Toxicology Paradise: Sorting Out Adverse and Non-adverse Findings in Animal Toxicity Studies.

A challenge for all toxicologists is defining what study findings are actually adverse versus non-adverse in animal toxicity studies, and which ones are relevant for generating a no observed adverse effect level (NOAEL) to assess human risk. This article presents views on this challenge presented by toxicologists, toxicologic pathologists, and regulatory reviewers at the 2019 annual meeting of the American College of Toxicology during a workshop entitled "Toxicology Paradise: Sorting Out Adverse and Non-adverse Findings." The speakers noted that setting a NOAEL is not always straightforward, not only for small molecules but also for biopharmaceuticals, and that a "weight of evidence" approach often is more useful than a rigid threshold-setting algorithm. Regulators from the US Food and Drug Administration and European Union told how assessment of adverse nonclinical findings is undertaken to allow clinical studies to commence and drug marketing approvals to succeed, along with the process that allows successful dialogs with regulators. Nonclinical case studies of findings judged to be adverse versus non-adverse were presented in relation to the many factors that might halt or delay clinical development. The process of defining adverse findings and the NOAEL in final study reports was discussed, as well as who should be involved in the process.

Increased prevalence of potential right-to-left shunting in children with sickle cell anaemia and stroke.

'Paradoxical' embolization via intracardiac or intrapulmonary right-to-left shunts (RLS) is an established cause of stroke. Hypercoagulable states and increased right heart pressure, which both occur in sickle cell anaemia (SCA), predispose to paradoxical embolization. We hypothesized that children with SCA and overt stroke (SCA + stroke) have an increased prevalence of potential RLS. We performed contrasted transthoracic echocardiograms on 147 children (aged 2-19 years) with SCA + stroke) mean age 12·7 ± 4·8 years, 54·4% male) and a control group without SCA or stroke (n = 123; mean age 12·1 ± 4·9 years, 53·3% male). RLS was defined as any potential RLS detected by any method, including intrapulmonary shunting. Echocardiograms were masked and adjudicated centrally. The prevalence of potential RLS was significantly higher in the SCA+stroke group than controls (45·6% vs. 23·6%, P < 0·001). The odds ratio for potential RLS in the SCA + stroke group was 2·7 (95% confidence interval: 1·6-4·6) vs controls. In post hoc analyses, the SCA + stroke group had a higher prevalence of intrapulmonary (23·8% vs. 5·7%, P < 0·001) but not intracardiac shunting (21·8% vs. 18·7%, P = 0·533). SCA patients with potential RLS were more likely to report headache at stroke onset than those without. Intrapulmonary and intracardiac shunting may be an overlooked, independent and potentially modifiable risk factor for stroke in SCA.

Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial.

