Schroeder, Darrell R.

Abstract Rationale Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with no known efficacious therapy. Imatinib is a tyrosine kinase inhibitor with potential efficacy to treat fibrotic lung disease. Objectives To investigate the safety and clinical effects of imatinib in patients with IPF. Methods We studied 119 patients in an investigator-initiated, multicenter, multinational, double-blind clinical trial to receive imatinib or placebo for 96 weeks. Measurements and Main Results Over 96 weeks of follow-up, imatinib did not differ significantly from placebo (log rank P = 0.89) for the primary endpoint defined as time to disease progression (10% decline in percent predicted FVC from baseline) or time to death. There was no effect of imatinib therapy on change in FVC at 48, 72, or 96 weeks (P ≥ 0.39 at all time points) or change in diffusing capacity of carbon monoxide at 48, 72, or 96 weeks (P ≥ 0.26 at all time points). Change in resting PaO2 favored imatinib therapy at 48 weeks (P = 0.005) but not at 96 weeks (P = 0.074). During the 96-week trial there were 8 deaths in the imatinib group and 10 deaths in the placebo group (log rank test P = 0.64). Thirty-five (29%) patients discontinued the study without reaching the primary endpoint (imatinib, 32%; placebo, 27%; P = 0.51). Serious adverse events (SAEs) were not more common in the imatinib group (imatinib, 18 SAEs in 17 patients; placebo, 19 SAEs in 18 patients). Conclusions In a randomized, placebo-controlled trial of patients with mild to moderate IPF followed for 96 weeks, imatinib did not affect survival or lung function. Clinical trial registered with www.clinicaltrials.gov (NCT00131274).

Background The authors' department conducted a performance improvement initiative aimed to reduce the rate of perioperative corneal injuries. This study reports the effects of the initiative and examines the risk factors for corneal injury. Method The rate of corneal injuries during nonophthalmologic procedures under anesthesia was compared between the two time periods: preinitiative baseline (August 1, 2005-December 31, 2005) and initiative period (January 1, 2006-April 30, 2007). To examine the risk factors for corneal injury, a nested case-control study with a 2:1 matched-set design was separately performed and included cases between January 1, 2006 and July 31, 2008. Results During the baseline period, the corneal injury rate was 1.51 per 1,000, and it decreased to 0.79 per 1,000 during the performance initiative (P = 0.008). Independent risk factors were longer anesthetics (odds ratio = 1.2, 95% confidence interval (CI) 1.1-1.3 per 30 min), lower American Society of Anesthesiologists physical status (odds ratio 0.5, 95% CI 0.3-0.8 for American Society of Anesthesiologists physical status 3-4 vs. 1-2), and student nurse anesthetist as a primary anesthesia provider (odds ratio 2.6, 95% CI 1.3-5.0). Conclusion Corneal injury rate in our institution was significantly reduced and remains at low levels long after initiation of perioperative eye care improvement initiative. The higher rate of corneal injuries among student nurse anesthetists highlights the importance of standardizing education and supervision among all anesthesia providers. We believe that our model of performance improvement initiative can be used to improve other perioperative outcomes.

Background Anesthetics administered to immature brains may cause histopathological changes and long-term behavioral abnormalities. The association between perinatal exposure to anesthetics during Cesarean delivery (CD) and development of learning disabilities (LD) was determined in a population-based birth cohort. Methods The educational and medical records of all children born to mothers residing in five townships of Olmsted County, Minnesota from 1976-1982 and remaining in the community at age 5 were reviewed to identify those with LDs. Cox proportional hazards regression was used to compare rates of LD between children delivered vaginally and via CD (with general or regional anesthesia). Results Of the 5,320 children in this cohort, 497 were delivered via CD (under general anesthesia n = 193, and regional anesthesia n = 304). The incidence of LD depended on mode of delivery (P = 0.050, adjusted for sex, birth weight, gestational age, exposure to anesthesia before age 4 yr, and maternal education). LD risk was similar in children delivered by vagina or CD with general anesthesia, but was reduced in children receiving CD with regional anesthesia (hazard ratio = 0.64, 95% confidence interval 0.44 to 0.92; P = 0.017 for comparison of CD under regional anesthesia compared to vaginal delivery). Conclusion Children exposed to general or regional anesthesia during CD are not more likely to develop LD compared to children delivered vaginally, suggesting that brief perinatal exposure to anesthetic drugs does not adversely affect long-term neurodevelopmental outcomes. The risk of LD may be lower in children delivered by CD whose mothers received regional anesthesia.

