, by using a random numbers table, to receive either oral clonidine 100 µg or placebo the night before surgery (10:00 pm), 1 h before the anesthesia, and 24 h after surgery. No other preoperative medication was given. Blinding and randomization were undertaken by two investigators who were not involved in the patients’ evaluations. Other individuals involved in patient care were unaware of which treatment group patients were in.
The primary outcomes were postoperative anxiety and pain, as assessed by pain scores, and analgesic consumption. The secondary outcome was hemodynamic stability, as assessed by systemic blood pressure and heart rate.
The day before surgery, all patients were seen by the same anesthesiologist, who provided them with information on the perioperative course and instructed them how to use the patient-controlled analgesia (PCA) pump and the visual analog scale (VAS) pain scoring system. Moreover, all patients underwent psychological testing. They answered a structured questionnaire to collect information concerning demographic characteristics. The evaluators were allowed to help patients read the questions during application of the anxiety scales and the Self-Reporting Questionaire-20 (11). The six evaluators had received 1 mo (60 h) of training with role-playing activities and discussion that focused on difficulties that might occur during the interviews. They presented the tests in a random order to prevent order effects and were assisted in 15% of the interviews by the principal investigator. To ensure blinding, postoperative assessment was not performed by the same physicians involved in the preoperative evaluation, and the staff that provided instructions on PCA use and program changes were unaware of group assignment.
A 100-mm VAS was used to assess pain, sleepiness, nausea, and vomiting. Scores ranged from 0 (absence of symptoms) to 100 (maximum symptoms). Furthermore, satisfaction with pain management was assessed by the same method, and scores ranged from 0 (very dissatisfied) to 100 (very satisfied). After surgery, the assessment was recorded at the following times: nausea and vomiting were recorded at 24, 48, and 72 h; pain and sleepiness were recorded at 6, 12, 18, 24, 48, and 72 h; state anxiety was recorded at 6, 24, 48, and 72 h; and satisfaction with pain management was recorded 72 h after surgery. Sleepiness, nausea, and vomiting were defined as the global average of ratings obtained at each time point.
All the psychological tests used in this study were validated in the Brazilian population. To measure anxiety, the State-Trait Anxiety Inventory (STAI) (12) was used. The Montgomery-Äsberg Depression Rating Scale was used to measure depressive symptoms (13). The Self-Reporting Questionaire-20 was used to screen for minor psychiatric disorders (sensitivity, 86%; specificity, 77%). Exposure to alcohol was evaluated by the CAGE (cut down, annoyed, guilty feeling, eye opener) questionnaire (sensitivity and specificity of 88% and 83%, respectively) (14).
Systemic blood pressure and heart rate were measured by the automated oscillographic method and recorded at the following times: during the preanesthetic assessment (T0), upon arrival at the operating room (T1), at least every 5 min during anesthesia, and at admission to the recovery room (T5). For each patient, a mean value was determined from heart rate and arterial blood pressure measurements for the following times: during the first 30 min (T2), at 1 h (T3), and at the end of the anesthesia (T4).
Hypotension was defined as systolic blood pressure <20% of the values before the epidural anesthesia and was treated with IV ephedrine 5 mg. Bradycardia was defined as heart rate less than 40 bpm and was treated with IV atropine 0.5 mg.
On arrival in the anesthetic room, all patients received standard monitoring. Before the epidural anesthesia, physiologic solutions of 0.9% 10 mL/kg and IV fentanyl 100 µg were administered. Then, all patients had an extradural catheter inserted at lumbar segments L2-3 or L3-4. Ropivacaine (10 mg/mL) 16–20 mL was administered epidurally. If there were signs of inadequate analgesia, additional doses of 5 mL were used. A continuous propofol infusion (0.08–0.1 mg · kg–1 · min–1) was administered to maintain conscious sedation during surgery. Intraoperative variables, including ropivacaine and ephedrine doses, length of surgery, blood loss, and anesthetic and surgical complications, were noted. At the end of the surgery, the sedation was stopped, and the extradural catheter was removed.
After being transferred to the postanesthesia care unit, patients were connected to a morphine PCA with a delivered dose of 2.5 mg of morphine, a 10-min lockout, and a maximum 4-h dose of 30 mg. If their pain was unrelieved, the PCA doses were increased by 0.8 mg until pain control was achieved. The PCA was maintained during the first 72 h after the procedure. The analgesic consumption was measured by recording the amount of morphine used by PCA adjusted by patient weight. No other pain medication was allowed. If required, metoclopramide 10 mg was administered for nausea. If this was ineffective, ondansetron 4 mg was given. For analytical purposes, the number of antiemetic doses used in the first 72 h after surgery was considered for both antiemetics (metoclopramide and ondansetron).
A checklist was used to monitor respiratory, urinary, cardiovascular, and neurological complications. This checklist covered points related to the surgery, anesthesia, surgical wound, electrolytic disturbance, and bleeding. The presence of infection was defined by clinical and laboratory investigation. The diagnosis was established by a gynecologist unaware of the treatment group.
