Antiemetic Efficacy of Ipa Inhalation

Post-Operative Nausea and Vomiting

Antiemetic Efficacy of IPA Inhalation in High-Risk PONV Patients

Antiemetic Efficacy of IPA Inhalation in High-Risk PONV Patients

Post-operative nausea and vomiting (PONV) is considered a significant enough threat to patient health that surgical patients are often treated prophylactically to prevent its occurrence (reviewed by Murphy, Hooper, Sullivan, Clifford, and Apfel, 2006). PONV has been defined as an episode of nausea, vomiting, or retching (non-productive vomiting) that occurs within 24 hours following surgery, which can cause patient distress, post-operative complications, prolonged recovery times, and increase the cost of post-surgical care. The prevalence of PONV for the average surgical patient is estimated to be between 20 and 30%, but high-risk patients may have up to an 80% or higher chance of experiencing this condition. The high variability in PONV risk precludes standard prophylactic treatment, due to the cost and the increased risk to patient health that unnecessary treatment poses. The most common approach to PONV prophylactic treatment is therefore screening patients in advance for PONV risk factors.

PONV risk factors can be divided into three categories: patient-specific, anesthetic-related, and surgery-related (reviewed by Murphy, Hooper, Sullivan, Clifford, and Apfel, 2006). Patient-specific factors tend to be fixed, in contrast to anesthetic- or surgery-related factors. These fixed factors include gender, smoking status, and age. Essentially, women are 2-3 times more likely to experience PONV once they have reached puberty and smokers and older adults benefit from a reduced PONV risk. Other patient-specific risk factors include a history of PONV or motion sickness, a history of migraine, health problems, and perioperative anxiety. However, only gender, smoking status, history of PONV, and motion sickness are reliable predictors of PONV risk.

The anesthesia-associated factors that increase the risk of PONV are volatile anesthetics, nitrous oxide, length of anesthesia exposure, and the use of opiates post-operatively (reviewed by Murphy, Hooper, Sullivan, Clifford, and Apfel, 2006). These risk factors are considered variable because substitutes less likely to cause PONV can be used for some patients. The surgical risk factors include the length and type of surgery.

The most common antiemetic used to reduce the risk of PONV is ondansetron, which is administered prophylactically 15 to 30 minutes before the end of surgery (reviewed by Pelligrini, DeLoge, Bennett, and Kelly, 2009). This drug has been shown to lower PONV incidence by 50 to 80% in low-risk patients; however, high-risk patients experience only a 25% reduction in PONV incidence with ondansetron. High-risk patients are therefore often treated post-operatively with multiple antiemetics, the most common being promethazine in combination with ondansetron. In contrast to ondansetron though, promethazine can produce significant adverse side effects, including sedation, dry mouth, and rarely, hypotension. Such side effects tend to increase the risk of patient noncompliance when promethazine has been prescribed for home use, since some patients have reported the side effects to be unacceptably severe. In addition, some patients may harbor 5-HT receptor mutations that render them less susceptible to the effects of ondansetron and other 5-HT antagonist antiemetics (reviewed by Lummis, 2012, p. 4). There is thus a need for alternative antiemetic treatments for these patients.

Towards the goal of identifying alternative antiemetic treatments for patients with a high risk of PONV, Pelligrini and colleagues (2009) tested the antiemetic efficacy of 70% isopropyl alcohol (IPA) inhalation. While IPA inhalation has been shown to be an effective antiemetic for low-risk patients, it has not been tested on high-risk patients or high-risk patients treated prophylactically with ondansetron. The following report will examine the research study conducted by Pelligrini and colleagues (2009) for its value in providing empirical support for treating high-risk PONV patients with IPA inhalation.

Study Design

Study subjects were screened for any physical or psychological problems that would interfere with the outcome of the study, including suspected PONV risk factors like obesity (Pelligrini, DeLoge, Bennett, and Kelly, 2009). A total of 96 patients provided informed consent, but only 85 subjects completed the study (Pelligrini, DeLoge, Bennett, and Kelly, 2009). The medications used for preoperative anxiolysis and sedation were left to the discretion of the anesthetist. After patients gave informed consent, they were asked to verbally report their level of nausea on a numeric rating scale (VNRS) of 0 to 10 preoperatively (Pelligrini, DeLoge, Bennett, and Kelly, 2009). A score of 0 represented no nausea and 10 the “worst imaginable.

