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Date: June 8th, 2018

Reference: April MD, et al. Aromatherapy Versus Oral Ondansetron for Antiemetic Therapy Among Adult Emergency Department Patients: A Randomized Controlled Trial. Ann Emerg Med 2018

Guest Skeptic: Meghan Groth is a pharmacist who has been practicing in emergency medicine for the past six years. She’s recently transitioned into industry, taking on a position as a medical science liaison in New England. She’s been a contributor for the Academic Life in Emergency Medicine and Emergency Medicine PharmD blogs and is a member of the ALiEMU Capsules team.

Case: A 32-year-old woman presents to your emergency department with complaints of nausea (nausea VAS is about a 5 on a scale of 0 to 10) and states she’s worried she’s coming down with some sort of stomach flu. She’s hemodynamically stable and looks a bit queasy but isn’t actively retching when you see her.

Background: Nausea and vomiting are frequent complaints of patients presenting to the emergency department, accounting for just under five million visits per year.

A number of prescription medications are available to treat these symptoms, including ondansetron, droperidol, metoclopramide, promethazine, and prochlorperazine.

The most commonly utilized antiemetic in US emergency departments is ondansetron, a 5-HT 3 antagonist.

Despite its widespread use, a dose of intravenous ondansetron takes about 30 minutes to take effect, which has led to an interest in more rapidly acting interventions for actively nauseous patients on the verge of vomiting.

A new Cochrane Review by Hines et al published in 2018 looked at aromatherapy for post-operative nausea and vomiting. They concluded that aromatherapy may have similar effectiveness to placebo based on low-quality evidence.

There’s some data supporting the use of an inhalation of isopropyl alcohol in emergency department patients (Beadle, et al Ann Emerg Med 2015). We covered that paper on the SGEM in Episode #144.

The SGEM bottom line from that critical review was that for patients presenting to the emergency department with complaints of nausea and vomiting, a nasal inhalation of isopropyl alcohol is a quick, inexpensive way that may transiently improve symptoms without evidence of harm.

Clinical Question: Does nasally inhaled isopropyl alcohol reduce nausea in adult emergency department patients with or without oral ondansetron?

Reference: April MD, et al. Aromatherapy Versus Oral Ondansetron for Antiemetic Therapy Among Adult Emergency Department Patients: A Randomized Controlled Trial. Ann Emerg Med 2018

  • Population: Patients greater than 17-years-old presenting to the emergency department with a chief complaint of nausea, with self-reported nausea severity of three or greater on a numeric response scale (range 0 to 10).
    • Exclusion Criteria: Notably they excluded patients who had already had an intravenous catheter placed or who had received antiemetic therapy prior to enrollment. [rest on website] Allergy to isopropyl alcohol or ondansetron; inability to inhale through the nares; recent intake of medications contraindicating alcohol administration; altered mental status; a known history of QT-segment prolongation; clinical suspicion for serotonin syndrome; suspected or know pregnancy or treating provider discretion.
  • Intervention: There were three treatment arms in this study
    1. Inhaled isopropyl alcohol and 4 mg oral ondansetron
    2. Inhaled isopropyl alcohol and oral placebo
    3. Inhaled saline placebo with 4 mg oral ondansetron
  • Comparison: There was no dual placebo arm due to concerns that would discourage patient participation
  • Outcome:
    • Primary: Change in nausea from baseline to 30 minutes post-intervention as measured on a 0- to 100-mm VAS
    • Secondary: Change in pain VAS 30 minutes post intervention, nausea scores until emergency department disposition, pain score at emergency department disposition, and satisfaction VAS scores

Authors’ Conclusions: “Among ED patients with acute nausea and not requiring immediate intravenous access, aromatherapy with or without oral ondansetron provides greater nausea relief than oral ondansetron alone.”