Background Laboratory studies suggest that nitrous oxide augments brain injury after ischemia or hypoxia. The authors examined the relation between nitrous oxide use and outcomes using data from the Intraoperative Hypothermia for Aneurysm Surgery Trial. Methods The Intraoperative Hypothermia for Aneurysm Surgery Trial was a prospective randomized study of the impact of intraoperative hypothermia (temperature = 33 degrees C) versus normothermia (temperature = 36.5 degrees C) in patients with aneurysmal subarachnoid hemorrhage undergoing surgical clipping. Anesthesia was dictated by a limited-options protocol with the use of nitrous oxide determined by individual anesthesiologists. All patients were assessed daily for 14 days after surgery or until hospital discharge. Neurologic and neuropsychological testing were conducted at 3 months after surgery. Outcome data were analyzed via both univariate tests and multivariate logistic regression analysis correcting for factors thought to influence outcome. An odds ratio (OR) greater than 1.0 denotes a worse outcome in patients receiving nitrous oxide. Results Outcome data were available for 1,000 patients, of which 373 received nitrous oxide. There was no difference between groups in the development of delayed ischemic neurologic deficit. At 3 months after surgery, there were no significant differences between groups in any outcome variable: Glasgow Outcome Score (OR, 0.84; 95% confidence interval [CI], 0.63-1.14; P = 0.268), National Institutes of Health Stroke Scale (OR, 1.29; 95% CI, 0.96-1.73; P = 0.087), Rankin Disability Score (OR, 0.84; 95% CI, 0.61-1.15; P = 0.284), Barthel Activities of Daily Living Index (OR, 1.01; 95% CI, 0.68-1.51; P = 0.961), or neuropsychological testing (OR, 1.26; 95% CI, 0.85-1.87; P = 0.252). Conclusions In a population of patients at risk for ischemic brain injury, nitrous oxide use had no overall beneficial or detrimental impact on neurologic or neuropsychological outcomes.

Background The authors explored the relationship between nitrous oxide use and neurologic and neuropsychological outcome in a population of patients likely to experience intraoperative cerebral ischemia: those who had temporary cerebral arterial occlusion during aneurysm clipping surgery. Methods A post hoc analysis of a subset of the data from the Intraoperative Hypothermia for Aneurysm Surgery Trial was conducted. Only subjects who had temporary arterial occlusion during surgery were included in the analysis. Metrics of short-term and long-term (i.e., 3 months after surgery) outcome were evaluated via both univariate and multivariate logistic regression analysis. An odds ratio (OR) greater than 1.0 denotes a worse outcome in patients receiving nitrous oxide. Results The authors evaluated 441 patients, of which 199 received nitrous oxide. Patients receiving nitrous oxide had a greater risk of delayed ischemic neurologic deficits (i.e., the clinical manifestation of vasospasm) (OR, 1.78, 95% confidence interval [CI], 1.08-2.95; P = 0.025). However, at 3 months after surgery, there was no difference in any metric of gross neurologic outcome: Glasgow Outcome Score (OR, 0.67; CI, 0.44-1.03; P = 0.065), Rankin Score (OR, 0.74; CI, 0.47-1.16; P = 0.192), National Institutes of Health Stroke Scale (OR, 1.02; CI, 0.66-1.56; P = 0.937), or Barthel Index (OR, 0.69; CI, 0.38-1.25; P = 0.22). The risk of impairment on at least one test of neuropsychological function was reduced in those who received nitrous oxide (OR, 0.56; CI, 0.36-0.89; P = 0.013). Conclusion In this patient population, use of nitrous oxide was associated with an increased risk for the development of delayed ischemic neurologic deficits; however, there was no evidence of detriment to long-term gross neurologic or neuropsychological outcome.