Scoring System to Optimize Pioglitazone Therapy After Stroke Based on Fracture Risk.

Background and Purpose- The insulin sensitizer, pioglitazone, reduces cardiovascular risk in patients after an ischemic stroke or transient ischemic attack but increases bone fracture risk. We conducted a secondary analysis of the IRIS trial (Insulin Resistance Intervention After Stroke) to assess the effect of pretreatment risk for fracture on the net benefits of pioglitazone therapy. Methods- IRIS was a randomized placebo-controlled trial of pioglitazone that enrolled patients with insulin resistance but without diabetes mellitus within 180 days of an ischemic stroke or transient ischemic attack. Participants were recruited at 179 international centers from February 2005 to January 2013 and followed for a median of 4.8 years. Fracture risk models were developed from patient characteristics at entry. Within fracture risk strata, we quantified the effects of pioglitazone compared with placebo by estimating the relative risks and absolute 5-year risk differences for fracture and stroke or myocardial infarction. Results- The fracture risk model included points for age, race-ethnicity, sex, body mass index, disability, and medications. The relative increment in fracture risk with pioglitazone was similar in the lower (

Greater fluctuations in serum sodium levels are associated with increased mortality in children with externalized ventriculostomy drains in a PICU.

OBJECTIVES: Dysnatremia is common in critically ill children due to disruption of hormonal homeostasis. Children with brain injury are at risk for syndrome of inappropriate antidiuretic hormone, cerebral salt wasting, and sodium losses due to externalized ventricular drain placement. We hypothesized that among PICU patients managed with an externalized ventricular drain, hyponatremia is common, hyponatremia is associated with seizures and in-hospital mortality, and greater sodium fluctuations are associated with in-hospital mortality. DESIGN: Retrospective observational study. SETTING: Tertiary care PICU. PATIENTS: All pediatric patients treated in the PICU with an externalized ventricular drain from January 2005 to December 2009. Patients were identified by searching the physician order entry database for externalized ventricular drain orders. Hyponatremia was defined as the minimum sodium during patients' externalized ventricular drain time and was categorized as mild (131-134 mEq/L) or moderate to severe (≤ 130 mEq/L). Magnitude of sodium fluctuation was defined as the difference between a patient's highest and lowest sodium during the time in which an externalized ventricular drain was in use (up to 14 d). Seizure was defined as a clinically evident convulsion during externalized ventricular drain presence. A priori confounders were age, history of epilepsy, and externalized ventricular drain indication. Multivariable regression was performed to test the association between sodium derangements and outcomes. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Three hundred eighty patients were eligible. One hundred nine (29%) had mild hyponatremia, and 30 (8%) had moderate to severe hyponatremia. Twenty-eight patients (7%) had a seizure while hospitalized. Eighteen patients died (5%) prior to discharge. Survivors had a median daily sodium fluctuation of 1 mEq/L [0-5] vs non-survivors 9 mEq/L [6-11] (p < 0.001) and a median sodium fluctuation of 5 mEq/L [2-8] vs non-survivors 15 mEq/L [9-24] (p < 0.001) during externalized ventricular drain management. After controlling for a priori covariates and potential confounders, hyponatremia was not associated with an increased odds of seizures or in-hospital mortality. However, greater fluctuations in daily sodium (odds ratio, 1.38; 95% CI, 1.06-1.8) and greater fluctuations in sodium during externalized ventricular drain management were associated with increased odds of in-hospital mortality (odds ratio, 1.59; 95% CI, 1.2-2.11). CONCLUSIONS: Hyponatremia was common in PICU patients treated with externalized ventricular drains but not associated with seizures or in-hospital mortality. Greater sodium fluctuations during externalized ventricular drain management were independently associated with increased odds of in-hospital mortality.

Risk factors associated with infections and need for permanent cerebrospinal fluid diversion in pediatric intensive care patients with externalized ventricular drains.

