Douglas J. Hsu

Extrapyramidal side effects with atypical neuroleptics in bipolar disorder

OBJECTIVE To examine, in a real-world clinical setting, the risk of extrapyramidal symptoms (EPS) with atypical neuroleptics in bipolar patients. METHODS The authors assessed 51 individual patient trials of atypical neuroleptic agents (17 risperidone, 13 olanzapine, 11 quetiapine, 8 ziprasidone, and 2 aripiprazole) in 37 bipolar patients (type I or type II). Risk of EPS was assessed using the Abnormal Involuntary Movement Scale, Barnes Akathisia Rating Scale, and the Simpson-Angus Scale. Mean duration of treatment was 25.5 weeks (range 3-107 weeks) and 60.8% of patients were female. RESULTS 62.7% of trials resulted in moderate to severe EPS. EPS and discontinuation frequencies were similar between specific neuroleptic agents or between high potency (risperidone/ziprasidone/aripiprazole; 52.9%, 27/51 trials) and low potency (quetiapine/olanzapine; 47.1%, 24/51 trials) agents. In a multiple regression model adjusted for confounders, akathisia was less common with low potency agents. Younger age was associated with more akathisia. 31.4% (11/35) of trials discontinued due to side effects. 7.8% (4/51) of trials led to mild de novo tardive dyskinesia. CONCLUSIONS Over one-half of bipolar patients experienced EPS in this real world clinical setting. This rate is much higher than the 5-15% range reported in clinical trials, suggesting potential problems with clinical trial generalizability.

Bipolar spectrum disorder: a pilot study.

Objective: To assess depressive features of a proposed definition of bipolar spectrum disorder (BSD). Methods: Thirty-six patients with bipolar disorder type I or II were compared to 37 patients with unipolar major depressive disorder through patient interview and chart review. Results: Univariate analysis suggests that 7 of 12 (recurrent major depressive episodes, brief major depressive episodes, atypical depressive symptoms, early age of onset, family history of bipolar disorder, antidepressant tolerance, and antidepressant-induced mania) features of major depressive episodes were more likely to occur in bipolar versus unipolar patients. After adjustment in a multivariable regression model, however, the five most powerful predictors of bipolar disorder were brief major depressive episodes, early age of onset, antidepressant- induced mania, postpartum depression, and atypical depressive symptoms. Conclusions: This preliminary study supports the idea that bipolar disorder is characterized by some depressive features less likely to be found in unipolar depression. Further prospective study needs to be conducted comparing BSD with unipolar depression.

The Association Between Indwelling Arterial Catheters and Mortality in Hemodynamically Stable Patients With Respiratory Failure: A Propensity Score Analysis

BACKGROUND Indwelling arterial catheters (IACs) are used extensively in the ICU for hemodynamic monitoring and for blood gas analysis. IAC use also poses potentially serious risks, including bloodstream infections and vascular complications. The purpose of this study was to assess whether IAC use was associated with mortality in patients who are mechanically ventilated and do not require vasopressor support. METHODS This study used the Multiparameter Intelligent Monitoring in Intensive Care II database, consisting of > 24,000 patients admitted to the Beth Israel Deaconess Medical Center ICU between 2001 and 2008. Patients requiring mechanical ventilation who did not require vasopressors or have a diagnosis of sepsis were identified, and the primary outcome was 28-day mortality. A model based on patient demographics, comorbidities, vital signs, and laboratory results was developed to estimate the propensity for IAC placement. Patients were then propensity matched, and McNemar test was used to evaluate the association of IAC with 28-day mortality. RESULTS We identified 1,776 patients who were mechanically ventilated who met inclusion criteria. There were no differences in the covariates included in the final propensity model between the IAC and non-IAC propensity-matched groups. For the matched cohort, there was no difference in 28-day mortality between the IAC group and the non-IAC group (14.7% vs 15.2%; OR, 0.96; 95% CI, 0.62-1.47). CONCLUSIONS In hemodynamically stable patients who are mechanically ventilated, the presence of an IAC is not associated with a difference in 28-day mortality. Validation in other datasets, as well as further analyses in other subgroups, is warranted.

Commentary: Evidence-based pharmacotherapy of bipolar disorder

This Commentary summarizes findings from three other papers in this issue with recommendations for evidence-based treatment with lithium, anticonvulsants, antipsychotics, and antidepressants in bipolar disorder. We will also provide a summary of levels of evidence and examine two important methodological issues in assessing drug-induced mania: reliance on significance testing for assessment of side-effects, and limitations of randomized controlled trials (RCTs) for assessing frequency of side-effects. If a study is not specifically powered and designed to assess a side-effect, then no significance testing should be conducted, and side-effects should simply be reported as effect estimates and confidence intervals. Further, RCTs only establish a categorical response to a research question, i.e. whether or not something happens. The frequency of an event (treatment response, side-effects) is often more accurately assessed with observational studies.

Long-term observational comparison of risperidone and olanzapine in bipolar disorder.

