Observational study of haloperidol in hospitalized patients with COVID-19

  1. Nicolas Hoertel
  2. Marina Sánchez-Rico
  3. Raphaël Vernet
  4. Anne-Sophie Jannot
  5. Antoine Neuraz
  6. Carlos Blanco
  7. Cédric Lemogne
  8. Guillaume Airagnes
  9. Nicolas Paris
  10. Christel Daniel
  11. Alexandre Gramfort
  12. Guillaume Lemaitre
  13. Mélodie Bernaux
  14. Ali Bellamine
  15. Nathanaël Beeker
  16. Frédéric Limosin
  17. on behalf of the AP-HP/Universities/INSERM Covid-19 research collaboration and AP-HP Covid CDR Initiative

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Abstract

Haloperidol, a widely used antipsychotic, has been suggested as potentially useful for patients with COVID-19 on the grounds of its in-vitro antiviral effects against SARS-CoV-2, possibly through sigma-1 receptor antagonist effect.

Methods

We examined the associations of haloperidol use with intubation or death and time to discharge home among adult patients hospitalized for COVID-19 at Assistance Publique-Hôpitaux de Paris (AP-HP) Greater Paris University hospitals. Study baseline was defined as the date of hospital admission. The primary endpoint was a composite of intubation or death and the secondary endpoint was discharge home among survivors in time-to-event analyses. In the primary analyses, we compared these two outcomes between patients receiving and not receiving haloperidol using univariate Cox regression models in matched analytic samples based on patient characteristics and other psychotropic medications. Sensitivity analyses included propensity score analyses with inverse probability weighting and multivariable Cox regression models.

Results

Of 15,121 adult inpatients with a positive COVID-19 PT-PCR test, 39 patients (0.03%) received haloperidol within the first 48 hours of admission. Over a mean follow-up of 13.8 days (SD = 17.9), 2,024 patients (13.4%) had a primary end-point event and 10,179 patients (77.6%) were discharged home at the time of study end on May 1 st . The primary endpoint occurred in 9 patients (23.1%) who received haloperidol and 2,015 patients (13.4%) who did not. The secondary endpoint of discharge home occurred in 16 patients (61.5%) who received haloperidol and 9,907 patients (85.8%) who did not. There were no significant associations between haloperidol use and the primary (HR, 0.80; 95% CI, 0.39 to 1.62, p = 0.531) and secondary (HR, 1.30; 95% CI, 0.74 to 2.28, p = 0.355) endpoints. Results were similar in multiple sensitivity analyses.

Conclusion

Findings from this multicenter observational study suggest that haloperidol use prescribed at a mean dose of 4.5 mg per day (SD = 5.2) for a mean duration of 8.4 days (SD = 7.2) may not be associated with risk of intubation or death, or with time to discharge home, among adult patients hospitalized for COVID-19.

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  1. Version published to 10.1371/journal.pone.0247122
  2. ScreenIT

    SciScore for 10.1101/2020.07.15.20150490: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementIRB: The Institutional Review Board of the AP-HP clinical data warehouse approved this study (CSE-20-20_COVID19).
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Medications and their mode of administration (i.e., dosage, frequency, date, condition of intake) were identified from medication administration data or scanned hand-written medical prescriptions, through two deep learning models based on BERT contextual embeddings,12 one for the medications and their mode of administration.
    BERT
    suggested: (BERT, RRID:SCR_018008)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Additional limitations of our study include missing data for some variables (i.e., 5.0%) and potential for inaccuracies in the electronic health records, such as the possible lack of documentation of illnesses or medications, or the misidentification of treatments’ mode of administration (e.g., dosage, frequency), especially for hand-written medical prescriptions. However, results remained unchanged after using multiple imputation to account for missing data (available on request). Furthermore, patients under haloperidol were prescribed a relatively low dosage, i.e., 3.6 mg per day (SD=4.3), and its antiviral properties might be observable at higher dosages. However, we did not find any significant associations between dosage and the two endpoints. Finally, despite the multicenter design, our results may not be generalizable to other settings, e.g. outpatients, or regions. In this observational study involving patients with Covid-19 who had been admitted to the hospital, haloperidol use was not associated with risk of intubation or death, or with time to hospital discharge home. These results suggest that haloperidol is unlikely to have a clinical efficacy for Covid-19.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  3. Version published to 10.1101/2020.07.15.20150490v1 on medRxiv