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From the *Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas; and Department of Anesthesiology, Cedars Sinai Medical Center in Los Angeles, Los Angeles, California.
Address correspondence and reprint requests to Paul F. White, PhD, MD, Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center at Dallas, 5161 Harry Hines Boulevard, CS 2. 282, Dallas, TX 75390-9068. Address e-mail to paul.white{at}utsouthwestern.edu.
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Abstract |
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METHODS: A total of 150 patients undergoing major laparoscopic (n = 80) or plastic (n = 70) surgery procedures received either an active TDS patch (containing scopolamine 1.5 mg) or a similar appearing sham patch 60 min before entering the operating room. All patients received a standardized general anesthetic technique. A second study medication was administered in a 2-mL numbered syringe containing either saline (for the two active TDS groups), droperidol, 1.25 mg, or ondansetron, 4 mg (for the sham patch groups), and was administered IV near the end of the procedure. The occurrence of postoperative nausea and vomiting/retching, need for rescue antiemetics, and the complete response rates (i.e., absence of protracted nausea or repeated episodes of emesis requiring antiemetic rescue medication) was reported. In addition, complaints of visual disturbances, dry mouth, drowsiness, and restlessness were noted up to 72 h after surgery.
RESULTS: There were no significant differences in any of the emetic outcomes or need for rescue antiemetics among the TDS, droperidol, and ondansetron groups in the first 72 h after surgery. The complete response rates varied from 41% to 51%, and did not significantly differ among the treatment groups. The overall incidence of dry mouth was significantly more frequent in the TDS groups than in the droperidol and ondansetron groups (21% vs 3%).
CONCLUSIONS: Premedication with TDS was as effective as droperidol (1.25 mg) or ondansetron (4 mg) in preventing nausea and vomiting in the early and late postoperative periods. However, the use of a TDS patch is more likely to produce a dry mouth.
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Introduction |
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At the present time, ondansetron, droperidol, and dexamethasone are the most commonly used prophylactic antiemetics (5). However, when used for routine prophylaxis, ondansetron is expensive (with a retail cost ranging from US $10 to 30) and has a relatively short duration of antiemetic action (6–12 h). The Food and Drug Administration-imposed "Black Box" warning has led to concerns regarding the use of droperidol (6). Although dexamethasone has been found to be as effective as both ondansetron and droperidol for antiemetic prophylaxis (7), concerns remain regarding its potential complications (e.g., delayed wound healing, hyperglycemia, risk of infections). Because multimodal approaches involving the use of combinations of antiemetics from differing drug groups have assumed increased importance in clinical practice (8), the search continues for cost-effective long-acting antiemetics with acceptable side effect profiles.
We hypothesized that premedication with a TDS patch would be more effective than droperidol 1.25 mg IV, and ondansetron 4 mg IV, in preventing PONV in the postdischarge period when administered for antiemetic prophylaxis as part of a multimodal strategy in surgical patients undergoing major plastic and laparoscopic surgery procedures.
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METHODS |
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In the preoperative holding area, approximately 60 min before entering the operating room, a TDS patch (Transderm ScopTM, ALZA, Palo Alto, CA) containing either no active substance (sham patch) or 1.5 mg scopolamine (programmed to deliver approximately 1.0 mg over 72 h) was applied to a hairless area behind one ear. Patients were instructed to remove the TDS patch on the third postoperative day. All patients were premedicated with midazolam 20 µg/kg IV, 5 min before entering the operating room. General anesthesia was induced with IV propofol 1–2 mg/kg and fentanyl 0.75–1.5 µg/kg IV (for laparoscopic surgery) or sufentanil 0.075–0.15 µg/kg IV (for plastic surgery). Cisatracurium, 0.2 mg/kg IV (for laparoscopic surgery), or rocuronium, 0.6 mg/kg IV (for plastic surgery), was used to facilitate tracheal intubation. After induction of anesthesia, dexamethasone (4 mg IV), was administered to all patients in both studies. Maintenance of anesthesia consisted of sevoflurane 0.75%–1.5% end-tidal (for plastic surgery) or desflurane 3%–6% end-tidal (for laparoscopic surgery). In addition, a sufentanil infusion, 0.15 µg · kg–1 · h–1 (for plastic surgery) or intermittent bolus doses of fentanyl 50 µg IV (for laparoscopic surgery), was administered for intraoperative analgesia. In the plastic surgery study, a 2-ml clear solution containing either saline 2 mL (for patients receiving the active TDS patch) or droperidol 1.25 mg (for patients receiving the sham patch) was administered for antiemetic prophylaxis at the start of skin closure. In the laparoscopic surgery study, a 2-ml syringe containing either saline 2 mL (for patients receiving the active TDS patch), or ondansetron 4 mg (for patients receiving the sham patch) was administered IV upon withdrawal of the laparoscope.