BACKGROUND: For children with sickle cell anaemia and high transcranial doppler (TCD) flow velocities, regular blood transfusions can effectively prevent primary stroke, but must be continued indefinitely. The efficacy of hydroxycarbamide (hydroxyurea) in this setting is unknown; we performed the TWiTCH trial to compare hydroxyurea with standard transfusions. METHODS: TWiTCH was a multicentre, phase 3, randomised, open-label, non-inferiority trial done at 26 paediatric hospitals and health centres in the USA and Canada. We enrolled children with sickle cell anaemia who were aged 4-16 years and had abnormal TCD flow velocities (≥ 200 cm/s) but no severe vasculopathy. After screening, eligible participants were randomly assigned 1:1 to continue standard transfusions (standard group) or hydroxycarbamide (alternative group). Randomisation was done at a central site, stratified by site with a block size of four, and an adaptive randomisation scheme was used to balance the covariates of baseline age and TCD velocity. The study was open-label, but TCD examinations were read centrally by observers masked to treatment assignment and previous TCD results. Participants assigned to standard treatment continued to receive monthly transfusions to maintain 30% sickle haemoglobin or lower, while those assigned to the alternative treatment started oral hydroxycarbamide at 20 mg/kg per day, which was escalated to each participant's maximum tolerated dose. The treatment period lasted 24 months from randomisation. The primary study endpoint was the 24 month TCD velocity calculated from a general linear mixed model, with the non-inferiority margin set at 15 cm/s. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of assigned treatment. This study is registered with ClinicalTrials.gov, number NCT01425307. FINDINGS: Between Sept 20, 2011, and April 17, 2013, 159 patients consented and enrolled in TWiTCH. 121 participants passed screening and were then randomly assigned to treatment (61 to transfusions and 60 to hydroxycarbamide). At the first scheduled interim analysis, non-inferiority was shown and the sponsor terminated the study. Final model-based TCD velocities were 143 cm/s (95% CI 140-146) in children who received standard transfusions and 138 cm/s (135-142) in those who received hydroxycarbamide, with a difference of 4·54 (0·10-8·98). Non-inferiority (p=8·82 × 10(-16)) and post-hoc superiority (p=0·023) were met. Of 29 new neurological events adjudicated centrally by masked reviewers, no strokes were identified, but three transient ischaemic attacks occurred in each group. Magnetic resonance brain imaging and angiography (MRI and MRA) at exit showed no new cerebral infarcts in either treatment group, but worsened vasculopathy in one participant who received standard transfusions. 23 severe adverse events in nine (15%) patients were reported for hydroxycarbamide and ten serious adverse events in six (10%) patients were reported for standard transfusions. The most common serious adverse event in both groups was vaso-occlusive pain (11 events in five [8%] patients with hydroxycarbamide and three events in one [2%] patient for transfusions). INTERPRETATION: For high-risk children with sickle cell anaemia and abnormal TCD velocities who have received at least 1 year of transfusions, and have no MRA-defined severe vasculopathy, hydroxycarbamide treatment can substitute for chronic transfusions to maintain TCD velocities and help to prevent primary stroke. FUNDING: National Heart, Lung, and Blood Institute, National Institutes of Health.

Controlled trial of transfusions for silent cerebral infarcts in sickle cell anemia.

BACKGROUND: Silent cerebral infarcts are the most common neurologic injury in children with sickle cell anemia and are associated with the recurrence of an infarct (stroke or silent cerebral infarct). We tested the hypothesis that the incidence of the recurrence of an infarct would be lower among children who underwent regular blood-transfusion therapy than among those who received standard care. METHODS: In this randomized, single-blind clinical trial, we randomly assigned children with sickle cell anemia to receive regular blood transfusions (transfusion group) or standard care (observation group). Participants were between 5 and 15 years of age, with no history of stroke and with one or more silent cerebral infarcts on magnetic resonance imaging and a neurologic examination showing no abnormalities corresponding to these lesions. The primary end point was the recurrence of an infarct, defined as a stroke or a new or enlarged silent cerebral infarct. RESULTS: A total of 196 children (mean age, 10 years) were randomly assigned to the observation or transfusion group and were followed for a median of 3 years. In the transfusion group, 6 of 99 children (6%) had an end-point event (1 had a stroke, and 5 had new or enlarged silent cerebral infarcts). In the observation group, 14 of 97 children (14%) had an end-point event (7 had strokes, and 7 had new or enlarged silent cerebral infarcts). The incidence of the primary end point in the transfusion and observation groups was 2.0 and 4.8 events, respectively, per 100 years at risk, corresponding to an incidence rate ratio of 0.41 (95% confidence interval, 0.12 to 0.99; P=0.04). CONCLUSIONS: Regular blood-transfusion therapy significantly reduced the incidence of the recurrence of cerebral infarct in children with sickle cell anemia. (Funded by the National Institute of Neurological Disorders and Stroke and others; Silent Cerebral Infarct Multi-Center Clinical Trial ClinicalTrials.gov number, NCT00072761, and Current Controlled Trials number, ISRCTN52713285.).

Stress reticulocytes lose transferrin receptors by an extrinsic process involving spleen and macrophages.