All subjects received the same anesthetics for induction, but the agents used for maintenance were based on the anesthetist’s choice (Pelligrini, DeLoge, Bennett, and Kelly, 2009). Ondansetron was administered 15 to 30 minutes before extubation intravenously (IV). All information concerning surgical procedures was recorded for later comparisons. Patients were extubated before transfer to a postanesthesia care unit (PACU) or same-day surgery unit (SDSU), where they were asked to provide a VNRS rating and given promethazine or IPA. Patients were asked to continue reporting nausea or vomiting events, and IPA or promethazine use, for 24 hours following surgery. IPA patients were also provided promethazine suppositories for PONV rescue, in case the IPA failed to reduce their symptoms to acceptable levels.

Study Findings

Patients were randomly assigned to either the IPA or promethazine group. Demographically, the IPA group were on average younger (34 vs. 36 years of age, p = 0.052) (Pelligrini, DeLoge, Bennett, and Kelly, 2009). The IPA patients were also more likely to receive nitrous oxide (59% vs. 37%, p = 0.049), therefore these patients would be expected to have a higher PONV risk than the control group receiving promethazine. Given that patients had between 3 and 5 risk factors for PONV, the predicted prevalence of PONV was estimated to be approximately 60%. Ondansetron treatment was expected to reduce nausea by 25 to 42%, but the overall incidence of reported nausea events were 76 and 60% for the IPA and promethazine groups, respectively. The authors interpreted this to indicate that ondansetron is not very effective in high-risk patients, although it seemed to be somewhat effective during the first few hours post-surgery.

The difference in overall nausea events was not statistically significant (p = 0.119), but when the data was stratified by location, IPA patients were significantly more likely to experience a nausea event at home (p = 0.019 ) (Pelligrini, DeLoge, Bennett, and Kelly, 2009). The efficacy of IPA as an antiemetic is supported by the fact that few IPA patients resorted to promethazine rescue at home (7% vs. 23%, p = 0.039). Probably the most striking result of the study was that IPA treatment reduced the time to 50% reduction in VNRS score compared to promethazine in all settings (PACU, p = 0.045; SDSU, p = 0.032; home, p = 0.017). Finally, IPA patients reported no side effects, while promethazine patients reported sedation and dry mouth.

Critique

Pelligrini and colleagues (2009) directly compared the efficacy of the standard post-operative antiemetic promethazine to that of IPA inhalation, within a surgical and post-operative setting. They chose to focus on patients at high-risk for experiencing PONV, because these patients have few options for treating this condition. Since there were 56.4 million ambulatory and impatient surgical procedures performed in the U.S. In 2006 and at least 30.7% of these received general anesthesia (Cullen, Hall, and Golosinskiy, 2009, p. 5), the expected 20 to 30% prevalence rate for PONV suggests a significant number of patients could benefit from alternative antiemetic to promethazine. This need is even greater for high-risk PONV patients.

The theoretical model Pelligrini and colleagues (2009) relied on was a PONV risk scores model, which is generally-accepted and evidence-based (Apfel, 2005, p. 492-492). The predictive value of this model was supported by the results of the study, which revealed an overall PONV prevalence rate between 60 and 76% despite aggressive prophylactic antiemetic treatment. Since the primary outcome of the study was nausea events, which is a subjective experience and thus refractory to quantification, this was a qualitative and thus naturalistic inquiry. The primary survey instrument used was the VNRS, which tracked the patients’ reports of nausea for the first 24 hours post-surgery.

