An Exploratory Reanalysis of the Randomized Trial on Efficacy of Corticosteroids as Rescue Therapy for the Late Phase of Acute Respiratory Distress Syndrome.

OBJECTIVES: In the Acute Respiratory Distress Syndrome Network randomized controlled trial, methylprednisolone treatment was associated with increased return to mechanical ventilation with partial loss of early improvements. We hypothesize a causal relationship between protocol-driven rapid discontinuation of methylprednisolone post extubation and return to mechanical ventilation. To explore this possibility, we investigated the timing that events occurred in each treatment arm during active treatment intervention (efficacy) and after stopping therapy. DESIGN AND SETTINGS: Retrospective intention-to-treat analysis of multicenter randomized controlled trial. PATIENTS AND INTERVENTIONS: Patients were randomized to methylprednisolone (2 mg/kg/d) or placebo (89 vs 91). The target sample size was reduced post hoc and provided 80% power for an optimistic 50% mortality reduction. MEASUREMENTS AND MAIN RESULTS: Findings are reported as methylprednisolone versus placebo. By day 28, fewer patients died before achieving extubation (15.7% vs 25.3% and risk ratio, 0.62; 95% CI, 0.34-1.13), more achieved successful extubation (71.9% vs 49.5% and risk ratio, 1.45; CI, 1.14-1.85), time to successful extubation was shorter (hazard ratio, 2.05; CI, 1.42-2.96), and more were discharged alive from the ICU (65.2% vs 48.3%; risk ratio, 1.35; CI, 1.04-1.75). After treatment discontinuation, more methylprednisolone-treated patients returned to mechanical ventilation (26.6% vs 6.7%; risk ratio, 3.98; CI, 1.24-12.79)-consistent with reconstituted systemic inflammation in the presence of adrenal suppression. Participants returning to mechanical ventilation without reinstitution of methylprednisolone had increased risk of ventilator dependence and mortality. Despite loss of early benefits, methylprednisolone was associated with sizable and significant improvements in all secondary outcomes and reduction in serious complications (shock and severe infections). CONCLUSIONS: During active intervention, methylprednisolone was safe and effective in achieving disease resolution. Our findings support rapid glucocorticoid discontinuation post extubation as likely cause of disease relapse. Gradual tapering might be necessary to preserve the significant improvements achieved during methylprednisolone administration.

Low-dose methylprednisolone treatment in critically ill patients with severe community-acquired pneumonia.

PURPOSE: Severe community-acquired pneumonia (CAP) requiring intensive care unit admission is associated with significant acute and long-term morbidity and mortality. We hypothesized that downregulation of systemic and pulmonary inflammation with prolonged low-dose methylprednisolone treatment would accelerate pneumonia resolution and improve clinical outcomes. METHODS: This double-blind, randomized, placebo-controlled clinical trial recruited adult patients within 72-96 h of hospital presentation. Patients were randomized in 1:1 ratio; an intravenous 40 mg loading bolus was followed by 40 mg/day through day 7 and progressive tapering during the 20-day treatment course. Randomization was stratified by site and need for mechanical ventilation (MV) at the time of randomization. Outcomes included a primary endpoint of 60-day all-cause mortality and secondary endpoints of morbidity and mortality up to 1 year of follow-up. RESULTS: Between January 2012 and April 2016, 586 patients from 42 Veterans Affairs Medical Centers were randomized, short of the 1420 target sample size because of low recruitment. 584 patients were included in the analysis. There was no significant difference in 60-day mortality between the methylprednisolone and placebo arms (16% vs. 18%; adjusted odds ratio 0.90, 95% CI 0.57-1.40). There were no significant differences in secondary outcomes or complications. CONCLUSIONS: In patients with severe CAP, prolonged low-dose methylprednisolone treatment did not significantly reduce 60-day mortality. Treatment was not associated with increased complications.