The postoperative outcome chosen for power analysis was postoperative pain on the VAS. The sample size was calculated on the basis of a mean difference of 10 mm (VAS) between groups, an of 0.05 (two-tailed test), and a power of 90%. The analysis indicated that 16 subjects would need to be included in each group. The differences between groups for normally distributed data were examined by the unpaired Student’s t-test. Categorical data were examined by 
2 testing. Because the treatment group did not differ significantly from the control group 6 h after surgery for pain (37.40 ± 23.25 mm versus 49.81 ± 31.24 mm; P = 0.08) and anxiety (41.63 ± 9.63 versus 37.33 ± 8.70; P = 0.07), pain and anxiety change were calculated for each patient, and the two experimental groups were compared by repeated-measures analysis of variance adjusted by the Bonferroni post hoc test for multiple comparisons. The treatment group was the grouping factor, and time was the repeated measure regarding the following outcomes: pain, anxiety, morphine consumption, systemic blood pressure, and heart rate. As in the nonadjusted analysis, the effect of the intervention was not detected for morphine consumption, systemic blood pressure, or heart rate. We performed the adjustment by ropivacaine doses to control a potential underestimation of the effect of clonidine produced by this covariant. For all analyses, statistical significance was set at P < 0.05 (two tailed). Data were analyzed with SPSS version 9.0 (SPSS, Chicago, IL).
The magnitude of the effect of clonidine on postoperative state anxiety 6 h after surgery was demonstrated by the number needed to treat (NNT). The cutoff point to classify the anxiety level in the STAI was based on the change score (postoperative state anxiety minus preoperative state anxiety): mildly anxious (scores 
0) and highly anxious (scores higher than zero). This strategy was used because a definition of what would be considered a variation of magnitude that was clinically relevant from preoperative to postoperative anxiety was not found. To analyze the effect of clonidine on anxiety, the patients were classified into two groups according to the pain level on VAS: absence of pain or mild pain (scores 30 mm) and moderate, intense, or worst possible pain (>30 mm) (15). The NNT to prevent an increase of heart rate more than 70 bpm throughout the surgery was also calculated. Confidence intervals (CIs) were calculated according to Sacket et al. (16).
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
|
|
|
|
In the presence of moderate to intense postoperative pain, 35.30% of the treated group presented intense state anxiety 6 h after surgery, compared with 69.60% in the placebo group. In contrast, in the absence of pain or with mild pain, 30.80% of the treated group presented intense state anxiety, compared with 33.30% in the placebo group. The NNT was 3 (95% CI, 1.72–9.42) to prevent intense postoperative anxiety in patients with moderate to intense pain, compared with 40 (95% CI, 18.79–99.68) in the absence of pain or with mild pain.
There was an effect of treatment group on postoperative pain reported on the VAS (F1,60 = 4.15; P = 0.04) and an effect of time (F1,60 = 8.40; P = 0.00). However, there was no interaction between factors (F1,60 = 0.49; P = 0.48) (Fig. 2).
|
Analysis of morphine consumption showed no effect of treatment group (F1,58 = 1.20; P = 0.28). The morphine consumption was not affected by the interaction between time and treatment (F1,58 = 1.24; P = 0.28) or by the interaction between time and ropivacaine dose (F1,58 = 0.03, P = 0.87). However, there was a significant reduction in morphine consumption across time that was independent of treatment group (F1,58 = 11.90; P = 0.00; Fig. 3).
|
There was an effect in the treatment group on the average heart rate in the perioperative period (F1,58 = 5.40; P = 0.03) and the effect of time (F1,58 = 2.41; P = 0.04), but there was no interaction between factors (F1,58 = 1.47; P = 0.20; Fig. 4). In the intervention group, 68% of patients had an average heart rate less than 70 bpm during surgery, compared with 21.40% in the placebo group (NNT, 2; 95% CI, 1.29–2.80). Patients who required larger ropivacaine doses during surgery had a statistically significant increase in heart rate (F1,58 = 4.36; P = 0.04).
|
There was no effect of treatment group on arterial blood pressure (F1,55 = 0.008; P = 0.93). The arterial blood pressure was not affected by the interaction between factors (F1,58 = 0.65; P = 0.62) or by the interaction between time and ropivacaine dose (F1,58 = 1.19; P = 0.32). However, the effect of time on arterial blood pressure was statistically significant and was independent of the treatment group (F1,58 = 1.70; P = 0.04).
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Although the anxiolytic and analgesic properties of oral clonidine have been reported by previous studies with larger doses than those used in this study (8), the benefit found was clinically relevant in terms of anxiolysis, especially in patients with moderate to intense pain, who had an incidence of intense anxiety approximately half that of the placebo group (35.30% vs 69.60%). This was achieved without any other clinically important side effects. Because no statistically significant difference was statistically observed between groups in the major aspects of the perioperative period, it is unlikely that factors other than the use of clonidine accounted for these results in the intervention group.