Quality Checklist for Randomized Clinical Trials:

  1. The study population included or focused on those in the emergency department. Yes
  2. The patients were adequately randomized. Yes
  3. The randomization process was concealed. Yes
  4. The patients were analyzed in the groups to which they were randomized. Yes
  5. The study patients were recruited consecutively (i.e. no selection bias). No
  6. The patients in both groups were similar with respect to prognostic factors. Unsure 
  7. All participants (patients, clinicians, outcome assessors) were unaware of group allocation. Unsure 
  8. All groups were treated equally except for the intervention. Unsure
  9. Follow-up was complete (i.e. at least 80% for both groups). Yes
  10. All patient-important outcomes were considered. Yes
  11. The treatment effect was large enough and precise enough to be clinically significant. Unsure

Key Results: 122 patients were enrolled and subsequently randomized, and 120 were included in the modified intent-to-treat population, resulting in a 98% follow up rate. Patient characteristics were pretty similar at baseline except that women represent 35% of the inhaled isopropyl alcohol plus oral placebo compared to ~50% women in the other two groups. The predominant cause of nausea being infectious gastroenteritis (55%) and the nausea score at baseline was just over 50 on a 0- to 100-mm VAS scale.

Inhaled isopropyl alcohol alone or in combination with oral ondansetron was superior to oral ondansetron alone.

  • Primary Outcome: Mean VAS nausea scale reduction at 30 minutes posttreatment was as follows:
    1. Inhaled isopropyl alcohol and 4 mg oral ondansetron 30 mm (95% CI 22 to 37 mm)
    2. Inhaled isopropyl alcohol and oral placebo 32 mm (95% CI 25 to 39 mm)
    3. Inhaled saline placebo with 4 mg oral ondansetron 9 mm (95% CI 5 to 14 mm)
  • Secondary Outcomes: Both groups receiving inhaled isopropyl alcohol experienced lower nausea VAS scores throughout their emergency department stay than the inhaled placebo/oral ondansetron group. These subjects also had lower nausea VAS scores at emergency department disposition and improved satisfaction scores when compared with the inhaled placebo/oral ondansetron group. Both inhaled isopropyl alcohol groups required less rescue antiemetic therapy.

  1. Blinding: The authors acknowledged their challenges with blinding the inhalational intervention in this study. They covered up the labels on the saline or isopropyl alcohol swabs, kept the swabs at arms’ length from study investigators, and asked patients to not reveal what they were sniffing. Even so, more than half (60%) of the subjects in the study correctly identified the inhaled product as either placebo or isopropyl alcohol when asked about it afterward. Given that the primary endpoint of the study was also a subjective measure (the nausea score on a VAS), this may have been affected by this obstacle. Also, the pain VAS suggests unblinding of subjects. Those in group three inhaling the placebo got the much less reduction in their mean pain score. Since treatment was left up to the attending physician, could patients in the placebo inhalation group have received more opioids for their pain leading to more nausea and vomiting?
  2. Standard of Care: Study investigators noted that subjects could receive standard of care after enrollment in the trial. This could have included intravenous catheter placement after enrollment and/or rescue anti-emetics and analgesics. In the results section, they described the proportion of patients who received rescue anti-emetics, but they didn’t describe those patients who had an IV placed and more importantly, those that received rescue analgesics. To me, it seems like if pain scores were going to be described as an endpoint, then receipt of analgesics would have been important to detail. Especially if the analgesic was an opioid that could produce nausea and vomiting.
  3. Pairwise Comparisons: They compared 1 vs. 2 and 2 vs. 3 but not 1 vs. 3? The comparison of group 1 vs. 2 is really just comparing the addition of oral ondansetron, where the comparison of 2 vs. 3 evaluates the effect of inhaled isopropyl alcohol versus oral ondansetron (both variables are flipped in this comparison). I would have liked to have seen a comparison of group 1 (isopropyl alcohol/oral ondansetron) and group 3 (inhaled placebo/oral ondansetron) that would have evaluated the effect of adding inhaled isopropyl alcohol against a background of oral ondansetron, as might be routinely expected in practice. The mean VAS reduction at 30 minutes for group 1 was 30 and for group 3 was 9, but the standard deviations are fairly large, and I’m not that great at calculating p-values off the top of my head. I would have found it valuable for the authors to have provided this statistical comparison as well.
  4. Not Consecutive Enrolment: Patients were recruited as a convenience sample. Nurses identified potential candidates. They also did not recruit 24/7, although study personnel were made available during a range of times to capture patients from evening/night time hours and over the weekend. Patients could also be excluded at the treating provider discretion. This introduces the possibility of selection bias.
  5. Strawman Comparison: The primary study end point was nausea score reduction at 30-minutes post-intervention. Under the best of circumstances, intravenous ondansetron has an onset of effect of 30 minutes (Roila and Del Favero) and the peak plasma concentration of oral ondansetron takes 90 minutes (Markham and Sorkin). If attempting to measure the effect of inhaled isopropyl alcohol with or without oral ondansetron, I’m not sure that 30 minutes is the most appropriate time point to do this. I’m concerned that it may have been too soon after intervention for the oral ondansetron to have taken effect. I think you can see this in the article with the inhalational placebo/oral ondansetron group, where the effect on VAS was definitely more pronounced at 60 minutes than at 30 minutes. It depends on what you’re trying to demonstrate; if you want to show that inhalational isopropyl alcohol works more quickly than oral ondansetron, then the 30-minute mark has some value. But if trying to test the overall efficacy of this intervention, 60 minutes or even 90 minutes omay have been more appropriate.