Upon completion of the operation (i.e., skin closure), residual neuromuscular block was reversed with neostigmine, 2.5–5 mg, and glycopyrrolate, 0.3–0.6 mg IV, and the maintenance anesthetics and analgesics were discontinued. Rescue medication in the predischarge period consisted of metoclopramide, 10 mg IV, in the recovery room and promethazine, 12.5–25 mg IM, on the postsurgical ward for the patients undergoing major laparoscopic surgery. For patients undergoing major plastic surgery, ondansetron, 4 mg IV, was administered for antiemetic rescue in the recovery room and promethazine, 12.5–25 mg IM was administered on the postsurgical ward. At the time of discharge, prochlorperazine, 25 mg supp, was prescribed to treat postdischarge emetic symptoms.
Emergence times were determined at 1 min intervals from discontinuation of the volatile anesthetic to awakening (i.e., opening eyes on verbal command) and orientation (i.e., correctly stating their name, date of birth, and the hospital). The times to postanesthesia care unit (PACU) discharge were assessed at 10-min intervals according to the standard modified Aldrete criteria (9). The incidences of patient complaints of nausea, or vomiting (or retching), visual disturbance, dry mouth, drowsiness, and restlessness, were recorded at 24, 48, and 72 h intervals as categorical responses (i.e., presence or absence) by a blinded observer who directly questioned each patient about these side effects. The need for rescue antiemetics during these postoperative periods was also noted. Complete responses to the multimodal prophylactic regimens were defined as the absence of protracted nausea (>15 min) or repeated episodes of vomiting/retching requiring rescue antiemetic therapy during the 72 h postoperative study period.
A power analysis (
= 0.05, ß = 80%) was performed before the initiation of the study using the software nQuery AdvisorTM (version 1.0, Janet D. Elashoff, 1995). This analysis suggested that group sizes of 35 or more should be adequate to detect a 33% decrease in emetic symptoms among groups assuming a 65% incidence in these at risk surgical populations (5). The Student’s t-test was used to analyze the parametric data, 
2 test or Fisher’s exact test was used to analyze the nonparametric data. A P value <0.05 was considered statistically significant.
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RESULTS |
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In the laparoscopic study, there were no differences between the TDS and ondansetron treatment groups with respect to the incidence of PONV symptoms during the 72-h study period (Table 4). The complete response rates did not differ significantly between the two treatment groups (51% and 47% in the ondansetron and TDS groups, respectively). The requirement for rescue antiemetics was nonsignificantly reduced in the TDS group during the 24–48 h period (21% vs 40%, P = 0.07). Moreover, clinically important recovery end-points (e.g., resumption of oral intake, time to ambulation and hospital discharge) did not differ between the two groups (Table 2).