Prolonged glucocorticoid treatment is associated with improved ARDS outcomes: analysis of individual patients' data from four randomized trials and trial-level meta-analysis of the updated literature.

PURPOSE: To investigate the effect of prolonged glucocorticoid treatment for patients with acute respiratory distress syndrome (ARDS). METHODS: We conducted two sets of intention-to-treat analyses: (1) a primary analysis of individual patients' data (IPD) of four randomized controlled trials (RCTs) which investigated methylprednisolone treatment (n = 322) and (2) a trial-level meta-analysis incorporating four additional RCTs which investigated hydrocortisone treatment in early ARDS (n = 297). We standardized definitions to derive outcomes in all datasets. The primary outcome for the IPD analysis was time to achieving unassisted breathing (UAB) by study day 28. Secondary outcomes included mechanical ventilation (MV) and intensive care unit (ICU)-free days, hospital mortality, and time to hospital mortality by day 28. RESULTS: By study day 28, compared to the placebo group, the methylprednisolone group had fewer patients who died before achieving UAB (12 vs. 29 %; p < 0.001) and more patients who achieved UAB (80 vs. 50 %; p < 0.001). In the methylprednisolone group, time to achieving UAB was shorter [hazard ratio 2.59, 95 % confidence interval (CI) 1.95-3.43; p < 0.001], and hospital mortality was decreased (20 vs. 33 %; p = 0.006), leading to increased MV (13.3 ± 11.8 vs. 7.6 ± 5.7; p < 0.001) and ICU-free days (10.8 ± 0.71 vs. 6.4 ± 0.85; p < 0.001). In those patients randomized before day 14 of ARDS onset, the trial-level meta-analysis indicated decreased hospital mortality (36 vs. 49 %; risk ratio 0.76, 95 % CI 0.59-0.98, I (2) = 17 %, p = 0.035; moderate certainty). Treatment was not associated with increased risk for infections (risk ratio 0.77, 95 % CI 0.56-1.08, I (2) = 26 %; p = 0.13; moderate certainty). CONCLUSIONS: Prolonged methylprednisolone treatment accelerates the resolution of ARDS, improving a broad spectrum of interrelated clinical outcomes and decreasing hospital mortality and healthcare utilization.

Admission hyperglycemia and other risk factors as predictors of hospital mortality in a medical ICU population.

BACKGROUND: Tight glycemic control is recommended for patients in the ICU, as hyperglycemia is associated with increased morbidity and mortality. DESIGN: Observational cohort of patients admitted to a 12-bed, inner-city, medical ICU (MICU). SUBJECTS: A total of 1,185 of 1,506 patients from July 1, 1999, to December 31, 2002, selected based on a diagnosis other than diabetic ketoacidosis or glycemia > 280 mg/dL or < 80 mg/dL. PURPOSES: To determine if the highest serum glucose level within 24 h after ICU admission is associated with increased hospital mortality when adjusted for confounders. MEASUREMENTS: Age, gender, race, worst values within 24 h after ICU admission to construct the acute physiology and chronic health evaluation (APACHE) II score, and highest glucose within 24 h after ICU admission. Hospital mortality was the primary outcome. Admitting diagnosis, MICU length of stay (LOS), and hospital LOS were obtained. Glucose, albumin (n = 867), and lactic acid (n = 319) were stratified for analysis. ANALYSIS: Univariate analysis identified factors included in the multivariate model. RESULTS: Patients were predominantly African-American (79%) and men (56%; mean age, 49.2 years). The mean ICU admission highest glucose level was 139 +/- 43.7 mg/dL (+/- SD). MICU LOS and hospital LOS were 6.2 days and 12.9 days, respectively, and 50% of patients received mechanical ventilation. MICU and hospital mortality were 18% and 20%, respectively; standardized mortality ratio was 66%. On univariate analysis, survivors (n = 945) and nonsurvivors (n = 240) showed APACHE II score, mechanical ventilation, hypoalbuminemia, lactic acidemia, and logistic organ dysfunction system score to be hospital mortality predictors; however, the highest admission serum glucose level was not. Logistic regression estimated APACHE II score/per point (odds ratio, 1.06; 95% confidence interval, 1.02 to 1.11), mechanical ventilation (odds ratio, 3.06; 95% confidence interval, 1.34 to 6.96), severe hypoalbuminemia (< 2 g/dL) [odds ratio, 2.98; 95% confidence interval, 1.3 to 7.02], and severe lactic acidemia (> or = 8 mmol/L) [odds ratio, 7.3; 95% confidence interval, 2.14 to 24.9], but not ICU admission hyperglycemia, to be associated with hospital mortality. CONCLUSIONS: Conventional factors of disease severity, but not highest glucose value during the first 24 h after ICU admission, predict hospital mortality in an inner-city MICU.

