The Critical Care Crisis of Opioid Overdoses in the United States.

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.

Hospitalizations, costs and outcomes associated with heroin and prescription opioid overdoses in the United States 2001-12.

BACKGROUND AND AIMS: The full burden of the opioid epidemic on US hospitals has not been described. We aimed to estimate how heroin (HOD) and prescription opioid (POD) overdose-associated admissions, costs, outcomes and patient characteristics have changed from 2001 to 2012. DESIGN: Retrospective cohort study of hospital admissions from the National Inpatient Sample (NIS). SETTING: United States of America. PARTICIPANTS: Hospital admissions in patients aged 18 years or older admitted with a diagnosis of HOD or POD. The NIS sample included 94 492 438 admissions from 2001 to 2012. The final unweighted study sample included 138 610 admissions (POD: 122 147 and HOD: 16 463). MEASUREMENTS: Primary outcomes were rates of admissions per 100 000 people using US Census Bureau annual estimates. Other outcomes included in-patient mortality, hospital length-of-stay, cumulative and mean hospital costs and patient demographics. All analyses were weighted to provide national estimates. FINDINGS: Between 2001 and 2012, an estimated 663 715 POD and HOD admissions occurred nation-wide. HOD admissions increased 0.11 per 100 000 people per year [95% confidence interval (CI) = 0.04, 0.17], while POD admissions increased 1.25 per 100 000 people per year (95% CI = 1.15, 1.34). Total in-patient costs increased by $4.1 million dollars per year (95% CI = 2.7, 5.5) for HOD admissions and by $46.0 million dollars per year (95% CI = 43.1, 48.9) for POD admissions, with an associated increase in hospitalization costs to more than $700 million annually. The adjusted odds of death in the POD group declined modestly per year [odds ratio (OR) = 0.98, 95% CI = 0.97, 0.99], with no difference in HOD mortality or length-of-stay. Patients with POD were older, more likely to be female and more likely to be white compared with HOD patients. CONCLUSIONS: Rates and costs of heroin and prescription opioid overdose related admissions in the United States increased substantially from 2001 to 2012. The rapid and ongoing rise in both numbers of hospitalizations and their costs suggests that the burden of POD may threaten the infrastructure and finances of US hospitals.

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

BACKGROUND: Health policy debate commonly focuses on frequently hospitalized patients, but less research has examined trends in long-stay patients, despite their high cost, effect on availability of hospital beds, and physical and financial implications for patients and hospitals. METHODS: Using the National Inpatient Sample, a nationally representative sample of acute care hospitalizations in the US, we examined trends in long-stay hospitalizations from 2001-2012. We defined long stays as those 21 days or longer and evaluated characteristics and outcomes of those hospitalizations, including discharge disposition and length of stay and trends in hospital characteristics. We excluded patients under 18 years of age and those with primary psychiatry, obstetric, or rehabilitation diagnoses, and weighted estimates to the US population. RESULTS: Prolonged hospitalizations represented only 2% of hospitalizations, but approximately 14% of hospital days and incurred estimated charges of over $20 billion dollars annually. Over time, patients with prolonged hospitalizations were increasingly younger, male, and of minority status, and these hospitalizations occurred more frequently in urban, academic hospitals. In-hospital mortality for patients with prolonged stays progressively decreased over the 10-year period from 14.5% to 11.6% (P <.001 for trend in grouped years), even accounting for changes in demographics and comorbidity. CONCLUSIONS: The profile of patients with prolonged hospitalizations in the US has changed, although their impact remains large, as they continue to represent 1 of every 7 hospital days. Their large number of hospital days and expense increasingly falls upon urban academic medical centers, which will need to adapt to this vulnerable patient population.

Identification of Barriers to Influenza Vaccination in Patients with Chronic Obstructive Pulmonary Disease: Analysis of the 2012 Behavioral Risk Factors Surveillance System.

INTRODUCTION: Patients with chronic obstructive pulmonary disease (COPD) are at increased risk for influenza-related morbidity and mortality. Influenza vaccination is known to decrease influenza incidence, severity, hospitalizations, and mortality. Identification of barriers to influenza vaccination among patients with COPD may aid in efforts to increase vaccination rates. This study aims to identify predictors of influenza vaccination in COPD patients. METHODS: This study used data from the 2012 Behavioral Risk Factor Surveillance System (BRFSS). Participants with self-reported COPD and receiving an influenza vaccination in the prior 12 months were identified. Independent predictors of the exposure were identified by estimating a parsimonious logistic regression model of influenza vaccination. All analyses were performed using weighted data. RESULTS: The final study sample consisted of 36,811 COPD participants, with 48.5% of COPD patients reporting having been vaccinated and 51.5% reporting being unvaccinated. A total of 15 independent predictors of influenza vaccination in COPD patients were identified. Negative predictors included predisposing factors (younger age, male gender, household children, black or non-white/non-Hispanic/non-black race/ethnicity, lower education level, heavy alcohol use, current tobacco use) and enabling factors that reflect access to medical care (insurance status, ability to afford care, having a recent check-up). Positive predictors of influenza vaccination included need factors (chronic comorbidities), being a military veteran, or being a former smoker. CONCLUSIONS: This analysis identifies multiple predictors of influenza vaccination in persons with COPD. Identification of at risk-groups provides the foundation for development of focused efforts to improve influenza vaccination rates in patients with COPD.