As they mature into erythrocytes during normal erythropoiesis, reticulocytes lose surface transferrin receptors before or concurrently with reticulin. Exosome release accounts for most of the loss of transferrin receptors from reticulocytes. During erythropoietic stress, reticulocytes are released early from hematopoietic tissues and have increased reticulin staining and transferrin receptors. Flow cytometry of dually stained erythrocytes of mice recovering from phlebotomy demonstrated delayed loss of reticulin and transferrin receptors during in vitro maturation compared to in vivo maturation, indicating that an in vivo process extrinsic to the reticulocytes facilitates their maturation. Splenectomy or macrophage depletion by liposomal clodronate inhibited in vivo maturation of reticulocytes and increased the numbers of reticulin-negative, transferrin receptor-positive cells during and after recovery from phlebotomy. This reticulin-negative, transferrin receptor-positive population was rarely found in normal mice. Transmission electron microscopy demonstrated that the reticulin-negative, transferrin receptor-positive cells were elongated and discoid erythrocytes, but they had intracellular and surface structures that appeared to be partially degraded organelles. The results indicate that maturation of circulating stress reticulocytes is enhanced by an extrinsic process that occurs in the spleen and involves macrophage activity. Complete loss of reticulin with incomplete loss of surface transferrin receptors in this process produces a reticulin-negative, transferrin receptor-positive erythrocyte population that has potential utility for detecting prior erythropoietic stresses including bleeding, hemolysis and erythropoietin administration, even after recovery has been completed. Am. J. Hematol. 91:875-882, 2016. © 2016 Wiley Periodicals, Inc.

Associated risk factors for silent cerebral infarcts in sickle cell anemia: low baseline hemoglobin, sex, and relative high systolic blood pressure.

The most common form of neurologic injury in sickle cell anemia (SCA) is silent cerebral infarction (SCI). In the Silent Cerebral Infarct Multi-Center Clinical Trial, we sought to identify risk factors associated with SCI. In this cross-sectional study, we evaluated the clinical history and baseline laboratory values and performed magnetic resonance imaging of the brain in participants with SCA (HbSS or HbSß° thalassemia) between the ages of 5 and 15 years with no history of overt stroke or seizures. Neuroradiology and neurology committees adjudicated the presence of SCI. SCIs were diagnosed in 30.8% (251 of 814) participants who completed all evaluations and had valid data on all prespecified demographic and clinical covariates. The mean age of the participants was 9.1 years, with 413 males (50.7%). In a multivariable logistic regression analysis, lower baseline hemoglobin concentration (P < .001), higher baseline systolic blood pressure (P = .018), and male sex (P = .030) were statistically significantly associated with an increased risk of an SCI. Hemoglobin concentration and systolic blood pressure are risk factors for SCI in children with SCA and may be therapeutic targets for decreasing the risk of SCI. This study is registered at www.clinicaltrials.gov as #NCT00072761.

Silent cerebral infarction, income, and grade retention among students with sickle cell anemia.

Children with sickle cell anemia have a higher-than-expected prevalence of poor educational attainment. We test two key hypotheses about educational attainment among students with sickle cell anemia, as measured by grade retention and use of special education services: (1) lower household per capita income is associated with lower educational attainment; (2) the presence of a silent cerebral infarct is associated with lower educational attainment. We conducted a multicenter, cross-sectional study of cases from 22 U.S. sites included in the Silent Infarct Transfusion Trial. During screening, parents completed a questionnaire that included sociodemographic information and details of their child's academic status. Of 835 students, 670 were evaluable; 536 had data on all covariates and were used for analysis. The students' mean age was 9.4 years (range: 5-15) with 52.2% male; 17.5% of students were retained one grade level and 18.3% received special education services. A multiple variable logistic regression model identified that lower household per capita income (odds ratio [OR] of quartile 1 = 6.36, OR of quartile 2 = 4.7, OR of quartile 3 = 3.87; P = 0.001 for linear trend), age (OR = 1.3; P < 0.001), and male gender (OR, 2.2; P = 0.001) were associated with grade retention; silent cerebral infarct (P = 0.31) and painful episodes (P = 0.60) were not. Among students with sickle cell anemia, household per capita income is associated with grade retention, whereas the presence of a silent cerebral infarct is not. Future educational interventions will need to address both the medical and socioeconomic issues that affect students with sickle cell anemia.