Predictors of intensive care unit and hospital length of stay in diabetic ketoacidosis.

OBJECTIVE: To determine the predictive value for prolonged intensive care unit (ICU) and hospital length of stay (LOS) in patients with diabetic ketoacidosis (DKA) of the Acute Physiology and Chronic Health Evaluation II (APACHE II) score and Logistic Organ Dysfunction System (LODS), and to identify associated characteristics. DESIGN: Prospective cohort, 18-month observation. SUBJECTS AND SETTING: All admissions to a 12-bed, inner-city, university-affiliated hospital, medical ICU from July 1999 to December 2000. MEASUREMENTS: Data for APACHE II and LODS scoring systems were collected within 24 hours of admission. Lengths of ICU and hospital stay were the primary outcomes. Prolonged ICU and hospital LOS were defined as 3 or more and 6 or more days. RESULTS: A total of 584 patients, mean age 49, 56% men, 82% African American were admitted to the ICU. At admission they had (mean +/-SD) APACHE II (18 +/- 10), LODS (5 +/- 4), and predicted mortality of 32% +/- 29%. DKA was the admitting diagnosis in 42 (7.6%) patients; they had lower APACHE II (12 +/- 6), LODS (2 +/- 1), and predicted mortality 5% +/- 5% than the general ICU population (all, P <.001). Hospital mortality in non-DKA patients was 18%; there were no deaths in patients with DKA. Among DKA patients, those with insulin noncompliance had a shorter hospital stay (2.8 +/- 1 d) than those with an underlying illness as the DKA trigger (4.8 +/- 3, P =.02). Between patients with DKA, regardless of the LOS, there were no significant differences in APACHE II, LODS, or predicted mortality. CONCLUSIONS: ICU-admitted patients with DKA are less ill, and have lower disease severity scores, mortality, and shorter length of ICU and hospital stay than non-DKA patients. Disease severity scores are not, but precipitating cause is, predictor associated with prolonged hospital LOS in patients with DKA.

Biological background knowledge and learning from a drug and alcohol education program.

The authors asked whether having a base of relevant biological knowledge put school children in a better position to understand the effects of alcohol and cocaine and to learn about these effects when exposed to a curriculum presenting a physiological theory of drug action. Participants were 337 ethnically diverse 3rd- through 6th-grade students who were pretested, trained, and posttested. Multiple regression analyses revealed that knowledge of the basic functions of the heart, blood, and brain predicted certain drug-knowledge variables. Students with greater biological background knowledge also learned more from instruction, a finding with implications for enhancing drug and other health education programs.

Differences between Black and White elementary school children's orientations toward alcohol and cocaine: a three-study comparison.

To trace the origins of race differences in substance use, this study examined differences between Black and White elementary school children's knowledge of alcohol and cocaine, beliefs about their short- and long-term effects, and attitudes toward and intentions to use them across three independent samples (N = 181, N = 287, N = 234). Black children were more negatively oriented toward alcohol and cocaine than White children from an early age. Most notably, in all samples Black children had less positive attitudes toward adult alcohol use and lower intentions to use alcohol. Black children were also more likely to attribute negative long-term health and social effects to alcohol and cocaine use, but there were few significant race differences in knowledge or in expectancies regarding short-term effects of use. Since race differences in beliefs, exposure to alcohol, and socioeconomic factors could not explain race differences in attitudes toward substance use, other cultural differences must be considered.

