PUBLICATION #1 — Critical care
Pre-intensive care unit use of selective serotonin reuptake inhibitors and mortality in critically ill adults with mental disorders: analysis from the MIMIC-IV database.
Nina C Andersen-Ranberg, Lone M Poulsen, Anders Perner, Jørn Wetterslev, Stine Estrup, Johanna Hästbacka, Matt Morgan, Giuseppe Citerio, Jesus Caballero, Theis Lange, Maj-Brit N Kjær, Bjørn H Ebdrup, Engstrøm, Markus H Olsen, Marie Oxenbøll Collet, Camilla B Mortensen, Sven-Olaf Weber, A Sofie Andreasen, Morten H Bestle, Bülent Uslu, Helle Scharling Pedersen, Louise Gramstrup Nielsen, Hans C Toft Boesen, Jacob V Jense, Lars Nebrich, Kirstine La Cour, Jens Laigaard, Cecilie Haurum, Marie W Olesen, Christian Overgaard-Steensen, Bo Westergaard, Björn Brand, Gitte Kingo Vesterlund, Pernille Thornberg Kyhnauv, Vibe S Mikkelsen, Simon Hyttel-Sørensen, Inge de Haas, Søren R Aagaard, Line O Nielsen, Anne S Eriksen, Bodil S Rasmussen, Helene Brix, Thomas Hildebrandt, Martin Schønemann-Lund, Hans Fjeldsøe-Nielsen, Anna-Maria Kuivalainen, Ole Mathiesen; AID-ICU Trial Group
Abstract: Transl Psychiatry. 2023 Jun 6;13(1):187. doi: 10.1038/s41398-023-02487-2.
Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed drugs for mental disorders in critically ill patients. We performed a retrospective cohort study to investigate the association between pre-ICU use of SSRIs and mortality in critically ill adults with mental disorders. We identified critically ill adults with mental disorders based on the Medical Information Mart in Intensive Care-IV database. The exposure was the use of SSRIs during the period after hospital admission and before ICU admission. The outcome was in-hospital mortality. Time-dependent Cox proportional hazards regression models were used to estimate the adjusted hazard ratio (aHR) with 95% confidence interval (CI). To further test the robustness of the results, we performed propensity score matching and marginal structural Cox model estimated by inverse probability of treatment weighting. The original cohort identified 16601 patients. Of those, 2232 (13.4%) received pre-ICU SSRIs, and 14369 (86.6%) did not. Matched cohort obtained 4406 patients, with 2203 patients in each group (SSRIs users vs. non-users). In the original cohort, pre-ICU use of SSRIs was associated with a 24% increase in the hazard for in-hospital mortality (aHR, 1.24; 95% CI, 1.05-1.46; P = 0.010). The results were robust in the matched cohort (aHR, 1.26; 95% CI, 1.02-1.57; P = 0.032) and the weighted cohort (aHR, 1.43; 95% CI, 1.32-1.54; P < 0.001). Pre-ICU use of SSRIs is associated with an increase in the hazard for in-hospital mortality in critically ill adults with mental disorders.
Annotation
The finding:
The authors used a large database to address whether SSRIs initiated prior to ICU-level care influenced mortality risk, adjusting for a variety of potential confounding factors. SSRIs were independently associated with increased risk of mortality (between 24% and 43%, depending on the statistical model). The authors found that the mortality risk was enhanced in elderly, females, those admitted to medical orsurgical ICUs, and those with a depression diagnosis. The risk of death was reduced when SSRIs were held, thought his may increase the risk of uncomfortable – but not lethal – withdrawal effects.
Strength and weaknesses:
Strengths include a large sample size, several statistical models to control for potential confounders, allowing severity of organ failure (SOFA score) into the model as a time-varying factor, and assessing delirium and/or coma as potential mediators of the primary outcome. As with any observational study, the authors acknowledged potential unmeasured confounders (i.e., patients were not randomized to SSRI exposure). Additionally, they could have included more variables as potential time-varying confounders (including markers of brain dysfunction).
Relevance:
Though one recent analysis suggested a protective effect of SSRIs on in-ICU delirium, another found no such effect. The current study suggests that C-L psychiatrists should consider discontinuing SSRIs, perhaps particularly in elderly female patients with depression admitted to medical or surgical ICUs.
PUBLICATION #2 — Critical care
Haloperidol for the Treatment of Delirium in ICU Patients.
