Observational cohort study of the triggers, diagnoses and outcomes of the medical emergency team (MET) response in adult psychiatry inpatients colocated with acute medical services in Australia.

OBJECTIVES: Medical emergencies in psychiatric inpatients are challenging due to the model of care and limited medical resources. The study aims were to determine the triggers and outcomes of a medical emergency team (MET) call in psychiatric wards, and the risk factors for MET activation and mortality. DESIGN: Retrospective multisite cohort study. SETTING: Psychiatry units colocated with acute medical services at three major metropolitan hospitals in Melbourne, Australia. PARTICIPANTS: We studied 487 adult inpatients who experienced a total of 721 MET calls between January 2015 and January 2020. Patients were relatively young (mean age, 45 years) and had few medical comorbidities, but a high prevalence of smoking, excessive alcohol intake and illicit drug use. OUTCOME MEASURES: We performed a descriptive analysis of the triggers and outcomes (transfer rates, investigations, final diagnosis) of MET calls. We used logistic regression to determine the factors associated with the primary outcome of inpatient mortality, and the secondary outcome of the need for specific medical treatment compared with simple observation. RESULTS: The most common MET triggers were a reduced Glasgow Coma Scale, tachycardia and hypotension, and 49% of patients required transfer. The most frequent diagnosis was a drug adverse effect or toxidrome, followed by infection and dehydration. There was a strong association between a leave of absence and MET calls, tachycardia and the final diagnosis of drug adverse effects. Mortality occurred in 3% after MET calls. Several baseline and MET clinical variables were associated with mortality but a model with age (per 10 years, OR 1.61, 95% CI 1.29 to 2.01) and hypoxia (OR 3.59, 95% CI 1.43 to 9.04) independently predicted mortality. CONCLUSION: Vigilance is required in patients returning from day leave, and drug adverse effects remain a challenging problem in psychiatric units. Hypoxic older patients with cardiovascular comorbidity have a higher risk of death.

Severe Tachycardia Associated with Psychotropic Medications in Psychiatric Inpatients: A Study of Hospital Medical Emergency Team Activation.

The use of antipsychotic medications is associated with side effects, but the occurrence of severe tachycardia (heart rate ≥ 130 per minute) is not well described. The aim of this study was to determine the frequency and strength of the association between antipsychotic use and severe tachycardia in an inpatient population of patients with mental illness, while considering factors which may contribute to tachycardia. We retrospectively analyzed data from 636 Medical Emergency Team (MET) calls occurring in 449 psychiatry inpatients in three metropolitan hospitals co-located with acute medical services, and used mixed-effects logistic regression to model the association between severe tachycardia and antipsychotic use. The median age of patients was 42 years and 39% had a diagnosis of schizophrenia or psychotic disorder. Among patients who experienced MET calls, the use of second-generation (atypical) antipsychotics was commonly encountered (70%), but the use of first-generation (conventional) antipsychotics was less prevalent (10%). Severe tachycardia was noted in 22% of all MET calls, and sinus tachycardia was the commonest cardiac rhythm. After adjusting for age, anticholinergic medication use, temperature >38 °C and hypoglycemia, and excluding patients with infection and venous thromboembolism, the odds ratio for severe tachycardia with antipsychotic medication use was 4.09 (95% CI: 1.64 to 10.2).

Editor's Highlight: Transgenic Zebrafish Reporter Lines as Alternative In Vivo Organ Toxicity Models.

Organ toxicity, particularly liver toxicity, remains one of the major reasons for the termination of drug candidates in the development pipeline as well as withdrawal or restrictions of marketed drugs. A screening-amenable alternative in vivo model such as zebrafish would, therefore, find immediate application in the early prediction of unacceptable organ toxicity. To identify highly upregulated genes as biomarkers of toxic responses in the zebrafish model, a set of well-characterized reference drugs that cause drug-induced liver injury (DILI) in the clinic were applied to zebrafish larvae and adults. Transcriptome microarray analysis was performed on whole larvae or dissected adult livers. Integration of data sets from different drug treatments at different stages identified common upregulated detoxification pathways. Within these were candidate biomarkers which recurred in multiple treatments. We prioritized 4 highly upregulated genes encoding enzymes acting in distinct phases of the drug metabolism pathway. Through promoter isolation and fosmid recombineering, eGFP reporter transgenic zebrafish lines were generated and evaluated for their response to DILI drugs. Three of the 4 generated reporter lines showed a dose and time-dependent induction in endodermal organs to reference drugs and an expanded drug set. In conclusion, through integrated transcriptomics and transgenic approaches, we have developed parallel independent zebrafish in vivo screening platforms able to predict organ toxicities of preclinical drugs.

Humanizing the zebrafish liver shifts drug metabolic profiles and improves pharmacokinetics of CYP3A4 substrates.

Understanding and predicting whether new drug candidates will be safe in the clinic is a critical hurdle in pharmaceutical development, that relies in part on absorption, distribution, metabolism, excretion and toxicology studies in vivo. Zebrafish is a relatively new model system for drug metabolism and toxicity studies, offering whole organism screening coupled with small size and potential for high-throughput screening. Through toxicity and absorption analyses of a number of drugs, we find that zebrafish is generally predictive of drug toxicity, although assay outcomes are influenced by drug lipophilicity which alters drug uptake. In addition, liver microsome assays reveal specific differences in metabolism of compounds between human and zebrafish livers, likely resulting from the divergence of the cytochrome P450 superfamily between species. To reflect human metabolism more accurately, we generated a transgenic "humanized" zebrafish line that expresses the major human phase I detoxifying enzyme, CYP3A4, in the liver. Here, we show that this humanized line shows an elevated metabolism of CYP3A4-specific substrates compared to wild-type zebrafish. The generation of this first described humanized zebrafish liver suggests such approaches can enhance the accuracy of the zebrafish model for toxicity prediction.