Definitional issues in emotion regulation research.

Operational definitions of emotion regulation are frequently unclear, as are links between emotion regulation measures and underlying theoretical constructs. This is of concern because measurement decisions can have both intentional and unintentional implications for underlying conceptualizations of emotion regulation. This report examines the implications of some such decisions, including (a) focusing on types versus total amount of emotion regulation, (b) determining distinctiveness of measures of emotion versus emotion regulation strategies, (c) deciding whether and how to examine temporal sequencing of strategy use and emotion, d) using discrete versus global emotion measures, and (e) determining when emotion is being regulated. Finally, the need for better conceptualizations and empirical assessments of adaptive (vs. maladaptive) emotion regulation is discussed.

Characteristics associated with analgesia ordering in the intensive care unit and relationships with outcome.

OBJECTIVE: To describe clinical characteristics associated with analgesia utilization in the intensive care unit. DESIGN: A prospective cohort study of adult patients admitted to a medical intensive care unit. SUBJECTS: Four hundred adult patients. SETTING: Twelve-bed medical intensive care unit of an inner-city, university-affiliated hospital. MEASUREMENTS AND MAIN RESULTS: Collected data included demographics, sedation and neuromuscular blocking agents used, mechanical ventilation, hemodynamic monitoring, Therapeutic Intervention Scoring System score, Logistic Organ Dysfunction System (LODS) score, and Acute Physiology and Chronic Health Evaluation (APACHE) II score. Hospital outcome was noted. The odds ratio and 95% confidence intervals were determined by using multiple logistic regression analyses. Patients' mean age (+/-sd) was 47.8 +/- 17.1 yrs; 58% were male, 84% African-American. Their APACHE II-predicted hospital mortality rate was 33%. Analgesics were used in 36% of patients. There were no differences in demographics, initial LODS score, APACHE II score, and mechanical ventilation use between patients who did and did not receive analgesics. Multiple logistic regression analysis showed that analgesic use was independently associated with sedation (odds ratio, 2.47; 95% confidence interval, 1.47-4.14), neuromuscular blockade (odds ratio, 4.98; 95% confidence interval, 1.85-13.41), and pulmonary artery flotation catheter utilization (odds ratio, 2.31; 95% confidence interval, 1.27-4.20). The median duration of mechanical ventilation was 5 days for those who received analgesia compared with 2 for those who did not (p =.0001). The median length of stay in the intensive care unit (4 vs. 2, p <.0001) and hospital (11 vs. 7, p <.0001) was higher in patients who received analgesics. There were no significant differences in intensive care unit and hospital mortality rates between patients who did and did not receive analgesics. CONCLUSIONS: Intensive care unit patients for whom analgesics were prescribed have a higher frequency of hemodynamic monitoring and use of sedative and neuromuscular blocking agents, more mechanical ventilation days, and longer intensive care unit and hospital lengths of stay.

Teaching a coherent theory of drug action to elementary school children.

This study examined whether two versions of a drug and alcohol curriculum explaining how substances affect behavior and health, one version more causally coherent than the other, were more effective than a control curriculum on disease in changing school-age children's (N=327) beliefs and attitudes regarding cocaine and alcohol. Few differences were found between the two drug and alcohol curricula. Compared to children receiving the control curriculum, however, both treatment groups demonstrated greater understanding of the circulation of alcohol and cocaine throughout the body, the true long-term effects of these substances, and the stimulant effects of cocaine. Moreover, they had less positive attitudes and intentions toward cocaine. Several differences were evident at both a 3-month post-test and a 1-year follow-up, pointing to the potential value of applying an intuitive theories perspective in designing drug prevention and other health education programs.