Abdominal pain in children with sickle cell disease.

The differential diagnosis of abdominal pain is broad in any child, and further complicated in children with sickle cell disease (SCD). Acute causes of abdominal pain may require emergent surgery, such as for appendicitis or obstruction caused by a bezoar. Rapid intervention is necessary and life-saving in children with SCD and acute splenic or hepatic sequestration. The majority of children with SCD presenting to the physician's office or emergency department will have subacute reasons for their abdominal pain, including but not limited to constipation, urinary tract infection, peptic ulcer disease, and cholecystitis. Vaso-occlusive pain often presents in children as abdominal pain, but is a diagnosis of exclusion. The case of a 10-year-old girl with intermittent abdominal pain is used as a starting point to review the pathophysiology, diagnosis, and treatment of the most acute and common causes of abdominal pain in children with SCD.

Outcomes of matched sibling donor hematopoietic stem cell transplantation for severe sickle cell disease with myeloablative conditioning and intermediate-dose of rabbit anti-thymocyte globulin.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy for sickle cell disease (SCD) in children. Despite excellent outcomes of matched sibling donor (MSD) HSCT, there is still 5-10% chance of rejection and transplant related mortality (TRM) with 12-23% incidence of graft versus host disease (GVHD). We postulated that an intermediate dose of rabbit anti-thymocyte globulin (r-ATG, 10 mg/kg cumulative) would be effective in preventing both rejection and GVHD. PATIENTS AND METHODS: Fifteen patients, median age 5 (range 1.5-18) years, underwent MSD HSCT using busulfan (≥ 12.8 mg/kg with first dose pharmacokinetics), cyclophosphamide (total 200 mg/kg) and r-ATG. Bone marrow was the stem cell source; tacrolimus and methotrexate were given for GVHD prophylaxis. RESULTS: All patients achieved donor engraftment and there was no TRM. One patient rejected donor cells at 2 months post-transplant. Majority of the patients had high and sustained level of donor chimerism. None of the patients developed ≥ Grade II GVHD. Incidence of CMV (10%) and EBV (9%) reactivations was low with rapid immune-reconstitution. Overall survival was 100% with event free survival of 93%. CONCLUSIONS: Eliminating the risks of TRM and GVHD by optimizing the regimen may lead to further acceptance of HSCT for SCD.

Predictors of health-related quality of life over time among adolescents and young adults with sickle cell disease.

Little is known about what factors affect the health-related quality of life (HRQoL) of adolescents and young adults (AYAs) with sickle cell disease (SCD), and how their HRQoL changes over time. This retrospective study included 87 AYAs attending a SCD Adolescent Clinic who completed a measure of HRQoL at each visit over the course of approximately 1.3 years. Results suggested that the following were associated with poorer physical HRQoL: being female, more healthcare utilization events, and presence of internalizing symptoms. Internalizing and externalizing symptoms were the only factors correlated with poorer psychosocial HRQoL. Generalized linear mixed models indicated that physical and psychosocial HRQoL improved among all participants during the assessment period, and those with externalizing behaviors reported faster improvement in physical HRQoL over time. AYAs with SCD may benefit from early mental health screening and intervention to optimize clinical care.

Young adults with SCD in US children's hospitals: are they different from adolescents?

