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ANALGESIA

The Antipruritic and Antiemetic Effects of Epidural Droperidol: A Study of Three Methods of Administration

In Ho Lee, MD^*, and Il Ok Lee, MD

From the *Department of Anesthesiology, Cheil General Hospital, and Women’s Healthcare Center, Kwandong University College of Medicine, Seoul, Korea; and Department of Anesthesiology, Korea University College of Medicine, Seoul, Korea.

Address correspondence and reprint requests to Il Ok Lee, MD, Department of Anesthesiology, Guro Hospital, Guro gu Gurodong gil 97, Korea University College of Medicine, Seoul, South Korea. Address e-mail to iloklee{at}korea.ac.kr.

Abstract

BACKGROUND: In this study, we compared rates of postoperative nausea and vomiting (PONV) and pruritus after using different protocols for administering epidural droperidol.

METHODS: Using the same dose of droperidol, we evaluated the effectiveness of three different methods of administration (single, continuous, and combined) on the frequency of PONV and pruritus induced by continuous infusion of epidural fentanyl for 48 h postoperatively. One hundred sixty ASA physical status I and II patients who underwent surgical resection for colorectal cancer under general anesthesia combined with epidural anesthesia were randomly allocated into four groups: (a) control group (no droperidol), (b) single injection group (droperidol 2.5 mg), (c) continuous group (droperidol 1.25 mg/day) and (d) combined single (droperidol 1.25 mg) and continuous (droperidol 0.625 mg/day) group.

RESULTS: Pruritus and PONV were significantly less frequent in all droperidol groups, when compared with the control group (P < 0.05). The incidence and the incidence over time of PONV were similar among all groups who received epidural droperidol.

CONCLUSION: Epidural droperidol is effective for reducing pruritus and PONV, regardless of the method of administration.

IV and epidural droperidol administration reduce postoperative nausea and vomiting (PONV) and pruritus in patients who are given epidural opioids postoperatively (1–6). The plasma level of IV droperidol is high compared with the epidural route (1), and the antipruritic effect of IV droperidol ceases when the dose is increased from 2.5 to 5.0 mg (4). In contrast, the antipruritic effect of epidural droperidol is dependent on dose range, i.e., from 1.25 to 5 mg (5). Additionally, there is a risk of sedation with all routes of administration because droperidol is a neuroleptic drug (7).

The purpose of this study was to determine any beneficial effects of small-dose droperidol on the frequency of PONV and pruritus when administered as a combined bolus and continuous infusion, when compared with a single bolus or an infusion without bolus.

METHODS

This randomized, double-blind, controlled trial was approved by the institutional human investigation committee at our hospital. Eight hundred sixty-four patients underwent elective laparotomy at Korea University hospital from June 2000 to October 2001. Using the following critia, 257 patients were excluded: recent use of opioids, any cutaneous pathology with pruritus, administration of antiemetic medication within 24 h before surgery, a history of motion sickness, convulsion, parkinsonism or psychiatric problems, and an inability to answer questions. Of the eligible 607 patients, 185 with an ASA physical status of I or II, and who were operated on by the same surgeon, were approached and offered participation in the trial.

After obtaining informed consent, 160 patients were enrolled in the study. Any patient who could not tolerate the preoperative epidural procedure because of pain or discomfort was excluded. Patients with epidural failure were excluded and their postoperative pain control was changed to the IV route. Patients who underwent dural puncture were also excluded.

Glycopyrrolate (0.2 mg) and midazolam (3 mg) were given 30 min preoperatively via the IM route. In the operating room, before the induction of general anesthesia, patients were placed in the lateral decubitus position. A 19-gauge epidural catheter (Perifix 401; Arrow, Melsungen, AG) was introduced through the T9-12 interspaces and advanced 3–4 cm into the epidural space in a cephalad direction. The level was determined according to the approximate dermatomal coverage required for the surgical procedure; the lower border of the shoulder blade, which is level with the seventh thoracic vertebra, was used as an anatomical landmark. An epidural test dose of 3 mL of 2% lidocaine with 1:100,000 epinephrine was administered through the catheter.

General anesthesia was induced with thiopental 5 mg/kg IV and fentanyl 2 µg/kg, and was maintained with enflurane, 50% nitrous oxide, and oxygen. All patients received vecuronium 0.1 mg/kg to facilitate tracheal intubation and to maintain subsequent intraoperative neuromuscular blockade. At the end of surgery, residual neuromuscular blockade was reversed with pyridostigmine 10 mg and glycopyrrolate 0.2 mg IV. The operation began with a vertical abdominal skin incision.