Nina C Andersen-Ranberg, Lone M Poulsen, Anders Perner, Jørn Wetterslev, Stine Estrup, Johanna Hästbacka, Matt Morgan, Giuseppe Citerio, Jesus Caballero, Theis Lange, Maj-Brit N Kjær, Bjørn H Ebdrup, Engstrøm, Markus H Olsen, Marie Oxenbøll Collet, Camilla B Mortensen, Sven-Olaf Weber, A Sofie Andreasen, Morten H Bestle, Bülent Uslu, Helle Scharling Pedersen, Louise Gramstrup Nielsen, Hans C Toft Boesen, Jacob V Jense, Lars Nebrich, Kirstine La Cour, Jens Laigaard, Cecilie Haurum, Marie W Olesen, Christian Overgaard-Steensen, Bo Westergaard, Björn Brand, Gitte Kingo Vesterlund, Pernille Thornberg Kyhnauv, Vibe S Mikkelsen, Simon Hyttel-Sørensen, Inge de Haas, Søren R Aagaard, Line O Nielsen, Anne S Eriksen, Bodil S Rasmussen, Helene Brix, Thomas Hildebrandt, Martin Schønemann-Lund, Hans Fjeldsøe-Nielsen, Anna-Maria Kuivalainen, Ole Mathiesen; AID-ICU Trial Group.
Abstract: N Engl J Med. 2022 Dec 29;387(26):2425-2435. doi: 10.1056/NEJMoa2211868. Epub 2022 Oct 26.
Haloperidol is frequently used to treat delirium in patients in the intensive care unit (ICU), but evidence of its effect is limited. In this multicenter, blinded, placebo-controlled trial, we randomly assigned adult patients with delirium who had been admitted to the ICU for an acute condition to receive intravenous haloperidol (2.5 mg 3 times daily plus 2.5 mg as needed up to a total maximum daily dose of 20 mg) or placebo. Haloperidol or placebo was administered in the ICU for as long as delirium continued and as needed for recurrences. The primary outcome was the number of days alive and out of the hospital at 90 days after randomization. A total of 1000 patients underwent randomization; 510 were assigned to the haloperidol group and 490 to the placebo group. Among these patients, 987 (98.7%) were included in the final analyses (501 in the haloperidol group and 486 in the placebo group). Primary outcome data were available for 963 patients (97.6%). At 90 days, the mean number of days alive and out of the hospital was 35.8 (95% confidence interval [CI], 32.9 to 38.6) in the haloperidol group and 32.9 (95% CI, 29.9 to 35.8) in the placebo group, with an adjusted mean difference of 2.9 days (95% CI, -1.2 to 7.0) (P = 0.22). Mortality at 90 days was 36.3% in the haloperidol group and 43.3% in the placebo group (adjusted absolute difference, -6.9 percentage points [95% CI, -13.0 to -0.6]). Serious adverse reactions occurred in 11 patients in the haloperidol group and in 9 patients in the placebo group. Among patients in the ICU with delirium, treatment with haloperidol did not lead to a significantly greater number of days alive and out of the hospital at 90 days than placebo.
Annotation
The finding:
This is a multicentre, blinded, parallel group, placebo-controlled clinical trial with central randomization of 1000 critically ill patients with delirium. The study assesses the use of haloperidol on the number of days alive and out of the hospital at 90 days. The findings suggest that haloperidol does not significantly improve this primary endpoint. The study does show that use of up to 20 mg of intravenous haloperidol per day in critically ill patients was not associated with increased morbidity or mortality. There may be an all-cause mortality benefit with use of haloperidol in critically ill patients with delirium.
Strength and weaknesses:
Strengths include a large sample size, multicenter randomization, and placebo control with little loss to follow up. Interestingly, no primary or secondary outcomes in this study relate to complications of delirium, such as psychomotor agitation or frightening psychotic symptoms, which haloperidol is generally used to manage in clinical settings. Limitations of the study include under-reporting of medical comorbidities and use of other pharmacologic medications in study participants that may confound the results. Lastly, the study could have been better powered given the composite endpoints.
Relevance:
The use of haloperidol remains a staple in the management of delirium complications. The findings of this large study and those of MIND-USA (DOI: 10.1056/NEJMoa1808217) suggest haloperidol does not reduce length of stay nor increase the number of days alive and out of the ICU as it relates to delirium. Importantly however, both studies demonstrate that use of haloperidol in these populations, up to 20 mg per day in the case of AID-ICU, did not result in increased morbidity or mortality and may provide an all-cause mortality benefit in critically ill patients with delirium.
