Atypical antipsychotics are used in cardiac intensive care units (CICU) to treat delirium despite limited data on safety in patients with acute cardiovascular conditions. Patients treated with these agents may be at higher risk for adverse events such as QTc prolongation and arrhythmias. We performed a retrospective cohort study of 144 adult patients who were not receiving antipsychotics before admission and received olanzapine (n = 50) or quetiapine (n = 94) in the Michigan Medicine CICU. Data on baseline characteristics, antipsychotic dose and duration, length of stay, and adverse events were collected. Adverse events included ventricular tachycardia (sustained ventricular tachycardia attributed to the medication), hypotension (systolic blood pressure <90 mm Hg attributed to the medication), and QTc prolongation (QTc increase by ≥60 ms or to an interval ≥500 ms). Twenty-six patients (18%) experienced an adverse event. Of those adverse events, 20 patients (14%) experienced QTc prolongation, 3 patients (2%) had ventricular tachycardia, and 3 patients (2%) had hypotension. Patients who received quetiapine had a higher rate of adverse events (25% vs 6%, p = 0.01) including QTc prolongation (18% vs 6%, p = 0.046). Intensive care unit length of stay was shorter in patients who received olanzapine (6.5 vs 9.5 days, p = 0.047). Eighteen patients (13%) had their antipsychotic continued at discharge from the hospital. In conclusion, QTc prolongation was more common in patients treated with quetiapine versus olanzapine although the number of events was relatively low with both agents in a CICU cohort.
Graphical abstract
Delirium occurs in up to 20% of patients admitted to the cardiac intensive care unit (CICU). The CICU population faces multiple unique risk factors for delirium including immobility related to the use of mechanical circulatory and ventilatory support, targeted temperature management, and metabolic along with physiologic derangements related to heart failure. Delirium affects multiple short- and long-term patient outcomes. It has been associated with an increased risk for a prolonged length of stay, discharge to a skilled nursing facility or long-term care, in-hospital mortality, and long-term cognitive impairment. In light of these consequences, both the Society of Critical Care Medicine and the American Heart Association have published guidelines on the prevention and management of delirium. Because the routine use of antipsychotics is not recommended for the treatment of delirium because of their limited efficacy in clinical trials, these guidelines state that some patients may benefit from short-term use. , Patients with cardiovascular disease may be at particularly high risk for adverse outcomes associated with atypical antipsychotic use, such as arrhythmias as a consequence of QTc prolongation, and have therefore been excluded from most studies evaluating the use of atypical antipsychotics in the critically ill. , As such, there is limited data on the safety and efficacy of atypical antipsychotics in the CICU population. Quetiapine has been previously recommended as the antipsychotic of choice given concerns for QTc prolongation and ventricular arrhythmias with haloperidol. However, in noncritically ill patients, there is a higher incidence of QTc prolongation with quetiapine compared with olanzapine. We sought to describe the safety of 2 atypical antipsychotics, quetiapine and olanzapine, in patients admitted to the CICU.
We performed a retrospective cohort study of adult patients (≥18 years) who received quetiapine or olanzapine while in the Michigan Medicine CICU from June 2016 to June 2020. Patients were excluded if they received both quetiapine and olanzapine during their hospitalization or were prescribed first or second-generation antipsychotics as an outpatient before hospitalization. Data on demographics, comorbid conditions, presence of delirium, mechanical ventilation, laboratory and hemodynamic values within 12 hours before atypical antipsychotic initiation and corrected QT interval measurements (QTc) as reported on electrocardiograms were collected. Data on concomitant medications including antiarrhythmics, benzodiazepines, opioids, inotropes, antipsychotics, and QTc prolonging agents were also collected. Delirium was defined as a positive confusion assessment method for the intensive care unit (ICU) which is routinely measured in our CICU or documented delirium in the electronic medical record.
QTc-prolonging agents were defined as medications with a known risk of torsades de pointes (TdP) and QTc interval prolongation as listed on CredibleMeds. Concomitant use of medication was defined as the use of that medication within 24 hours of any dose of quetiapine or olanzapine. Class I and III antiarrhythmic medications were recorded if given within 24 hours of any dose of quetiapine or olanzapine.
