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EDITORIAL

We’re Tired of Waiting

J. Lance Lichtor, MD^*, and Peter S. A. Glass, MB ChB, FFA(SA)

From the *Department of Anesthesiology and Pediatrics, University of Massachusetts, Medical School, Worcester, Massachusetts; and Department of Anesthesia, SUNY Stony Brook, New York.

Address correspondence and reprint requests to Peter S. A. Glass, Department of Anesthesia, Stony Brook University Hospital/HSC L4-060, Stony Brook, NY 11794. Address e-mail to Peter.Glass{at}stonybrook.edu.

I’m so tired, tired of waiting, tired of waiting, for the nausea and vomiting to end (with apologies to the Kinks).

The May 1942 issue of Anesthesiology1 reprints an abstract from an article published in 1941 in the British Medical Journal that examined the incidence of postoperative nausea and vomiting (PONV) in 1000 consecutive cases.2 How much progress have we made since 1941? This issue of Anesthesia & Analgesia includes a series of articles that continue to evaluate this "big little problem"3 and emphasizes the need to expand the definition of PONV from the first 24 h after surgery to the first 72 h, with the interval from 24 to 72 h defined as postdischarge nausea and vomiting (PDNV).

Much progress has been made in identifying the pathophysiology of nausea and vomiting, including identification of the receptor sites at which therapeutic interventions may be effective.4 This has stimulated the pharmaceutical industry to develop a host of new antiemetics, the majority of which have been serotonin type 3 receptor (5-HT₃) receptor antagonists: ondansetron, dolasetron, granisetron, and tropisetron. These drugs have similar efficacy for PONV, are relatively short lasting (elimination half-life <12 h), and vary in potency and metabolism.5

Palonosetron is the newest of the 5-HT₃ receptor antagonists. In this issue of Anesthesia & Analgesia, Rojas et al.6 describe the unique pharmacology of palonosetron compared with other 5-HT₃ receptor antagonists, including differences in half-life and receptor internalization that may provide a longer duration of action when compared with other 5-HT₃ antagonists. Also in this issue of Anesthesia & Analgesia, Kovac et al.7 and Candiotti et al.8 investigate whether palonosetron is clinically advantageous in the prevention of PONV and PDNV. The studies differed in location (United States versus Europe) and surgical populations. Eligible patients required at least two or more risk factors for PONV. Based on these Apfel risk factors,9 the likelihood of PONV in the study population would be 39% to 79%. The actual incidence of PONV in patients not receiving palonosetron was 64% for the Kovac et al. study7 and 74% for the Candiotti et al. study,8 and well within the expected range for this high risk population. At the highest dose studied (0.075 mg), the incidence of vomiting or need for antiemetic treatment was reduced during the first 24 h after surgery by approximately 20%-30% (64%-44%7 and 74%-57%8), which is indistinguishable from the reduction in PONV expected in high-risk patients given a single intervention (relative risk reduction expected is 26%).10 Thus, the unique differences in receptor binding and function do not appear to translate into improved efficacy in the first 24 h.

Both studies also looked at the incidence and severity of nausea alone, and found a marked reduction in incidence and severity within the first 24 h in patients receiving palonosetron, an advantage not demonstrated with the other 5-HT₃ receptor antagonists.

Does palonosetron provide a longer duration of effect, which might be suggested from both the long half-life and receptor internalization? Kovac et al. demonstrated continued efficacy compared with placebo for 24 to 72 h.7 Candiotti et al. observed the same trend, but it did not reach statistical significance.8

The Kaplan-Meier plots of the time to first emesis from these two studies, along with the results presented by White et al.,11 show that the highest likelihood of emesis is within the first 24 h, after which it diminishes significantly. This is an expected result. However, it begs the question of whether any therapy that reduces the incidence of PONV in the first 24 h will reduce the subsequent incidence of PONV as well. Thus, a single therapy that is effective for 24 h may provide clinical advantages for both PONV and PDNV.