To compare long-term effectiveness and safety of risperidone versus olanzapine as adjunctive maintenance treatments of bipolar disorder. Retrospective observational chart review of 29 outpatients with bipolar or schizoaffective disorder (type I = 15, type II = 3, NOS = 5, schizoaffective = 6) who received risperidone or olanzapine added to lithium or valproate >3 months. Acute indications were depression (n = 8), manic/hypomanic/mixed states (n = 8), rapid cycling (n = 6), other indications (n = 6), and prophylaxis (n = 1). Logistic regression models adjusted for potential confounding factors (i.e., severity of illness, comorbid substance abuse, diagnostic subtype). Overall duration of follow-up was 65.9+/-70.1 weeks. Mild to moderate response was similar in the risperidone and olanzapine groups after adjusting for potential confounders (OR = 0.91, 95% CI [0.05, 16.17]). Somewhat greater adjusted moderate to marked response (OR >3.60, 95% CI [0.31, >42.00]) and longer duration of treatment (HR = 0.52, 95% CI [0.22, 1.22]) occurred in the risperidone group, but were still compatible with the null hypothesis. Weight gain occurred more frequently with olanzapine (57%) than risperidone (13%). EPS was similar, and tardive dyskinesia did not occur. Risperidone and olanzapine appeared to have similar real-world maintenance effectiveness for bipolar disorder, but differed somewhat in side effects.

Beyond open big data: addressing unreliable research.

The National Institute of Health invests US

The Critical Care Crisis of Opioid Overdoses in the United States

30.9 billion annually in medical research. However, the subsequent impact of this research output on society and the economy is amplified dramatically as a result of the actual medical treatments, biomedical innovations, and various commercial enterprises that emanate from and depend on these findings. It is therefore a great concern to discover that much of published research is unreliable. We propose extending the open data concept to the culture of the scientific research community. By dialing down unproductive features of secrecy and competition, while ramping up cooperation and transparency, we make a case that what is published would then be less susceptible to the sometimes corrupting and confounding pressures to be first or journalistically attractive, which can compromise the more fundamental need to be robustly correct.

Predictors of Timely Antibiotic Administration for Patients Hospitalized With Community-Acquired Pneumonia From the Cluster-Randomized EDCAP Trial

Rationale: Opioid abuse is increasing, but its impact on critical care resources in the United States is unknown. Objectives: We hypothesized that there would be a rising need for critical care among opioid‐associated overdoses in the United States. Methods: We analyzed all adult admissions, using a retrospective cohort study from 162 hospitals in 44 states, discharged between January 1, 2009, and September 31, 2015 to describe the incidence of intensive care unit (ICU) admissions for opioid overdose during this time. Admissions were identified using the Clinical Database/Resource Manager of Vizient, the successor to the University Health System Consortium. Results: Our primary outcome was opioid‐associated overdose admissions to the ICU. The outcome was defined on the basis of previously validated ICD‐9 codes. Our secondary outcomes were in‐hospital death and markers of ICU resources. The final cohort included 22,783,628 admissions; 4,145,068 required ICU care. There were 52.4 ICU admissions for overdose per 10,000 ICU admissions over the entire study (95% confidence interval [CI], 51.8‐53.0 per 10,000 ICU admissions). During this time period, opioid overdose admissions requiring intensive care increased 34%, from 44 per 10,000 (95% CI, 43‐46 per 10,000) to 59 per 10,000 ICU admissions (95% CI, 57‐61 per 10,000; P < 0.0001). The mortality rate of patients with ICU admissions with overdoses averaged 7% (95% CI, 7.0‐7.6%) but increased to 10% in 2015 (95% CI, 8.8‐10.8%). Conclusions: The number of deaths of ICU patients with opioid overdoses increased substantially in the 7 years of our study, reflecting increases in both the incidence and mortality of this condition. Our findings raise the need for a national approach to developing safe strategies to care for patients with overdose in the ICU, to providing coordinated resources in the hospital for patients and families, and to helping survivors maintain sobriety on discharge.

Long-term culture change related to rapid response system implementation

Introduction:To identify factors associated with timely initiation of antibiotic therapy for patients hospitalized with pneumonia. Design:Secondary analysis of a cluster-randomized, controlled trial. Setting:Thirty- two emergency departments (EDs) in Pennsylvania and Connecticut. Subjects:Patients with a clinical and radiographic diagnosis of community-acquired pneumonia. Interventions:From January to December 2001, EDs were randomly allocated to guideline implementation strategies of low (n = 8), moderate (n = 12), and high intensity (n = 12) to improve the initial site of treatment and the performance of evidence-based processes of care. Our primary outcome was antibiotic initiation within 4 hours of presentation, which at that time was the recommended process of care for inpatients. Results:Of the 2076 inpatients enrolled, 1632 (78.6%) received antibiotic therapy within 4 hours of presentation. Antibiotic timeliness ranged from 55.6% to 100% (P < 0.001) by ED and from 77.0% to 79.7% (P = 0.2) across the 3 guideline implementation arms. In multivariable analysis, heart rate ≥125 per minute (OR = 1.6, 95% CI 1.1–2.3), respiratory rate ≥30 per minute (OR = 2.3, 95% CI 1.6–3.4), and aspiration pneumonia (OR = 3.7, 95% CI 1.1–12.7) were positively associated with timely initiation of antibiotic therapy, whereas a hematocrit <30% (OR = 0.6, 95% CI 0.4–1.0) was negatively associated with this outcome. Conclusions:Timely initiation of antibiotic therapy is associated primarily with patient-related factors that reflect severity of illness at presentation. Although this study demonstrates an opportunity to improve performance on this quality measure in nearly one quarter of inpatients with pneumonia, we failed to identify any modifiable patient, provider, or hospital level factors to target in such quality improvement efforts.

Trends in Prolonged Hospitalizations in the United States from 2001 to 2012: A Longitudinal Cohort Study

Increasing attention to patient safety in training hospitals may come at the expense of trainee autonomy and professional growth. This study sought to examine changes in medical trainees’ self‐reported behaviour after the institution‐wide implementation of a rapid response system.