The primary outcome was the composite of adverse events, including QTc prolongation, hypotension, and ventricular tachycardia (VT), as described later. Secondary outcomes included the individual components of the primary composite outcome as well as the duration of mechanical ventilation, CICU length of stay, hospital length of stay, and continuation of atypical antipsychotic at discharge from the hospital.
VT was defined as sustained VT attributed to quetiapine or olanzapine within 12 hours of receiving the medication as documented in the electronic medical record by the provider team. Hypotension was defined as a systolic blood pressure <90 mm Hg attributed to quetiapine or olanzapine as documented in the electronic medical record. Change in the QTc interval was defined as the QTc value closest to 72 hours after atypical antipsychotic initiation minus the QTc interval immediately before atypical antipsychotic initiation. Clinically obtained electrocardiograms recorded at 25 mm/s paper speed, with amplitude 10 mm/mV, and sampled at 150 Hz using a Marquette Electronics ECG machine (Marquette, WI, USA) were reviewed for assessment of QT intervals. Initial automated measurement of the QTc interval through machine read was selected using Bazett’s formula. For patients with significantly prolonged QRS duration (>150 ms) on machine read, the QTc interval was corrected. For subjects with QTc prolongation by machine read, QT intervals were also measured manually by a single, blinded investigator using digital calipers. The QT was measured in all leads and the longest was selected and subsequently corrected using Bazett’s formula. Drug-induced QTc prolongation was defined as (1) a QTc change from less than 500 ms to greater than 500 ms or (2) a QTc increase of 60 ms or greater following quetiapine or olanzapine administration. We used a threshold of 500 ms because a QTc greater than 500 ms has been associated with a 2-fold to 3-fold higher risk for TdP.
We compared characteristics and adverse events in patients treated with quetiapine versus olanzapine. Additionally, we compared characteristics of patients who did versus did not experience QTc prolongation, both overall and separately by medication. We assessed the statistical significance of comparisons using the chi-square test for categorical variables, Student t test for continuous variables distributed parametrically, and Kruskal-Wallis test for continuous variables distributed nonparametrically. A p value <0.05 was considered to be statistically significant. Univariate analyses were performed on clinical predictors for QTc prolongation. Based on the predictors that were significant on univariate analyses, multivariate logistic regression was performed to identify factors associated with QTc prolongation for the entire cohort. Predictor variables considered included the following: age, gender, left ventricular ejection fraction, history of myocardial infarction, history of VT, lactate before initiation of atypical antipsychotic, atypical antipsychotic, antiarrhythmic within 24 hours, inotrope within 24 hours, and QTc prolonging medication within 24 hours. We considered a model which had interactions between atypical antipsychotics and QTc prolonging medications with p <0.05 being considered significant. Both were nonsignificant using Wald’s test so were then removed from the model. Statistical analysis was performed using IBM SPSS Statistics for Windows, Version 26.0. (IBM Corp. Released 2019. Armonk, New York: IBM Corp). The study, HUM00185798, was approved by the University of Michigan Institutional Review Board.
We identified 217 adult patients who received quetiapine or olanzapine in the CICU. Baseline patient characteristics are displayed in Table 1 . A total of 73 patients were excluded either for receiving both quetiapine and olanzapine during their hospitalization (n = 41) or for receiving either antipsychotic therapy as an outpatient (n = 32). Among the 144 patients included in the final analysis, 94 (65%) received quetiapine and 50 (35%) received olanzapine. The mean age was 64 years, 34% were female, and 87% were White. The mean body mass index was 29.1 ± 7.6 kg/m 2 . There was a high prevalence of comorbid conditions including heart failure (56%), myocardial infarction (45%), hypertension (67%), atrial fibrillation (36%), and chronic kidney disease (39%). The most common admission diagnoses were cardiogenic shock (20%), acute decompensated heart failure (16%), and respiratory failure (15%, Table 1 ). While in the CICU, 8 patients (6%) received targeted temperature management and 59 (41%) received mechanical ventilation.
