Post-operative Nausea and Vomiting (PONV): An Overview INTRODUCTION Postoperative nausea and vomiting (PONV) is a common problem in the

ambulatory surgery patient population, occurring in an estimated 35% of all patients. If high-risk patients are considered as a separate group, then as much as 70% of these patients will experience PONV. Clearly this is a problem that is worth addressing and a great deal of time, money and effort is spent each year dealing with the prevention and treatment of PONV. In addition to possible medical consequences of vomiting, ambulatory surgery centers are especially concerned with the control of PONV in order to prevent extended post-operative stays or unplanned admissions and the expense that accompanies them. A PRIORITY FOR PATIENTS However, there is a reason above and beyond the financial to approach this problem aggressively. Patient satisfaction with their ambulatory experience is closely tied with their ability to avoid nausea and vomiting after their surgery. In multiple surveys, patients list the avoidance of nausea and vomiting as their number one concern when faced with surgery and anesthesia. In fact, this issue ranks ahead of such things as pain, death, myocardial infarction and stroke for patients. While this may reflect some degree of denial, it also demonstrates clearly just how important this issue has become for ambulatory facilities today. So, even though aggressive prevention and management of PONV might incur some additional costs, it is worth doing to insure patient satisfaction remains high. RISK STRATIFICATION IS IMPORTANT Developing a cost-effective approach to the problem of PONV begins with proper risk-stratification. By focusing attention (and resources) on those groups of patients most likely to develop PONV, the overall cost of dealing with PONV is reduced. For example, if the risk of PONV in all patients is 30%, then 100 patients must be treated to achieve results in 30 individuals. However, if we can identify a group of patients where the risk is 70%, the same resources utilized to treat 100 patients in this group yields effective results in 70 individuals. This is good medicine too, as fewer patients are exposed to medications that they dont need and thus avoid additional costs and the possibility of side effects. A number of published studies have detailed the development of risk stratification scoring systems. However most anesthesia providers, by virtue of experience and training, can easily classify patients as low, moderate or high risk without the use of scoring systems. Certain patient characteristics are associated with a higher risk of PONV: younger age, female gender, large body habitus, history of PONV or motion sickness, anxiety, etc. Certain types of surgery are also known to predispose to PONV: head and neck procedures, intra-abdominal surgery, larparoscopic and gynecologic procedures, etc. Lastly, certain types of medications used in anesthesia are known to increase the incidence of PONV: opioids, reversal agents for neuromuscular blockade, etc. For those patients at low risk of PONV, no prophylaxis or minimal prophylaxis is likely the best choice. For patients at moderate risk, some prophylaxis followed by aggressive treatment if nausea and vomiting develops is warranted. For those patients at highest risk, aggressive prophylaxis and treatment may seem costly, but becomes cost-effective when the issues of patients satisfaction and avoidance of unplanned admission are considered. For patients in this last group, the concept of multi-modal therapy has yielded the best results (see additional discussion below). DROPERIDOL AND THE FDA For many years, droperidol was the foundation for any strategy or protocol utilized against PONV. Droperidol is very effective in small doses for the prevention and treatment of PONV and is often considered the gold standard when it comes to comparing the efficacy of other medications. The

fact that the medication was also very inexpensive led to its widespread and common usage among anesthesiologists faced with the issue of PONV. However, in December of 2001 the Food and Drug Administration (FDA) issued a Black Box warning about droperidol. This is the most severe warning that can be issued and was related to deaths associated with cardiac rhythm abnormalities in patients treated with droperidol. Specifically, the warning states that (this drug) should be reserved for use in the treatment of patients who fail to show an acceptable response to other adequate treatments and also recommended that monitoring should be used for a period of hours after administration of droperidol. Although many in the anesthesiology community disputed the need for this warning, the fact remains that the use of droperidol has fallen off precipitously since this action by the FDA. While droperidol use is not specifically prohibited, it has gone from a low-cost, first-line treatment that was considered safe to a high-cost (when monitoring is used), second- or third-line treatment of questionable safety. SEROTONIN ANTAGONISTS The serotonin antagonists (ondansetron, dolasetron and now granisetron) were already in common usage at the time of the FDA warning. While they were considered by most to be as effective as droperidol, their higher cost led them to be used routinely as second line agents or only for those patients at high risk. With droperidol in question, however, these agents became first-line agents and the issue of PONV became a much more costly one to address. Although a number of other medications (promethazine, prochlorperazine, scopolamine, propofol, etc.) are available at a lower cost, none have the efficacy when used alone that the serotonin antagonists offer and significant side effects and/or sedation are often seen with these other agents. When the serotonin antagonists were first introduced to clinical anesthesia practice, many people extrapolated the results seen in chemotherapy patients and concluded that the issue of PONV had finally been conquered. In addition to efficacy, these medications allow avoidance of the extrapyramidal side effects and sedation seen with other agents. Another positive is their minimal side effect profile (rare headache and dizziness, rare and clinically insignificant increase in liver enzymes). While these agents have not become the magic bullet or holy grail that some once hoped for, they are among the most efficacious options available for single agent prevention and treatment of PONV. As a result, although many institutions attempted to regulate the usage of these agents, they have become the most common option chosen by most anesthesiologists. Most clinical trials have shown this class of drugs to have equal efficacy when equivalent dosages are compared. In addition, a class effect has been suggested whereby a lower dose might be effective for prophylaxis as compared to the dose necessary to treat actual nausea and/or vomiting. So far, the FDA has not approved any of these agents to be utilized at these lower dosages. Granisetron, the most recently approved of the group for the indication of PONV, lags significantly behind in published trials to prove its efficacy. In addition, ondansetron has an orally dissolving tablet formulation that might offer an alternative to the intravenous/injectable formulation that serotonin antagonists are commonly available in. LOW DOSE STEROIDS More recent evidence has shown that dexamethasone is effective prophylaxis for PONV, at least as effective as droperidol and the serotonin antagonists when used as a single agent. The proper dose for this application appears to be very low, i.e. 5 mg IV given early during the anesthetic. At this dose, and given only in a single dose, there appear to be no significant side effects of the type associated with high-dose or chronic steroid use. As opposed to the serotonin antagonists, dexamethasone is a generic formulation and is therefore extremely inexpensive. As a result, it offers a nice replacement for droperidol when it comes to use for PONV prophylaxis. Unfortunately, it has no role in the treatment of established nausea and/or