Patients were randomly allocated to one of four groups (n = 40 each) according to a random-number table. An independent pharmacist prepared four sets of 10 mL syringes and infusions (Infusor LV5; Baxter Healthcare, USA) for Groups A, B, C, and D. These sets were kept concealed in numbered envelopes. The participants and researchers were blinded as to group assignment: Group A, control group (intraoperative single epidural injection of placebo); Group B, patients who received a single intraoperative epidural injection of droperidol (2.5 mg); Group C, patients who received a continuous postoperative epidural infusion (1.25 mg/day) of droperidol; and Group D, patients who received a combined single intraoperative epidural injection of droperidol (1.25 mg) and continuous postoperative epidural infusion (0.625 mg/day) of droperidol over the 48 h study period. The administered dosage for the droperidol groups was 2.5 mg. At skin closure, ropivacaine 0.17% 12 mL was injected as a bolus: ropivacaine 0.2% 10 mL and 1 mL of fentanyl (50 µg) plus 1 mL of saline (Groups A and C) or 1 mL of droperidol 2.5 mg (Group B) or 1 mL of mixed saline and droperidol 1.25 mg (Group D). The epidural catheter was connected to a continuous epidural infusor that contained ropivacaine 0.2% 239 mL and 10 mL of fentanyl (500 µg) and 1 mL of saline (Groups A and B) or 1 mL of droperidol 2.5 mg (Group C) or 1 mL of mixed saline and droperidol 1.25 mg (Group D), i.e., a total of 250 mL. Continuous epidural drugs were infused at a rate of 5 mL/hr (ropivacaine 9.56 mg/h and fentanyl 10 µg/h) for 50 h. Postoperatively, any fluid or air that may have accumulated and caused PONV was drained via a nasogastric tube.

The severity of pruritus, PONV, pain, and sedation were evaluated at 1, 6, 24, and 48 h postoperatively by an anesthesiologist who was blinded to the study treatments. The early postoperative phase was defined as the period from cessation of the operation to 6 h postoperatively, and the late postoperative phase was from 6 to 48 h postoperatively.

The severity of pruritus was assessed using a four-point scale: 0, absent; 1, mild (localized to one area such as the face or arms and not troubling the patient); 2, moderate (affecting a larger area such as the face and arms or the face and anterior surface of the thorax, but not disturbing the patient and therefore not requiring treatment); or 3, severe (extensive or generalized, often disturbing the patient to the point that treatment was indicated). The severity of PONV was assessed using a four-point scale: 0, absent (no nausea/vomiting); 1, mild (mild nausea/vomiting, patient not requesting an antiemetic); 2, moderate (nausea/vomiting, patient requesting an antiemetic); or 3, severe (nausea/vomiting, resistant to antiemetic). The number of patients who had suffered pruritus or PONV was recorded as the incidence or the incidence over time at the time of observation and these were then compared among groups. Pain on coughing was assessed by using a visual analog scale (0 [no pain at all] to 10 [the worst pain imaginable]). Sedation was assessed by using sedation scores on a scale of 0–3 (0, alert or drowsy but easily aroused by verbal commands alone; 1, sleeping and aroused by verbal commands; 2, sleeping and not aroused by verbal stimuli, but aroused by tactile stimulation; 3, sleeping and not aroused by tactile stimulation).

Insufficient analgesia was treated with IV ketorolac 30 mg or supplemental bolus epidural injections of ropivacaine 0.2% 10 mL. When severe PONV occurred, metoclopramide 10 mg or ondansetron 4 mg was given IV as a rescue medicine. When patients experienced severe pruritus, naloxone 40 µg or propofol 10 mg was injected IV as a rescue medicine. Side effects such as cardiac arrhythmias or extrapyramidal symptoms were recorded.

Data were analyzed using SigmaStat for Windows version 3.1 (SPSS). In the preliminary pilot study with 40 patients, the incidence of pruritus as a primary outcome variable was analyzed with ANOVA. The sample size was determined by using a power analysis based on the assumptions that the expected incidence of pruritus in the control group would be 70%, and a 50% reduction in the incidence of pruritus in the treatment group would be of clinical relevance. A power analysis revealed that a group size of 32 patients per group would be required to detect a difference in the incidence of pruritus ( = 0.05; power = 0.8). Considering the drop-out rate, we planned to study 40 patients in each group. The Kolmogorov–Smirnov test was used to analyze normal distribution.

Demographic data and the severity of pain and sedation were compared with ANOVA (or Kruskal–Wallis ANOVA on ranks) using Bonferroni correction for multiple comparisons. The incidence over time of PONV and pruritus were compared with repeated measures ANOVA (or Friedman repeated measures ANOVA on ranks); multiple comparison procedures were done with Tukey’s test. Categorical variables were analyzed using the ²-test (or Fisher’s exact test). P values <0.05 were considered statistically significant. Data were expressed as means ± standard deviations or as medians with interquartile ranges (25%–75%).

RESULTS

Eighteen patients were excluded from the study. An epidural catheter could not be placed in eight patients because of technical reasons and preoperative patient discomfort; therefore, an epidural catheter was placed postoperatively. Five patients were excluded because of epidural failure (catheter dislocation in two patients and dural puncture in three patients). There were missing data from five patients. The data from the remaining 142 patients were analyzed. All the groups were demographically similar, and there were no differences in the epidural levels or the duration of surgery (Table 1).

