Date: November 24th, 2017
Reference: Roldan et al. Trial Comparing Haloperidol Combined With Conventional Therapy to Conventional Therapy Alone in Patients With Symptomatic Gastroparesis. AEM November 2017
Guest Skeptic: Dr. Justin Morgenstern is an emergency physician and the Director of Simulation Education at Markham Stouffville Hospital in Ontario. He is the creator of the excellent #FOAMed project called First10EM.com
Case: You charge nurse approaches as you finish charting on the trauma patient who was just transferred out. “Mrs. G. is back again, vomiting and screaming in pain. This is the third time this month, and nothing ever seems to help. Is there anything we can do for her?”
Mrs. G is a 37-year-old female with gastroparesis secondary to diabetes. You know her well, and none of the usual anti-emetics seem to help her symptoms. While inwardly wishing you worked in a country where droperidol was available, you wonder whether there is any new research to guide your management.
Background: Gastroparesis is a challenging and frustrating condition for both patients and providers. Patients can present with abdominal pain, nausea, vomiting, early satiety and postprandial fullness. Gastroparesis has also been called delayed gastric emptying and it literally means paralysis of the stomach.
The most common cause of gastroparesis is idiopathic. However, when a cause is known it is often due to diabetes or surgery. Unfortunately, nothing really works well for this condition. The Food and Drug Administration has only approved metoclopramide for gastroparesis. It works by blocking dopamine receptors with antiemetic and prokinetic properties.
Multiple other drugs have been tried to treat gastroparesis. This includes serotonin 5-HT3 antagonists (ondansetron), histamine antagonists (meclizine and promethazine) prokinetic agents like serotonin 5-HT4 receptor agonists (cisipride) and motilin receptor agonists (erythromycin).
One drug that has been tried is haloperidol. It is an antipsychotic drug used for a number of psychiatric conditions including schizophrenia. Haloperidol blocks the dopamine receptors in the brain. It has been used for years to treat nausea and vomiting in post-operative patients and cancer patients.
A retrospective study was published earlier this year on haloperidol for the treatment of gastroparesis secondary to diabetes mellitus. It was called HUGS and showed lower hospital admissions and opioid use in patients receiving 5mg of haloperidol (Ramirez et al AJEM). You can find a good review on this paper on REBEL EM.
There has never been a randomized control trial looking at the efficacy of haloperidol on nausea and vomiting in any setting, until now.
Clinical Question: Does haloperidol, when added to conventional therapy, decrease abdominal pain and nausea at one hour in patients presenting to the emergency department with known gastroparesis?
Reference: Roldan et al. Trial Comparing Haloperidol Combined With Conventional Therapy to Conventional Therapy Alone in Patients With Symptomatic Gastroparesis. AEM November 2017.
- Population: Adults 18 years and older presenting to the emergency department with abdominal pain due to their known gastroparesis.
- Exclusions: Past history or current evidence of QT prolongation, hypotension (systolic blood pressure < 90 mm Hg), presence of other acute abdominal pathologic conditions, allergy to haloperidol, pregnancy, incarcerated status, or an inability to give informed consent.
- Intervention: Haloperidol 5mg IV
- Comparison: Placebo
- Primary Outcomes: Abdominal pain measured on a validated 10-point visual analog scale (VAS) and nausea intensity scored on a 5-point VAS at one hour.
- Secondary Outcomes: Disposition status, emergency department length of stay, adverse events and nausea resolution at one hour. Nausea resolution was defined as the patient not requesting additional antiemetic medication.
Dr. Carlos Roldan is an assistant professor of Pain Medicine and a Clinical Associate Professor of Emergency Medicine at the University of Texas MD Anderson Cancer Center
Authors’ Conclusions: “Haloperidol as an adjunctive therapy is superior to placebo for acute gastroparesis symptoms.”
Quality Checklist for Randomized Clinical Trials:
- The study population included or focused on those in the emergency department. Yes
- The patients were adequately randomized. Yes
- The randomization process was concealed. Yes
- The patients were analyzed in the groups to which they were randomized. Yes
- The study patients were recruited consecutively (i.e. no selection bias). Yes
- The patients in both groups were similar with respect to prognostic factors. Unsure
- All participants (patients, clinicians, outcome assessors) were unaware of group allocation. Yes
- All groups were treated equally except for the intervention. No
- Follow-up was complete (i.e. at least 80% for both groups). Yes
- All patient-important outcomes were considered. Unsure
- The treatment effect was large enough and precise enough to be clinically significant. Yes
Key Results: 33 patients were included in the study s(15 in the haloperidol group and 18 in the placebo group). The mean age was in the mid 40’s with about 75% women.
Primary Outcomes: Haloperidol group works better than placebo for treating pain and nausea from gastroparesis.
- Primary Outcomes:
- Pain: Decreased from a mean of 8.5 to 3.1 with haloperidol (p<0.001). Decreased from a mean of 8.3 to 7.2 with placebo (p=0.11).
- Nausea: Decreased from a mean of 4.5 to 1.8 with haloperidol (p<0.001). Decreased from a mean of 4.1 to 3.4 with placebo (p=0.05)
- Secondary Outcomes:
- Disposition: Fewer patients were admitted to hospital in the haloperidol group (27% vs 72%, p=0.009).