Comment on Authors’ Conclusion Compared to SGEM Conclusion: This study adds to the previous research by Beadle and colleagues (SGEM#144) where we concluded that an inhalation of isopropyl alcohol could be considered for transient, symptomatic relief of nausea in emergency department patients, but the present study probably excluded those with more severe nausea/vomiting because they excluded those with IV catheters in place prior to enrollment. That being said, it does appear that an inhalation of isopropyl alcohol with or without oral ondansetron was effective in reducing nausea VAS scores. We are concerned that this might be due to a placebo effect and are disappointed they did not report any safety data.

SGEM Bottom Line: In moderately nauseated adult patients presenting to the emergency department who do not need immediate IV access, an inhalation of isopropyl alcohol monotherapy may be a reasonable option. However, it could just be a placebo effect.

Case Resolution: You have to step out of the patient’s room to tend to a critically ill patient. You let her know that you’ll be back as soon as you can to examine her and get the appropriate tests underway, but in the meantime, you’d like her to take some deep inhalations of an isopropyl alcohol swab while she waits.

Clinical Application: This evaluation adds to the available literature on inhaled isopropyl alcohol as symptomatic relief for patients in the emergency department experiencing mild to moderate nausea and vomiting. It’s an inexpensive and potentially effective intervention when used on its own or added to ondansetron. We still cannot rule out the placebo effect until a better placebo can be investigated. Perhaps making both smell like peppermint to mask the isopropyl alcohol smell or making the placebo smell like something that is known to induce nausea and see if that too reduces nausea in the test subjects.

What Do I Tell My Patient?  It looks like you’re feeling fairly nauseous at the moment.  I would like to spend a little more time finding out about what brings you here. However, I need to step out to check on another patient. For the moment, please take a few deep inhalations of this alcohol swab. There have been some studies that show this could, ease some of your nausea and vomiting while you wait. We will also get some lab tests done. When I get back we can see if you need something else for the nausea.

Keener Kontest: Last weeks’ winner was David Lemonick from Pittsburgh. He knew Vince Wilfork was the NFL player recently on the HBO show Hard Knocks talking about using acupuncture for the treatment of muscle pain after workouts. David has won the keener contest multiple times and will be receiving a super-duper prize from a group that helped inspire the SGEM. Remember, you have to play to win and win to find out what the cool skeptical prize is.

Listen to the SGEM podcast on iTunes to hear this weeks’ question. If you know the answer send an email to TheSGEM@gmail.com with “keener” in the subject line. The first correct answer will receive a cool skeptical prize.

Other FOAMed:

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.