The single injection group, the continuous group, and the combined group reported significantly fewer incidences of pruritus when compared with the control group during postoperative epidural analgesia (P < 0.05) (Table 2). The number of patients who received rescue medicine for pruritus was similar among groups.

With respect to the severity and incidence of PONV, the single injection group, continuous group, and combined group showed a significantly reduced severity and incidence of PONV when compared with the control group during postoperative epidural analgesia (P < 0.05) (Table 3). The number of patients who received rescue medicine for PONV was similar among groups.

The single injection group and the combined group had a significantly reduced incidence of PONV when compared with the control group during early postoperative epidural analgesia (P < 0.05) (Table 4). With respect to the incidence of pruritus over time, the continuous injection group and combined group showed significantly reduced incidences of PONV when compared with the control group during late postoperative epidural analgesia (P < 0.05) (Table 4).

There were no significant differences among the four groups with respect to the severity of pain on coughing and sedation (Fig. 1). All patients received excellent analgesia, although some patients required supplemental bolus epidural injections or nonsteroidal antiinflammatory drugs.

View larger version (6K): [in this window] [in a new window]   Figure 1. Boxplots displaying the severity of pain when coughing and severity of sedation during postoperative continuous epidural analgesia. Group A = control group, Group B = single epidural injection of droperidol (2.5 mg), Group C = continuous epidural infusion (1.25 mg/day) of droperidol. Group D = combined single (1.25 mg) and continuous epidural infusion (0.0625 mg/day) of droperidol. There were no significant differences among groups. The boundaries of the box indicate the interquartile range (25%–75%). A line within the box marks the median. Error bars: 5% and 95% percentiles of the values. Circles: the largest or the smallest values above and below those percentiles, respectively.

Extrapyramidal side effects or cardiac arrhythmias were not observed in any patients.

DISCUSSION

In our previous study (8), the single bolus group showed beneficial effects concerning pruritus and PONV when compared with the control group, whereas the continuous group did not show a statistically significant effect for PONV when compared with the control group. In this study, we injected a small dose of droperidol (0.125 mg) as a bolus in the combined group. We wanted to determine the effects of a small dose of droperidol as a bolus in the combined group compared with the single bolus droperidol group (0.25 mg), and to compare the four different groups.

We chose the epidural instead of the IV route to avoid any abrupt increase in the plasma level (1,9). Concerning droperidol’s IV kinetics, the plasma concentration decreases rapidly in the first 15 min after injection (10,11). Naji et al. (1) used epidural droperidol, and found that blood levels of droperidol after 45 min were close to peak plasma levels, suggesting that droperidol requires longer contact with the central nervous system before it is absorbed.

Although a significant inhibitory effect of IV droperidol 2.5 mg on morphine-induced pruritus has been reported, this effect is reversed by a larger (5 mg) dose (4). Likewise, Horta et al. (5) reported a significant increase in somnolence with 5 mg epidural droperidol and a dose-related reduction in epidural morphine-induced pruritus. To avoid any significant side effects from droperidol in this experiment, we set the dose of epidural droperidol at 2.5 mg and the optimal method of administration was investigated. Because our purpose was to compare all groups under the same total dose (2.5 mg) of droperidol, we used a fixed rate continuous infusion. Although patient-controlled analgesia was not used, we considered the combination of continuous epidural ropivacaine and fentanyl administration that was used to be effective for epidural analgesia (12,13).

Considering the short plasma half-life of droperidol (approximately 2.8 h) (1), the prolonged effect in the single injection group during the study period was probably the result of the slow dissociation of droperidol from its receptors or its retention in the brain (10). It is also possible that the metabolites of droperidol retain some degree of pharmacological activity (14). All of these potential mechanisms reinforce the long pharmacokinetic duration of droperidol and this can also be explained as the preemptive effect of prophylaxis.

Comparing the incidence over time of PONV and pruritus, the bolus group showed antiemetic efficacy and the continuous group showed antipruritic efficacy. Although the combined Group D displayed a beneficial effect, i.e., a reduction in the incidence over time of both pruritus and PONV, there were no significant differences among the droperidol groups. In this experiment, our results showed that all droperidol groups (B, C, and D) experienced decreased frequencies of PONV and pruritus.

Although we did not observe cardiac or central nervous system side effects, it is important to recognize the lack of laboratory data documenting the safety of neuraxial droperidol (including the potential for neurotoxicity) (15,16). Epidural droperidol administration has not been approved by the Food and Drug Administration in the United States.

In conclusion, we observed that epidural droperidolis effective for reducing pruritus and PONV, regardless of the method of administration.

Footnotes

Accepted for publication October 17, 2006.

Presented at the 59th Canadian Anaesthesiologists’ Society, June 23, 2003, Ottawa, Canada.

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