BACKGROUND: The period of transition from pediatric to adult care is a vulnerable time for patients with sickle cell disease (SCD). The optimal time for transition is unknown and there is no standard of care regarding this timing in the United States. PROCEDURES: We collected administrative data from the Pediatric Health Information System for all SCD admissions from 2000 to 2009. We compared reasons for hospitalization and resulting charges in adolescents (13-17 years) and young adults (18-21 years). RESULTS: We identified 25,371 admissions of adolescents (n = 18,299) and young adults (n = 7,072) with SCD. Median admissions per patient per year was higher in young adults (0.6) compared to adolescents (0.2, P < 0.001), but reasons for hospitalization were similar between the two age groups. Complications of adult SCD such as nephropathy and pulmonary hypertension were rare (<2.5% of discharges) but more frequent in older patients (P = 0.001). Although length of stay was similar between the two groups (median = 4 days), young adults tended to incur higher charges (median +$1,314, P < 0.001) and were less likely to utilize private insurance (P < 0.001). Deaths (0.2% of admissions) were rare and similar across age groups (P = 0.7). CONCLUSION: In a national sample of US children's hospitals, adolescents (13-17 years) and young adults (18-21 years) with SCD had similar reasons for hospitalization and low mortality. Further studies are needed to investigate whether extending the age of transition to ≥ 21 years as a national standard may decrease morbidity and mortality, improve health-related quality of life, or increase readiness for transition in patients with SCD.

Caregivers' perspectives on barriers to transcranial Doppler screening in children with sickle-cell disease.

BACKGROUND: Current guidelines recommend that children with HbSS or HbSß°thal undergo yearly transcranial Doppler screenings (TCD) to identify those at high risk for stroke. Compliance is low with yearly TCD screenings. Our objective was to describe caregiver experiences and knowledge of TCD screenings as well as barriers that may prevent screening. PROCEDURE: Qualitative, in-depth interviews structured around the Health Belief Model were conducted with 36 caregivers of children eligible for annual TCD screenings. Interviews were coded and general themes were extracted. RESULTS: Two-thirds (69%) of caregivers believed that stroke occurs sometimes (33%) or frequently (36%) in children with sickle-cell disease (SCD). Lack of knowledge was the most commonly described barrier to annual TCD screening, with 22% of caregivers reporting no knowledge of screening, and 42% unaware that the screen should be performed annually. Lack of self-efficacy and fear of chronic transfusions were other barriers endorsed by caregivers. Barriers less commonly identified (endorsed by <10% of caregivers) included financial barriers, transportation issues, missed appointments, and hours of radiology clinic. Fifty-eight percent of the caregivers' children with SCD had undergone a TCD in the 18 months prior to the study interview. CONCLUSIONS: From the caregiver perspective, lack of knowledge and low self-efficacy play a larger role than practical barriers in compliance with annual TCDs. Ongoing education at multiple patient encounters and encouragement of caregivers' empowerment and role in obtaining annual screenings may increase TCD compliance.

Sickle cell trait, hemoglobin C trait, and invasive pneumococcal disease.

BACKGROUND: The cause of historically higher rates of invasive pneumococcal disease among blacks than whites has remained unknown. We tested the hypothesis that sickle cell trait or hemoglobin C trait is an independent risk factor for invasive pneumococcal disease. METHOD: Eligible children were born in Tennessee (1996-2003), had a newborn screen, enrolled in TennCare aged <1 year, and resided in a Tennessee county with laboratory-confirmed, pneumococcal surveillance. Race/ethnicity was ascertained from birth certificates. Children were followed through 2005 until loss of enrollment, pneumococcal disease episode, fifth birthday, or death. We calculated incidence rates by race/ethnicity and hemoglobin type before and after pneumococcal conjugate vaccine (PCV7) introduction. Poisson regression analyses compared invasive pneumococcal disease rates among blacks with sickle cell trait or hemoglobin C trait with whites and blacks with normal hemoglobin, controlling for age, gender, time (pre-PCV7, transition year, or post-PCV7) and high-risk conditions (eg, heart disease). RESULTS: Over 10 years, 415 invasive pneumococcal disease episodes occurred during 451,594 observed child-years. Before PCV7 introduction, disease rates/100,000 child-years were 2941 for blacks with sickle cell disease, 258 for blacks with sickle cell trait or hemoglobin C trait and 188, 172, and 125 for blacks, whites, and Hispanics with normal hemoglobin. Post-PCV7, rates declined for all groups. Blacks with sickle cell trait or hemoglobin C trait had 77% (95% CI = 22-155) and 42% (95% CI = 1-100) higher rates than whites and blacks with normal hemoglobin. CONCLUSION: Black children with sickle cell trait or hemoglobin C trait have an increased risk of invasive pneumococcal disease.