It is not clear from the studies that 0.075 mg is truly the optimal dose for 72 h prophylaxis. The doses chosen for these studies were based on the findings of Tang et al. who demonstrated a dose response for palonosetron up to 30 µg/kg, with 1 µg/kg being the lowest effective dose in the first 24 h.12 Future studies will need to assess whether doses above 0.075 mg increase efficacy in preventing PDNV.

How well are we doing in 2008 with our "big little problem"? In 1999 Apfel et al. documented a 30% incidence of PONV for all comers, with an incidence based on patient risk factors (female gender, history of motion sickness or PONV, nonsmoking, and use of postoperative opioids).9,10 In patients with two major risk factors, the likelihood of PONV was 39%, which increased to 79% if all four risk factors were present. White et al. investigated how well clinicians are presently doing in preventing PONV (and PDNV).11 In a multicenter study of nearly 400 patients with at least two major risk factors for PONV, routine PONV prophylaxis resulted in a 46% overall incidence of PONV (defined as no emesis or need for rescue antiemetic) in the first 24 h. This is not a tremendous improvement over the expected incidence when no prophylaxis is provided. When the clinicians in the study chose to follow the ASA guidelines for the prevention of PONV, the incidence decreased to 31%. This study reaffirmed that increasing the number of prophylactic antiemetics decreased the incidence of PONV, as recommended in a recent consensus guideline.13 These results suggest that many of us remain reluctant to be more aggressive with PONV prophylaxis, and deprive patients of the potential benefits of the advances in the past 10 yr. Indeed, a remarkable 98% response can be achieved with the aggressive approach of Scuderi et al.14: total IV anesthesia with propofol and remifentanil, no nitrous oxide, no neuromuscular blockade, aggressive IV hydration, triple prophylactic antiemetics (ondansetron, droperidol, and dexamethasone), and ketorolac for postoperative analgesia.

What is the current status of PDNV? Gupta et al. found a 32.6% incidence of PDNV.15 In the high-risk patients receiving placebo the incidence of PDNV was approximately 60% in the studies by Kovac et al. and Candiotti et al. However, as shown by White et al.,16 the risk factors for PONV established by Apfel et al.9 may not be applicable to PDNV. Ambulation and postdischarge opioid consumption may alter the risk factors for PDNV.17 Identifying risk factors for PDNV are needed as we try to improve treatment.

A common finding of the PONV studies published in this issue of Anesthesia & Analgesia is that the incidence of postdischarge emesis (10%-20% after 24 h) is much lower than the incidence of PDNV (30%-60%). Perhaps, nausea is the larger clinical problem in the days after surgery. These studies also demonstrate that increasing the number of prophylactic antiemetics,11 using antiemetics with a longer duration of action,7,8 or providing prophylactic antiemetics throughout the postdischarge period17 reduce the incidence of PDNV. Given the cost of therapy,18 clinical prophylaxis of PDNV should be based on head-to-head comparison of antiemetic regimens.

Fisher challenged the belief that the incidence of PONV and PDNV is an important outcome,19 suggesting that daily function is a better end-point. The reports by Kovac et al.,7 Candiotti et al.,8 White et al.,11 and Pan et al.17 in this issue of Anesthesia & Analgesia demonstrated that the reduction of PONV and PDNV interfered with daily function, confirming the importance of increasing our effort in minimizing "this big little problem."

We now know that very aggressive prophylaxis measures, combined with changes in anesthetic technique, can reduce the incidence of PONV to nearly 0. The new 5-HT₃ receptor antagonist palonosetron may provide advantages in both duration of action and in efficacy, extending antiemetic prophylaxis into the postdischarge period. Our patients are tired of waiting for the nausea and vomiting to end after surgery. We are tired of waiting for the "big little problem" to be solved.

	Footnotes

 
Accepted for publication April 8, 2008.

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