The clonidine group had a reduction in intraoperative ropivacaine consumption, even with a significantly longer surgery time. This finding is supported by the results of a previous study that used larger doses (150 µg) than were used in this research (17). The mechanism of clonidine-induced enhancement of sensory block with spinal anesthesia remains to be proven. The antinociceptive effect produced by the orally administered 2-adrenergic agonist is mainly caused by direct spinal activation due to the spread of the drug via the systemic circulation into the spinal cord. This supposed mechanism is supported by results obtained in animal experiments (18,19). Moreover, this result can be explained by the improvement in the quality of sedation, determined by preoperative clonidine use, during surgery.
Patients treated with clonidine reported less pain, although the intervention did not result in a reduction in morphine consumption. This finding is in agreement with previous studies that used preoperative oral clonidine to improve postoperative PCA with IV morphine (20). However, the analgesic effect of oral clonidine has been controversial. Some authors have not detected improved postoperative analgesia or a reduction in morphine consumption (21). Other investigations showed that oral clonidine not only had a good analgesic effect, but also had a synergic effect with opioids administered by the neuroaxial route (9,22). Whether the analgesic effect of clonidine varies for different surgical procedures or by route of administration should be investigated. Furthermore, the absence of a statistical difference between groups for morphine consumption could be explained by behavioral factors which influenced PCA morphine consumption. According to a previous study, most patients use morphine even when they do not feel pain: they use it because they fear pain or discomfort (23). In some studies, patients pressed the button as soon as they felt pain and in preparation for movement. However, there are patients who do not use morphine despite pain, in an attempt to avoid sleepiness, nausea, vomiting, addiction, or overdose (4,23). These factors must be considered when using PCA morphine consumption as a pain measure, because it is not a reliable index of analgesic efficacy.
The reduction in heart rate in patients treated with clonidine was statistically and clinically significant. Bradycardia and hypotension are adverse effects of 2-adrenergic agonists. However, these effects prevent tachycardia and hypertension, and this reduces the risk of cardiac ischemia by blunting the sympathetic activity on the cardiovascular system after surgical stress and emergence from anesthesia (24). Thus, clonidine may be an alternative therapy in patients with cardiac risk factors who are undergoing noncardiac surgery and have contraindications to ß-blockade. In this study, neither clinically significant hypotension nor use of larger doses of vasopressor drugs was observed. However, the population studied was ASA status I–II patients, and, thus, future clinical trials should explore whether the hemodynamic stability we observed will be confirmed in patients with cardiac risk factors.
In this study, clonidine induced anxiolysis and analgesia throughout the postoperative period, whereas increased sleepiness was noted only in the first six hours after surgery. These findings indicate that the anxiolytic and analgesic actions of clonidine are more potent than the sedative action and that larger doses might be required for sedation. Although the sedation and sleep effects of clonidine have been related to dose (25,26), the optimal dose for anxiolysis, without deep sedation, has not been reported. Oral doses between 100 and 300 µg have been used for premedication. Ota et al. (17) found a dose-related effect of oral clonidine with a plateau at 150 µg. Doses larger than 150 µg resulted in more adverse effects (18). For the best effect with minimum side effects, clonidine 100 µg was administered. The meaningful improvements in anxiety, pain, anesthetic consumption, and hemodynamic stability determined by this intervention are indubitably relevant. However, these findings contrast with the effect of clonidine on pain and anxiety reported by a previous study that used the same preoperative clonidine dose (8). This discrepancy may be explained by the additional postoperative clonidine dose. This dose was used because the half-time of clonidine is relatively short, ranging from 6 to 24 hours (27). Thus, when we used only the preoperative dose, the patients were probably without the potential benefits of clonidine for most of the postoperative period.
Several methodological issues related to the design of this study must be addressed. First, baseline psychological characteristics were assessed to detect possible confounding variables that might have been misbalanced even with randomization, because this study had <100 subjects. Second, the VAS and the STAI were reported as change scores from six hours after surgery as a baseline with which all subsequent pain and anxiety ratings would be compared. This methodological strategy has been used in previous studies with similar characteristics (28) because it probably permits a better control for personality-related variability in self-reported measures.
In conclusion, clonidine provided a clinically relevant anxiolytic effect, especially in patients with moderate to intense postoperative pain. Furthermore, clonidine blunted the sympathetic activity with good hemodynamic stability. These results suggest that clonidine should be a good therapeutic alternative to other preoperative sedatives, but further studies are necessary to compare its effects with those of different anxiolytics on postoperative outcomes over time.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
|
|
 |
|
  W. Caumo, F. Torres, N. L. Moreira Jr, J. A. S. Auzani, C. A. Monteiro, G. Londero, D. F. M. Ribeiro, and M. P. L. Hidalgo The Clinical Impact of Preoperative Melatonin on Postoperative Outcomes in Patients Undergoing Abdominal Hysterectomy Anesth. Analg., November 1, 2007; 105(5): 1263 - 1271. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
). The clonidine group reported a larger reduction in anxiety throughout the postoperative period. STAI = State-Trait Anxiety Inventory.