vomiting. For that purpose, the serotonin antagonists likely remain the most efficacious choice for single agent treatment. COMBINATION THERAPY When single agent therapy is ineffective, combination therapy has been shown to be effective. The weight of evidence clearly shows that if an agent is ineffective against PONV, repeating a second dose of that agent is unlikely to increase efficacy. In fact, in addition to increasing cost, it is likely to increase the incidence of side effects. Therefore, the common practice of giving a second dose of the serotonin antagonists is not only expensive, but also useless. The key to choosing additional agents when a single agent fails is to choose an agent with a different mechanism of action. Nausea and vomiting involves multiple receptors, neurotransmitters, neural pathways, etc. Choosing agents that affect different receptors is the key to successful combination therapy. For example, if the serotonin receptors have already been blocked, consider adding an anticholinergic, antidopaminergic, or antihistamine. This concept is also one of the key principles of multi-modal therapy (see discussion below), which has yielded the best results with regards to prevention of PONV. However, multi-modal therapy is clearly both costly and labor-intensive and therefore should be reserved for those patients at the very highest risk of PONV where failure to prevent symptoms can result in very poor patient satisfaction and/or the high cost of an unplanned and undesired admission. SUGGESTED REGIMEN It is clear that the problem of PONV is a significant one in terms of medical care, financial issues and in view of the goal of patient satisfaction. Stratifying risk is the first step in a cost-effective and evidence-based approach to dealing with this problem. Once a patient is placed into the proper risk-group, then specific recommendations can be made regarding proper care. In low-risk patients, it is likely that no treatment is necessary. However, because a single dose of dexamethasone is so inexpensive, many advocate giving this to all patients (similar to how droperidol was used in the past). In moderate-risk patients, dexamethasone alone provides a cost-effective approach to prophylaxis. If this prophylaxis fails, then a serotonin antagonist should be used as soon as nausea or vomiting occurs. If treatment with this single agent fails, then aggressive and properly chosen combination therapy should be utilized. In high-risk patients, dexamethasone plus a serotonin antagonist should be utilized for prophylaxis. If this prophylaxis fails, repeating the dose of the serotonin antagonist is not indicated. Instead, aggressive and properly chosen combination therapy should be utilized. In the very high-risk patient, full use of multi-modal therapy should be undertaken (see below) in an attempt to maximize success rate of prophylaxis. MULTI-MODAL THERAPY: A CONCEPT THAT WORKS Dr. Scuderi was the first to show that the goal of complete prevention of PONV is indeed possible even in a high-risk patient population. His protocol combined many different aspects of care in order to eliminate nausea and vomiting after surgery and anesthesia. This included such concepts as total intravenous anesthesia, the avoidance of certain medications known to cause PONV, aggressive intravenous fluid replacement, triple agent prophylaxis utilizing medications with different mechanisms of action, etc. While it is not known which parts of Scuderis protocol were most significant in terms of achieving the desired outcome, it was clear that attacking the problem from many different aspects does lead to higher rates of success. Today, the concept of multi-modal therapy includes many things including:

The use of properly chosen combination therapy (drugs that have different mechanisms of action) for example, dexamethasone plus a serotonin antagonist. The use of aggressive intravenous fluid replacement. Attention to post-operative pain control. Alteration of anesthetic technique: total intravenous anesthesia (TIVA), avoidance of certain medications known to cause PONV (e.g. opioids, inhalational agents, nitrous oxide, reversal agents for muscle relaxants), the use of regional anesthesia for pain control and/or instead of general anesthesia, etc. The use of alternative therapies such as acupressure, TENS, relaxation techniques, etc. While these therapies seem to be of limited efficacy when used as sole therapy, the use of them in combination with a multi-modal protocol seems to increase overall success.

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