ISABELA Studies: Plasma Exposure and Target Engagement Do Not Explain the Lack of Efficacy of Ziritaxestat in Patients with Idiopathic Pulmonary Fibrosis.

Autotaxin (ATX) contributes to the production of lysophosphatidic acid (LPA), which is associated with fibrosis development in idiopathic pulmonary fibrosis (IPF). The ATX inhibitor ziritaxestat failed to reduce decline in forced vital capacity (FVC) in patients with IPF in ISABELA 1 and 2 (NCT03711162 and NCT03733444), two identically designed phase III studies. In the current analysis, we evaluated pharmacokinetic and pharmacodynamic data from the pooled ISABELA studies to determine whether the lack of efficacy could be attributed to insufficient exposure and/or target engagement. Nonlinear mixed effect modeling was performed to predict ziritaxestat exposure in individual patients and describe its effect on LPA C18:2 levels. We assessed whether there was a correlation between ziritaxestat and ATX concentration and evaluated the relationship between LPA C18:2 reduction and change from baseline in FVC. Ziritaxestat exposure in patients with IPF was numerically lower in those who received ziritaxestat on top of pirfenidone than in those who received ziritaxestat on top of nintedanib or ziritaxestat alone. In most patients, LPA C18:2 reduction was comparable to that reported in healthy volunteers. ATX concentrations increased over time and correlated weakly with ziritaxestat exposure and LPA C18:2 reduction. No correlation between reduction in LPA C18:2 and change from baseline in FVC was apparent. Based on these evaluations, exposure and target engagement are not thought to have contributed to the lack of efficacy observed. We hypothesize that the lack of efficacy of ziritaxestat in the ISABELA program, despite adequate LPA reduction, could be due to the involvement of an alternative pro-fibrotic pathway.

Unraveling Compositional Study, Chemometric Analysis, and Cell-Based Antioxidant Potential of Selective High Nutraceutical Value Amaranth Cultivars Using a GC-MS and NMR-Based Metabolomics Approach.

Amaranthus (family Amaranthaceae) is a potentially nutritious pseudocereal also known as a functional food owing to its high nutritional quality grains especially rich in essential amino acids. Emerging study, however, unambiguously indicates that apart from essential nutrients like protein, other phytochemicals present in amaranth seeds provide excellent health benefits. Squalene is one such phytonutrient found in Amaranthus seeds, which is also its largest vegetal source. In this research work, GC-MS and NMR spectroscopy-based metabolomics have been utilized for the compositional analysis of Amaranthus seeds coupled with a multivariate data set. Investigation of nonpolar and polar seed extracts of six different cultivars of amaranth identified 47 primary and secondary metabolites. One-way ANOVA showed significant quantitative metabolic variations in different cultivars of amaranth. Multivariate principal component analysis of both the GC-MS and NMR analyzed data broadly classified in two groups showed significant variations in the polar (lysine, arginine, GABA, and myoinositol) and nonpolar (squalene, tryptophan, and alkylated phenols, which are potential nutraceutical agents) metabolites. The squalene content estimated using HPLC varied significantly (1.61 to 4.72 mg g-1 seed dry weight) among six different cultivars. Positive correlations were found among the cellular antioxidant activity and squalene content. Cultivar AM-3 having the maximum squalene content showed the highest antioxidant activity evaluated on the cellular level over human embryonic kidney cells, clearly revealing potent intercellular reactive oxygen species scavenging capacity and strong membrane lipid peroxidation inhibition potential. Oxidative stress markers such as MDA, SOD, GSH, and CAT levels in cells further corroborated the research work. The study also indicated high concentrations of lysine (80.49 mg g-1 dry seeds) in AM-2, squalene (0.47% by weight) in AM-3, and 2,4-di-tert-butyl phenol (18.64% peak area) and myoinositol (79.07 mg g-1 dry seeds) in AM-5. This novel comparative metabolomic study successfully profiles the nutrient composition of amaranth cultivars and provides the opportunity for the development of nutraceuticals and natural antioxidants from this functional food.

Drug-drug interaction prediction of ziritaxestat using a physiologically based enzyme and transporter pharmacokinetic network interaction model.

Ziritaxestat, an autotaxin inhibitor, was under development for the treatment of idiopathic pulmonary fibrosis. It is a substrate of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein and a weak inhibitor of the CYP3A4 and OATP1B1 pathways. We developed a physiologically based pharmacokinetic (PBPK) network interaction model for ziritaxestat that incorporated its metabolic and transporter pathways, enabling prediction of its potential as a victim or perpetrator of drug-drug interactions (DDIs). Concurrently, we evaluated CYP3A4 autoinhibition, including time-dependent inhibition. In vitro information and clinical data from healthy volunteer studies were used for model building and validation. DDIs with rifampin, itraconazole, voriconazole, pravastatin, and rosuvastatin were predicted, followed by validation against a test dataset. DDIs of ziritaxestat as a victim or perpetrator were simulated using the final model. Predicted-to-observed DDI ratios for the maximum plasma concentration (Cmax ) and the area under the plasma concentration-time curve (AUC) were within a two-fold ratio for both the metabolic and transporter-mediated simulated DDIs. The predicted impact of autoinhibition/autoinduction or time-dependent inhibition of CYP3A4 was a 12% decrease in exposure. Model-based predictions for ziritaxestat as a victim of DDIs with a moderate CYP3A4 inhibitor (fluconazole) suggested a 2.6-fold increase in the AUC of ziritaxestat, while multiple doses of a strong inhibitor (voriconazole) would increase the AUC by 15-fold. Efavirenz would yield a three-fold decrease in the AUC of ziritaxestat. As a perpetrator, ziritaxestat was predicted to increase the AUC of the CYP3A4 index substrate midazolam by 2.7-fold. An overarching PBPK model was developed that could predict DDI liability of ziritaxestat for both CYP3A4 and the transporter pathways.