- Length of Stay: Median length of stay was statistically unchanged, but the point estimate was shorter in the haloperidol group (5 vs 9 hours, p=0.77).
- Resolution of Nausea: This was not listed in the results?
- Adverse Events: No adverse events were reported.
We see a lot of patients in the emergency department with cyclic vomiting syndromes. It is great to have the first ever randomized control trial to provide some additional evidence to help us better address this issue. Listen to the SGEM Podcast on iTunes to hear Carlos’ answers to our nerdy questions.
- Population and Sample Size: This study limited enrolment to patients with known gastroparesis. Given that the mechanism attributed to haloperidol is antagonism of dopamine receptors in the chemoreceptors trigger zone, why limit the study to only patients with gastroparesis rather than undifferentiated cyclic vomiting, which would have broader applicability in the emergency department? Your sample size calculation determined that 18 participants were needed in each group, but you only had 15 patients in the haloperidol group. Other researchers will add a buffer to increase the sample size in anticipation of losing a few patients. Did you consider doing this and how do you think the smaller sample size impacts the results/conclusions?
- ECG: You performed ECGs on all patients in order to exclude patients with a long QT. Is there any evidence that you are aware of the screening ECGs prevent adverse events with anti-psychotic use? Research protocols are much stricter than routine clinical practice. IF you were using haloperidol for these patients in your clinical practice would you get an ECG every time before administering this medication?
- Statistical vs. Clinical Significance: Although they were not statistically different, there seem to be important differences between the two groups in terms of the treatments they received. For example, 40% of the haloperidol group received morphine as compared to 28% of the placebo group. Similarly, 53% of the haloperidol group received and ondansetron as compared to only 28% of the placebo group . Do you think these imbalances might have affected your results? In addition, there was no statistical difference in emergency department length of stay. However, the five hours in the haloperidol group vs. nine hours in the placebo group might be clinically significant to the patient and the physician.
- Outcomes: First of all, you had two primary outcomes. Did you know that there can only be one primary outcome (Highlander)? You chose pain and nausea at one hour as your primary outcome. In terms of patient oriented outcomes, do you think choosing a longer follow up period might have been better? Pain score VAS has been validated previously. Has the 5-point nausea VAS been validated? One final thing under outcomes. Your secondary outcomes included nausea resolution at one hour defined as not requesting additional antiemetic medication. We could not find this reported in the result section?
- Adverse Events and Safety: Adverse events are typically under reported in studies. We really liked that you looked for adverse events and you did not claim safety. You recognized that the study was far too small to make such a positive claim. Instead, you stated that there were no adverse events reported. Would you consider doing a larger study on undifferentiated gastroparesis presentations to the emergency department and what size to you think it would take to claim safety of haloperidol?
Is there anything else you want the SGEMers to know about your study Carlos?
Comment on Authors’ Conclusion Compared to SGEM Conclusion: We generally agree with the authors’ conclusions.
SGEM Bottom Line: Consider adding 5mg IV haloperidol as an adjunct treatment to patients presenting to the emergency department with abdominal pain and nausea from their known gastroparesis.
Case Resolution: You discuss this new trial with your patient, and after a shared decision-making conversation, you decide to try haloperidol as part of their symptom control strategy.
Clinical Application: Adding this first, small randomized control trial to the large clinical experience, we think it is reasonable to consider trying haloperidol as an adjunct to treat gastroparesis.
What Do I Tell My Patient? As you know, the symptoms from gastroparesis can be very difficult to manage. There is new research paper saying a medication called haloperidol could help. This medicine has been successfully used for years to treat post-operative patients and cancer patients with nausea and vomiting. I am not saying you have cancer. What I am saying is you have tried all these other medications that have not worked. This recent small study on haloperidol suggests it could work for you. I can see you are suffering and want to try something to help.
Keener Kontest: Last weeks’ winner was David Bowden and EMT from Texas. David knew honey bees are able to behaviorally induce fever in a whole-of-colony response to a fungal parasite?
I made a mistake last week with the keener winner. It was basically a tie with Julien Ginsberg-Peltz a PedEM from Baystate Medical Center in Springfield, MA and Mateusz Szmidt from Liverpool, England. I think the problem was due to the time zone difference. Regardless, they are both getting a cool skeptical prize.
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.
SGEMHOP: Now it is your turn SGEMers. What do you think of this episode? Tweet your comments using #SGEMHOP. What questions do you have for Dr. Roldan and his team? Ask them on the SGEM blog. Share your experience using haloperidol for gastroparesis. The best social media feedback will be published in AEM.
Also, don’t forget those of you who are subscribers to Academic Emergency Medicine can head over to the AEM home page to get CME credit for this podcast and article.
- Go to the Wiley Health Learning website
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- REBEL EM – Diabetic Gastroparesis Needs HUGS
- EM in Focus – Haloperidol- one anti-emetic to rule them all.
- First10EM – Articles of the Month November 2017
- FOAMCast – Episode 73 – Gastroparesis & Biliary Pathology