While IPA inhalation as a PONV antiemetic appears to be effective and without side effects, it does not appear to be as effective as promethazine. Given that patients experiencing nausea tend to avoid taking oral medications by mouth and many patients dislike using suppositories (reviewed by Pelligrini, DeLoge, Bennett, and Kelly, 2009), patient compliance in a home environment is a significant issue. This study revealed that IPA inhalation significantly reduced reliance on home use of promethazine suppositories for rescue, which supports the efficacy of IPA as a PONV antiemetic; however, a recent meta-analysis found that when the results of this study and similar studies are averaged, there is no support for less reliance on promethazine rescue by IPA patients (Hines, Steels, Chang, and Gibbons, 2012). One advantage IPA seems to have over promethazine is how quickly PONV symptom severity were reduced. These results therefore provide qualitative support for using IPA inhalation as a PONV antiemetic in high-risk patients, but only if promethazine rescue is available.

A possible shortcoming was mentioned by Pelligrini and colleagues (2009) in the discussion; the lack of an inhalation control that would show IPA, and not the act of inhaling a vapor, was responsible for the antiemetic effect. This potential shortcoming was addressed by the authors, by citing a study that revealed that inhalation of saline was completely ineffective compared to IPA. The use of a single study to justify the lack of an appropriate control is not sufficient. Hines and colleagues (2012) reviewed the evidence supporting the efficacy of IPA apart from the placebo effect of inhalation, and found a single randomized, blinded study. This study revealed no difference in efficacy between IPA, peppermint oil, and saline inhalation.

Discussion

The study by Pelligrini and colleagues (2009) revealed IPA inhalation provides some benefit in PONV high-risk patients, although their claims that its efficacy is equal to promethazine or other equivalent drugs are unsupported by this critique and by other reviewers (Hines, Steels, Chang, and Gibbons, 2012). This raises the issue of medical ethics when treating high-risk patients with IPA, since this treatment is not as effective. Pelligrini and colleagues (2009) would probably cite patient reports of PONV antiemetic treatment satisfaction to support their conclusions, but patient satisfaction scores may not accurately reflect patient PONV experiences, since patients and researchers were not blinded to each other. The lack of an inhalation control also undermines the validity of the author’s conclusions that IPA inhalation could replace pharmacological agents for treating PONV. To conclude, it would be irresponsible to rely on IPA inhalation to treat PONV in high-risk patients without also providing access to pharmacological antiemetics for rescue. There is also substantial evidence of author bias throughout the study, including how the study was designed. If only the researchers and patients had been blinded to each other, then the patient reports of treatment satisfaction would have been more credible.

References

Apfel, Christian C. (2005). PONV: A problem of inhalational anaesthesia? Best Practice & Research Clinical Anaesthesiology, 19(3), 485-500.

Cullen, Karen A., Hall, Margaret J., and Golosinskiy, Aleksandr. (2009). Ambulatory surgery in the United States, 2006. National Health Statistics Reports, 11, 1-28. Retrieved 9 Oct. 2012 from http://www.cdc.gov/nchs/data/nhsr/nhsr011.pdf.

Hines, S., Steels, E., Chang, A., and Gibbons, K. (2012). Aromatherapy for treatment of postoperative nausea and vomiting (review). Cochrane Database of Systematic Reviews, April 18(4), 1-52. Retrieved 11 Oct. 2012 from http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD007598.pub2/abstract.

Lummis, Sarah C.R. (2012). 5HT3 receptors. Journal of Biological Chemistry, in press, October 4. Retrieved 8 Oct. 2012 from http://www.jbc.org/cgi/doi/10.1074/jbc.R112.406496.

Murphy, Marguerite J., Hooper, Vallire D., Sullivan, Ellen, Clifford, Theresa, and Apfel, Christian C. (2006). Identification of risk factors for postoperative nausea and vomiting in the perianesthesia adult patient. Journal of the PeriAnesthesia Nursing, 21(6), 377-384.

Pelligrini, Joseph, DeLoge, Jon, Bennett, John, and Kelly, Joseph. (2009). Comparison of inhalation of isopropyl alcohol vs. promethazine in the treatment of postoperative nausea and vomiting (PONV) in patients identified as at high risk for developing PONV. American Association of Nurse Anesthetists Journal, 77(4), 293-299.