Toxicity and toxicokinetics of metformin in rats.

Metformin is a first-line drug for the treatment of type 2 diabetes (T2D) and is often prescribed in combination with other drugs to control a patient's blood glucose level and achieve their HbA1c goal. New treatment options for T2D will likely include fixed dose combinations with metformin, which may require preclinical combination toxicology studies. To date, there are few published reports evaluating the toxicity of metformin alone to aid in the design of these studies. Therefore, to understand the toxicity of metformin alone, Crl:CD(SD) rats were administered metformin at 0, 200, 600, 900 or 1200 mg/kg/day by oral gavage for 13 weeks. Administration of > or =900 mg/kg/day resulted in moribundity/mortality and clinical signs of toxicity. Other adverse findings included increased incidence of minimal necrosis with minimal to slight inflammation of the parotid salivary gland for males given 1200 mg/kg/day, body weight loss and clinical signs in rats given > or =600 mg/kg/day. Metformin was also associated with evidence of minimal metabolic acidosis (increased serum lactate and beta-hydroxybutyric acid and decreased serum bicarbonate and urine pH) at doses > or =600 mg/kg/day. There were no significant sex differences in mean AUC(0-24) or C(max) nor were there significant differences in mean AUC(0-24) or C(max) following repeated dosing compared to a single dose. The no observable adverse effect level (NOAEL) was 200 mg/kg/day (mean AUC(0-24)=41.1 microg h/mL; mean C(max)=10.3 microg/mL based on gender average week 13 values). These effects should be taken into consideration when assessing potential toxicities of metformin in fixed dose combinations.

Growth patterns in children with sickle cell anemia during puberty.

BACKGROUND: Previous studies of children with homozygous sickle cell anemia (SCA) show impaired growth and maturation. The correlation of this suboptimal growth with metabolic and hematological factors during puberty is poorly understood. PROCEDURE: We studied a group of pre-adolescent children with SCA (19 males, 14 females) and healthy controls (16 males, 15 females) matched for race, sex, body size, and pubertal development. Height, weight, body mass index (BMI), and body composition changes were longitudinally assessed over a 2-year period and compared between the groups and with Z scores based on US growth charts. These changes were correlated with hemoglobin (Hgb) concentration and with energy expenditure (EE) measured using indirect whole-room calorimetry. RESULTS: Children with SCA progressed through puberty slower than control children. While, after 2 years, pubertal males with SCA were shorter, their annual increases in weight were not different from controls. The mean fat free mass (FFM) increments were significantly less in males and females with SCA than in control children. In males with SCA, growth in height declined over time and was significantly slower than in matched controls (P < 0.05). CONCLUSION: Growth delays were present during puberty in children with SCA. Decreased growth velocity in children with SCA was independently associated with decreased Hgb concentration and increased total EE.

Spinal epidural hematoma following a thoracic epidural in a child with sickle cell disease.

Acute liver dysfunction in the perioperative period may increase the risk of epidural hematoma in a patient with a neuraxial catheter. Coagulation testing needs to be carefully monitored in these patients. An epidural hematoma should be ruled out urgently by CT or MRI in cases of a persistent motor block.

Continuous autonomic assessment in patients with symptomatic heart failure: prognostic value of heart rate variability measured by an implanted cardiac resynchronization device.