| Variable | All Patients (n = 144) | Olanzapine (n = 50) | Quetiapine (n = 94) | p |
|---|---|---|---|---|
| Age (years) – mean ± SD | 64 ± 17 | 66 ± 13 | 63 ± 18 | 0.28 |
| Women | 49 (34%) | 13 (26%) | 36 (38%) | 0.14 |
| White | 125 (87%) | 43 (86%) | 82 (87%) | 0.84 |
| Left ventricular ejection fraction (%) – mean ± SD * | 43 ± 22 | 42 ± 24 | 43 ± 21 | 0.71 |
| Body mass index (kg/m 2 ) – mean ± SD | 29.1 ± 7.6 | 29.3 ± 7.7 | 29.0 ± 7.6 | 0.82 |
| Atrial fibrillation | 52 (36%) | 21 (42%) | 31 (33%) | 0.28 |
| Chronic kidney disease | 56 (39%) | 25 (50%) | 31 (33%) | 0.05 |
| Cirrhosis | 2 (1%) | 1 (2%) | 1 (1%) | 0.65 |
| Diabetes Mellitus | 59 (41%) | 22 (44%) | 37 (39%) | 0.59 |
| Heart failure | 81 (56%) | 34 (68%) | 47 (50%) | 0.04 |
| Hypertension | 96 (67%) | 36 (72%) | 60 (64%) | 0.32 |
| Myocardial infarction | 65 (45%) | 19 (38%) | 46 (49%) | 0.21 |
| Ventricular tachycardia | 32 (22%) | 13 (26%) | 19 (20%) | 0.43 |
| Admission diagnoses | ||||
| Cardiogenic shock | 29 (20%) | 10 (20%) | 19 (20%) | 0.11 |
| Acute decompensated heart failure | 23 (16%) | 7 (14%) | 16 (17%) | |
| Respiratory failure | 22 (15%) | 10 (20%) | 12 (13%) | |
| Endocarditis | 16 (11%) | 1 (2%) | 15 (16%) | |
| Cardiac arrest | 11 (8%) | 3 (6%) | 8 (9%) | |
| Ventricular arrhythmia | 7 (5%) | 2 (4%) | 5 (5%) | |
| ST-elevation myocardial infarction | 5 (4%) | 1 (2%) | 4 (4%) | |
| Other | 31 (22%) | 16 (32%) | 15 (16%) | |
| Clinical status at initiation of antipsychotic medication | ||||
| Richmond agitation and sedation scale score † – median (IQR) | 0 (−1.0–1.0) | 0 (−1.0–1.3) | 0 (0.0–1.0) | 0.81 |
| Systolic blood pressure (mm Hg) – mean ± SD | 123 ± 25 | 118 ± 25 | 125 ± 25 | 0.13 |
| Lactate (mmol/L) ‡ – mean ± SD | 1.6 ± 1.4 | 2.0 ± 1.8 | 1.4 ± 1.2 | 0.04 |
| QTc (ms) – mean ± SD | 464 ± 45 | 474 ± 49 | 459 ± 42 | 0.05 |
| Therapies at time of antipsychotic administration | ||||
| Targeted temperature management | 8 (6%) | 2 (4%) | 6 (6%) | 0.55 |
| Intubation with mechanical ventilation | 59 (41%) | 17 (34%) | 42 (45%) | 0.21 |
| Other medications administered within 24 h of antipsychotic initiation – no. (%) | ||||
| Antiarrhythmic | 44 (31%) | 16 (32%) | 28 (30%) | 0.78 |
| Inotrope | 24 (17%) | 7 (14%) | 17 (18%) | 0.53 |
| Opioid | 83 (58%) | 30 (60%) | 53 (56%) | 0.68 |
| Benzodiazepine | 57 (40%) | 13 (26%) | 44 (47%) | 0.02 |
| Antipsychotic | 20 (14%) | 8 (16%) | 12 (13%) | 0.59 |
| Other QTc-prolonging agent | 50 (35%) | 13 (26%) | 37 (39%) | 0.11 |
| Outcomes (days) – median (IQR) | ||||
| Duration of mechanical ventilation | 7 (3.5–9.5) | 6 (3.0–8.0) | 8 (4.0–10.8) | 0.14 |
| Intensive care unit length of stay (days) | 9 (5.0–14.0) | 6.5 (3.0–11.0) | 9.5 (5.0–15.0) | 0.05 |
| Hospital length of stay (days) | 17 (10.0–26.0) | 16 (10.0–23.5) | 19 (10.0–26.0) | 0.28 |
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