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DISCUSSION |
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In a systematic review of the efficacy and safety of TDS for the prevention of PONV, Kranke et al. (3) suggested that visual disturbances and dry mouth were common side effects in TDS-treated patients. Although we also found an increased incidence of dry mouth with TDS in the postoperative period, other side effects commonly associated with TDS did not differ from those reported in the groups receiving the two popular antiemetics. Analogous to the findings from this earlier literature review, we found that TDS was effective in the postoperative period, even when administered only 60 min before the start of surgery. When administered as part of a multidrug prophylactic regimen, Tarkkila et al. (10) also reported that premedication with TDS reduced postoperative emesis. When compared with earlier studies (2,4) in which the TDS patch was applied on the day before surgery, its application on the morning of surgery appears to result in an improved side effect profile.
Controversy still surrounds the side effects associated with TDS when administered for antiemetic prophylaxis (2–4,10). As a centrally-active anticholinergic compound, dry mouth and visual disturbances are expected side effects with TDS. Postoperative sedation has also been reported (4). In contrast to these earlier placebo-controlled noncomparator studies (2,4), the current studies suggest that the only side effect which differed significantly from droperidol and ondansetron was the incidence of dry mouth. As all of these patients also received the anticholinergic drug, glycopyrrolate, in combination with neostigmine at the end of surgery, the differences between the treatment groups with respect to this side effect may have been minimized.
Consistent with an earlier study by Honkavaara et al. (11) evaluating TDS in preventing emetic symptoms during the periovulatory period in women undergoing middle ear surgery, we found that TDS compared favorably to ondansetron. Tigerstedt et al. (12) also reported that TDS was comparable to droperidol (1.25 mg IV) in preventing PONV in women undergoing ambulatory surgery procedures. In the latter comparative study (12), visual disturbances were more frequent in the TDS group and postoperative sedation was more marked after droperidol. Importantly, all of these early studies focused on emetic symptoms occurring within the first 24 h after surgery.
In contrast, we evaluated the occurrence of PONV for up to 72 h after surgery. Unfortunately, our study design only assessed emetic symptoms at fixed 24 h intervals rather than at specific clinically relevant end-points (e.g., upon initial ambulation after surgery, at discharge from the PACU, upon returning to their home). In the laparoscopic surgery study, the need for rescue antiemetics in the TDS (versus ondansetron) group was reduced from 40% to 21% during the 24–48 h interval after surgery. However, this difference between the two groups failed to achieve statistical significance (P = 0.07). Additional studies involving more patients undergoing ambulatory surgery are needed to assess the potential benefits of TDS in preventing motion-induced and postdischarge emetic symptoms.
The current study was clearly under-powered to assess differences in PONV at 24–72 h after surgery due to the lower than expected incidences of emetic symptoms during this time interval (i.e., ranging from 0% to 6% in the four study groups). Although the incidence of postoperative nausea exceeded 60% in all four groups, the overall incidences of vomiting were substantially less in the 72 h study period (ranging from 5% to 21%). We speculate that the combination of a multimodal prophylactic regimen involving TDS, droperidol, or ondansetron in combination with dexamethasone, as well as the frequent use of rescue antiemetic medication to treat symptoms of nausea in the early postoperative period, was highly effective in limiting emesis in these two at risk surgical populations. These preliminary data will be useful to future investigators proposing studies to evaluate postdischarge emetic symptoms when using potentially longer-acting antiemetics (e.g., palonsetron, aprepitant).
In summary, these data support the use of TDS as a cost-effective alternative to ondansetron as part of a multidrug prophylaxis regimen in at risk patients undergoing major laparoscopic surgery. In addition, TDS is an acceptable alternative to droperidol for antiemetic prophylaxis in high-risk patients undergoing major plastic surgery procedures as part of a multidrug prophylactic regimen.
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ACKNOWLEDGMENTS |
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Footnotes |
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Supported by Baxter Healthcare and Margaret Milam McDermott Distinguished Chair in Anesthesiology, as well as the White Mountain Institute, a private foundation.
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This article has been cited by other articles:
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  P. S. A. Glass and P. F. White Practice Guidelines for the Management of Postoperative Nausea and Vomiting: Past, Present, and Future Anesth. Analg., December 1, 2007; 105(6): 1528 - 1529. [Full Text] [PDF]
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