BACKGROUND: Externalized ventricular drains (EVDs) are commonly used in pediatric intensive care units (PICU) but few data are available regarding infection rates, infection risks, or factors associated with conversion to permanent cerebrospinal fluid (CSF) diversion. METHODS: Retrospective observational study of patients managed with EVDs admitted to a tertiary care PICU from January 2005 to December 2009. RESULTS: Three hundred eighty patients were identified. Neurologic diagnostic groups were externalization of existing shunt in 196 patients (52 %), brain tumor in 122 patients (32 %), intracranial hemorrhage in 23 patients (6 %), traumatic brain injury in 17 patients (5 %), meningitis in 9 patients (2 %), or other in 13 patients (3 %). Six percent of all patients (24/380) had new infections associated with EVD management for an infection rate of 8.6 per 1,000 catheter days. The median time to positive cultures was 7 days (interquartile range 4.75, 9) after EVD placement. Patients with EVD infections had significantly longer EVD duration 6 versus 11.5 days (p = 0.0001), and higher maximum EVD outputs 1.9 versus 1.5 mL/kg/h (p = 0.0017). Need for permanent CSF diversion was associated with higher maximum EVD drainage (1.3 vs. 1.6 mL/kg/h p < 0.0001), longer EVD duration (5 vs. 4 days, p < 0.005), and younger age (4.5 vs. 8 years, p < 0.02) but not intracranial hypertension (72 vs. 82 % of patients, p = 0.4). CONCLUSIONS: In our large pediatric cohort, EVD infections were associated with longer EVD duration and higher maximum EVD output. Permanent CSF diversion was more likely in patients with higher maximum EVD drainage, longer EVD duration, and younger age.

Targeting Pioglitazone Hydrochloride Therapy After Stroke or Transient Ischemic Attack According to Pretreatment Risk for Stroke or Myocardial Infarction.

Importance: There is growing recognition that patients may respond differently to therapy and that the average treatment effect from a clinical trial may not apply equally to all candidates for a therapy. Objective: To determine whether, among patients with an ischemic stroke or transient ischemic attack and insulin resistance, those at higher risk for future stroke or myocardial infarction (MI) derive more benefit from the insulin-sensitizing drug pioglitazone hydrochloride compared with patients at lower risk. Design, Setting, and Participants: A secondary analysis was conducted of the Insulin Resistance Intervention After Stroke trial, a double-blind, placebo-controlled trial of pioglitazone for secondary prevention. Patients were enrolled from 179 research sites in 7 countries from February 7, 2005, to January 15, 2013, and were followed up for a mean of 4.1 years through the study's end on July 28, 2015. Eligible participants had a qualifying ischemic stroke or transient ischemic attack within 180 days of entry and insulin resistance without type 1 or type 2 diabetes. Interventions: Pioglitazone or matching placebo. Main Outcomes and Measures: A Cox proportional hazards regression model was created using baseline features to stratify patients above or below the median risk for stroke or MI within 5 years. Within each stratum, the efficacy of pioglitazone for preventing stroke or MI was calculated. Safety outcomes were death, heart failure, weight gain, and bone fracture. Results: Among 3876 participants (1338 women and 2538 men; mean [SD] age, 63 [11] years), the 5-year risk for stroke or MI was 6.0% in the pioglitazone group among patients at lower baseline risk compared with 7.9% in the placebo group (absolute risk difference, -1.9% [95% CI, -4.4% to 0.6%]). Among patients at higher risk, the risk was 14.7% in the pioglitazone group vs 19.6% for placebo (absolute risk difference, -4.9% [95% CI, -8.6% to 1.2%]). Hazard ratios were similar for patients below or above the median risk (0.77 vs 0.75; P = .92). Pioglitazone increased weight less among patients at higher risk but increased the risk for fracture more. Conclusions and Relevance: After an ischemic stroke or transient ischemic attack, patients at higher risk for stroke or MI derive a greater absolute benefit from pioglitazone compared with patients at lower risk. However, the risk for fracture is also higher. Trial Registration: clinicaltrials.gov Identifier: NCT00091949.

Taking care of volunteers in a stroke trial: a new assisted-management strategy.

BACKGROUND AND PURPOSE: Providing participants with evidence-based care for secondary prevention is an ethical and scientific priority for trials in stroke therapy. The optimal strategy, however, is uncertain. We report the performance of a new approach for delivering preventive care to trial participants. METHODS: Participants were enrolled in the Insulin Resistance Intervention after Stroke trial, which examined the insulin sensitiser, pioglitazone versus placebo for prevention of stroke and myocardial infarction after ischaemic stroke or transient ischaemic attack. Preventive care was the responsibility of the participants' personal healthcare providers, but investigators monitored care and provided feedback annually. We studied achievement of 8 prevention goals at baseline and 3 annual visits, with a focus on 3 priority goals: blood pressure <140/90 mm Hg, low-density lipoprotein (LDL) cholesterol <2.59 mmol/L and antithrombotic therapy. RESULTS: The proportion of participants achieving the priority goals was highest for antithrombotic use (96-99% in each year) and similar for blood pressure (66-72% in each year) and LDL (68-70% in each year). All 3 priority goals were achieved by 47-52% of participants in any given year. However, only 22% of participants achieved all 3 goals in each year. CONCLUSIONS: A strategy of monitoring care and providing feedback was associated with high average yearly achievement of 3 priority secondary prevention goals, but the majority of trial participants did not persist in being at goal over time. TRIAL REGISTRATION NUMBER: NCT00091949.