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.

Beyond open big data: addressing unreliable research.

The National Institute of Health invests US $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.

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 > or =125 per minute (OR = 1.6, 95% CI 1.1-2.3), respiratory rate > or =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.

Effectiveness of quetiapine in rapid cycling bipolar disorder: a preliminary study.

OBJECTIVE: The authors examined long-term effectiveness and study retention during open-label quetiapine treatment for rapid cycling bipolar disorder. METHODS: An open-label, nonrandomized trial was conducted in 41 patients with rapid-cycling bipolar disorder (type I=33, type II=7, NOS=1) who received flexibly dosed quetiapine monotherapy (n=19) or add-on therapy (n=22) for up to one year. Linear growth curves were calculated to assess longitudinal changes in depression and mania. RESULTS: Linear growth curves demonstrated highly significant reductions in manic (p<.0001) and depressive (p<.0001) symptoms. Effect sizes were large against manic symptoms (add-on therapy: Cohen's d=0.66; monotherapy: Cohen's d=0.75) but small-to-moderate against depression (monotherapy: d=0.29; add-on therapy: d=0.40). Most patients (68%) prematurely terminated the protocol (mean duration: 18.0+/-16.9 weeks, mean dose: 195.6+/-196.1 mg/day), most often because of the need for additional psychotropic treatments. LIMITATIONS: The study protocol involved an open label design with no placebo or active comparator group. The sample size provided adequate statistical power to detect large but not medium or small within-group effects. Premature dropout during the first six months precluded inferences about longer-term treatment outcome. CONCLUSIONS: These observational findings provisionally suggest some benefit with quetiapine for both manic and depressive symptoms in rapid cycling bipolar disorder, at dosages somewhat lower than previously described either for mania or bipolar depression. The relatively high dropout rate underscores the complexity of rapid cycling bipolar disorder and likely necessity for pharmacotherapy adjustments over time.

Pharmacological Treatment Patterns at Study Entry for the First 500 STEP-BD Participants.

OBJECTIVE: This study assessed patterns of psychopharmacological treatment for bipolar disorder. METHOD: Intake treatment data were examined for the first 500 patients in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study (1998 to 1999). Diagnoses were assessed by using the Structured Clinical Interview for DSM-IV mood modules. Data on treatments were obtained by interviewing patients during the initial psychiatric examination. RESULTS: Of the 500 participants, 73.6 percent had bipolar I disorder, 23.0 percent had bipolar II disorder, and 3.4 percent had bipolar disorder not otherwise specified. Upon examination, 63.4 percent were euthymic, 24.6 percent were depressed, and 12.0 percent were experiencing manic, hypomanic, or mixed states. Standard mood stabilizers (lithium, valproate, or carbamazepine) were the most commonly prescribed class of drugs that participants were taking at intake (71.9 percent). The next most common class of agents was antidepressants (40.6 percent), followed by novel anticonvulsants (31.8 percent), second-generation neuroleptics (27.2 percent), and benzodiazepines (25.0 percent). Eleven percent of patients were treated with standard mood stabilizer monotherapy. These prescribing patterns were further analyzed by subtype of illness and compared with patterns in other clinical and community settings. CONCLUSION: In a large, well-characterized cross-sectional analysis of prescription patterns in the U.S. psychiatric academic setting, patients with bipolar disorder were primarily treated with standard mood stabilizers, followed by moderate use of antidepressants, novel anticonvulsants, and second-generation neuroleptics. Results can be useful in understanding the current clinical standard of care, as well as in guiding research studies toward areas in which there is a relative absence of evidence to inform clinical practice. Studies of longitudinal prescribing patterns in bipolar disorder are also needed.

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.

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.

Strategies for preventing the recurrence of bipolar disorder.