BACKGROUND: Heart rate variability (HRV) as an indirect autonomic assessment provides prognostic information when measured over short time periods in patients with heart failure. Long-term continuous HRV can be measured from an implantable device, but the clinical value of these measurements is unknown. METHODS AND RESULTS: A total of 397 patients with New York Heart Association class III or IV heart failure were studied. Of these, 370 patients had information from their implanted cardiac resynchronization device for mortality risk stratification, and 288 patients had information for measured parameters (ie, HRV, night heart rate, and patient activity) and clinical event analyses. Continuous HRV was measured as the standard deviation of 5-minute median atrial-atrial intervals (SDAAM) sensed by the device. SDAAM <50 ms when averaged over 4 weeks was associated with increased mortality risk (hazard ratio 3.20, P=0.02) and SDAAM were persistently lower over the entire follow-up period in patients who required hospitalization or died. SDAAM decreased a median of 16 days before hospitalization and returned to baseline after treatment. Automated detection of decreases in SDAAM was 70% sensitive in detecting cardiovascular hospitalization, with 2.4 false-positives per patient-year of follow-up. CONCLUSIONS: This study demonstrates that SDAAM continuously measured from an implanted cardiac resynchronization device is lower in patients at high mortality and hospitalization risk. SDAAM declines as patient status decompensates. Continuous long-term SDAAM may be a useful tool in the clinical management of patients with chronic heart failure.

A critical assessment of treatment options for idiopathic pulmonary fibrosis.

BACKGROUND: To date, no management approach has proven to be efficacious for the treatment of idiopathic pulmonary fibrosis (IPF). Consequently, therapeutic options remain controversial and confusing for many clinicians. We sought to formally review available evidence on treatment options for IPF and to have a diverse panel of physicians rate the "appropriateness," "inappropriateness," or "uncertainty" of some of the available therapeutic options. METHODS: The RAND/UCLA Appropriateness Method was used to review and rate multiple clinical scenarios for the treatment of IPF. The panel was composed of nine physicians from geographically diverse areas who received a systematic review on the risks and benefits of commonly used treatments for IPF as background. RESULTS: A total of 324 clinical scenarios were rated: 25% as appropriate; 39%, uncertain; and 36%, inappropriate. The panel disagreed about 12% of the therapy indications in the final ratings, falling from 26% in the first-round ratings. CONCLUSIONS: Key themes emerged from the consensus process. Lacking evidence for a definitive therapy, it was considered most appropriate to enroll eligible patients in clinical trials and refer eligible patients for transplant evaluation. For patients without access to clinical trials, the committee was not unanimous regarding treatment recommendations. It was considered inappropriate for patients with a confident diagnosis of IPF to be treated with corticosteroids as the sole agent: corticosteroids should be used in conjunction with azathioprine. With progressive disease despite such combination use, there was agreement for the use of interferon gamma-1b in patients unwilling or unable to participate in available clinical trials.

Intrathoracic impedance to monitor heart failure status: a comparison of two methods in a chronic heart failure dog model.

In patients with heart failure (HF), a convenient and accurate assessment of HF status could enhance titration of medications and possibly reduce hospitalizations for fluid overload. This study examined the feasibility of monitoring HF status by measuring intrathoracic impedance with either an implantable cardioverter-defibrillator or a pacemaker. Six canines were each instrumented with four devices: two capable of measuring intrathoracic impedance between a right ventricular coil electrode and the device case, one custom pacemaker for inducing HF, and an implantable hemodynamic monitor to measure left ventricular end-diastolic pressure as an assessment of HF status. High-rate ventricular pacing for 3-7 weeks induced HF, followed by a 4-week recovery period. During high-rate pacing, left ventricular end-diastolic pressure was inversely correlated with impedance measurements from both systems (median r=-0.66; range r=-0.38 to -0.81). During recovery, the inverse correlation between left ventricular end-diastolic pressure and impedance was enhanced (median r=-0.88; range r=-0.58 to -0.95). The two types of impedance measurements were highly correlated (median r=-0.68 during pacing and r=-0.91 during recovery). These results suggest that various methods of measurement of intrathoracic impedance over time could be used to monitor HF status.