In interpreting the maintenance literature for bipolar disorder, attention needs to be paid to important methodological issues. In this article, we initially examine the methodological topics that need to be considered, and we then examine the content of the evidence regarding maintenance treatments. Agents used in the long-term treatment of bipolar disorder possess varying degrees of supportive evidence. By consensus, the number of randomized studies and years of clinical experience with lithium mark it as the evidentially strongest long-term agent for bipolar disorder. Recent studies also demonstrate likely long-term benefit with lamotrigine, and possibly olanzapine. Although we possess fewer randomized data, some such evidence exists and, along with clinical experience, supports the likely long-term utility of valproate in the treatment of bipolar disorder as well. Some psychotherapies also may possess adjunctive maintenance efficacy.

Antidepressants in bipolar disorder: the case for caution.

The 2002 American Psychiatric Association (APA) guidelines for the treatment of bipolar disorder recommended more conservative use of antidepressants. This change in comparison with previous APA guidelines has been criticized, especially from some groups in Europe. The Munich group in particular has published a critique of assumptions underlying the conservative recommendations of the recent APA treatment guidelines. In this paper, we re-examine the argument put forward by the Munich group, and we demonstrate that indeed, conceptually and empirically, there is a strong rationale for a cautious approach to antidepressant use in bipolar disorder, consistent with, and perhaps even more strongly than, the APA guidelines. This rationale is based on support for the following four propositions: (i) The risk of antidepressant induced mood-cycling is high, (ii) Antidepressants have not been shown to definitively prevent completed suicides and reduce mortality, whereas lithium has, (iii) Antidepressants have not been shown to be more effective than mood stabilizers in acute bipolar depression and have been shown to be less effective than mood stabilizers in preventing depressive relapse in bipolar disorder and (iv) Mood stabilizers, especially lithium and lamotrigine, have been shown to be effective in acute and prophylactic treatment of bipolar depressive episodes. We therefore draw three conclusions from this interpretation of the evidence: (i) There are significant risks of mania and long-term worsening of bipolar illness with antidepressants, (ii) Antidepressants should generally be reserved for severe cases of acute bipolar depression and not routinely used in mild to moderate cases and (iii) Antidepressants should be discontinued after recovery from the depressive episode, and maintained only in those who repeatedly relapse after antidepressant discontinuation (a minority we judge to represent only about 15-20% of bipolar depressed patients).

The bipolar spectrum: a clinical perspective.

The relative misdiagnosis and underdiagnosis of bipolar disorder is due in part to the 'soft' symptoms of bipolarity that characterize patients with non-classical bipolar disorder. While no agreement has been reached on the term for this group of patients, the most common classification used is 'bipolar spectrum', which shifts the emphasis in diagnosis away from polarity and toward other diagnostic validators. In order to recognize and properly treat patients with bipolar disorder, clinicians should focus on careful evaluation of patients with mixed anxiety/depressive symptoms or impulsivity conditions (substance abuse, borderline personality, bulimia, and attention deficit disorder). Furthermore, in the treatment of bipolar disorder, clinicians should also recognize that antidepressants can have a negative effect on patients by increasing the likelihood of more severe rapid cycling. While antidepressants may be useful in particularly difficult cases, emphasis should be placed on mood stabilizers for treatment of the bipolar spectrum.

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.

Oxcarbazepine treatment of bipolar disorder.

OBJECTIVE: To assess the effectiveness and safety of oxcarbazepine in bipolar disorder. METHOD: A chart review of naturalistic treatment with oxcarbazepine in 42 outpatients with DSM-IV bipolar disorder (10 males, 32 females; mean +/- SD age = 33.3 +/- 12.4 years; 25 with bipolar disorder type I, 4 with bipolar disorder type II, and 13 with bipolar disorder not otherwise specified) was conducted. Patients had received oxcarbazepine monotherapy or adjunctive therapy between April 2000 and April 2002. Treatment response was defined as a Clinical Global Impressions-Improvement scale score of 1 (marked improvement) or 2 (moderate improvement). RESULTS: Oxcarbazepine was moderately to markedly effective in 24 subjects (57%). Mixed symptoms were the most common indication (52% [22/42]). The mean oxcarbazepine dose was 1056.6 mg/day, and mean treatment duration was 16.2 weeks. Sedation (17/42, 40%) was the most common side effect, but 16 patients (38%) had no side effects. Twenty-two patients (52%) stopped treatment, mostly due to side effects (12/22). Males were more likely to respond than females (10/10 vs. 14/32, p =.006). Dose, bipolar subtype, indication, past nonresponse to mood stabilizers, concurrent mood stabilizer use, and monotherapy use of oxcarbazepine did not differentially predict response. CONCLUSION: Oxcarbazepine appeared effective in about one half of patients with bipolar disorder and was well tolerated.