Ziritaxestat, a Novel Autotaxin Inhibitor, and Lung Function in Idiopathic Pulmonary Fibrosis: The ISABELA 1 and 2 Randomized Clinical Trials.

Importance: There is a major need for effective, well-tolerated treatments for idiopathic pulmonary fibrosis (IPF). Objective: To assess the efficacy and safety of the autotaxin inhibitor ziritaxestat in patients with IPF. Design, Setting, and Participants: The 2 identically designed, phase 3, randomized clinical trials, ISABELA 1 and ISABELA 2, were conducted in Africa, Asia-Pacific region, Europe, Latin America, the Middle East, and North America (26 countries). A total of 1306 patients with IPF were randomized (525 patients at 106 sites in ISABELA 1 and 781 patients at 121 sites in ISABELA 2). Enrollment began in November 2018 in both trials and follow-up was completed early due to study termination on April 12, 2021, for ISABELA 1 and on March 30, 2021, for ISABELA 2. Interventions: Patients were randomized 1:1:1 to receive 600 mg of oral ziritaxestat, 200 mg of ziritaxestat, or placebo once daily in addition to local standard of care (pirfenidone, nintedanib, or neither) for at least 52 weeks. Main Outcomes and Measures: The primary outcome was the annual rate of decline for forced vital capacity (FVC) at week 52. The key secondary outcomes were disease progression, time to first respiratory-related hospitalization, and change from baseline in St George's Respiratory Questionnaire total score (range, 0 to 100; higher scores indicate poorer health-related quality of life). Results: At the time of study termination, 525 patients were randomized in ISABELA 1 and 781 patients in ISABELA 2 (mean age: 70.0 [SD, 7.2] years in ISABELA 1 and 69.8 [SD, 7.1] years in ISABELA 2; male: 82.4% and 81.2%, respectively). The trials were terminated early after an independent data and safety monitoring committee concluded that the benefit to risk profile of ziritaxestat no longer supported their continuation. Ziritaxestat did not improve the annual rate of FVC decline vs placebo in either study. In ISABELA 1, the least-squares mean annual rate of FVC decline was -124.6 mL (95% CI, -178.0 to -71.2 mL) with 600 mg of ziritaxestat vs -147.3 mL (95% CI, -199.8 to -94.7 mL) with placebo (between-group difference, 22.7 mL [95% CI, -52.3 to 97.6 mL]), and -173.9 mL (95% CI, -225.7 to -122.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, -26.7 mL [95% CI, -100.5 to 47.1 mL]). In ISABELA 2, the least-squares mean annual rate of FVC decline was -173.8 mL (95% CI, -209.2 to -138.4 mL) with 600 mg of ziritaxestat vs -176.6 mL (95% CI, -211.4 to -141.8 mL) with placebo (between-group difference, 2.8 mL [95% CI, -46.9 to 52.4 mL]) and -174.9 mL (95% CI, -209.5 to -140.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, 1.7 mL [95% CI, -47.4 to 50.8 mL]). There was no benefit with ziritaxestat vs placebo for the key secondary outcomes. In ISABELA 1, all-cause mortality was 8.0% with 600 mg of ziritaxestat, 4.6% with 200 mg of ziritaxestat, and 6.3% with placebo; in ISABELA 2, it was 9.3% with 600 mg of ziritaxestat, 8.5% with 200 mg of ziritaxestat, and 4.7% with placebo. Conclusions and Relevance: Ziritaxestat did not improve clinical outcomes compared with placebo in patients with IPF receiving standard of care treatment with pirfenidone or nintedanib or in those not receiving standard of care treatment. Trial Registration: ClinicalTrials.gov Identifiers: NCT03711162 and NCT03733444.

Frequency, Risk Factors, Causes, and Consequences of Diagnostic Errors in Critically Ill Medical Patients: A Retrospective Cohort Study.

OBJECTIVE: Diagnostic errors are a source of significant morbidity and mortality but understudied in the critically ill. We sought to characterize the frequency, causes, consequences, and risk factors of diagnostic errors among unplanned ICU admissions. DESIGN: We conducted a retrospective cohort study of randomly selected nonsurgical ICU admissions between July 2015 and June 2016. SETTING: Medical ICU at a tertiary academic medical center. SUBJECTS: Critically ill adults with unplanned admission to the medical ICU. MEASUREMENTS AND MAIN RESULTS: The primary investigator reviewed patient records using a modified version of the Safer Dx instrument, a validated instrument for detecting diagnostic error. Two intensivists performed secondary reviews of possible errors, and reviewers met periodically to adjudicate errors by consensus. For each confirmed error, we judged harm on a 1-6 rating scale. We also collected detailed demographic and clinical data for each patient. We analyzed 256 unplanned ICU admissions and identified 18 diagnostic errors (7% of admissions). All errors were associated with harm, and only six errors (33%) were recognized by the ICU team within the first 24 hours. More women than men experienced a diagnostic error (11.7% vs 2.7%; p = 0.015, χ test). On multivariable logistic regression analysis, female sex remained independently associated with risk of diagnostic error both at admission (odds ratio, 5.18; 95% CI, 1.34-20.08) and at 24 hours (odds ratio, 11.6; 95% CI, 1.37-98.6). Similarly, Quick Sequential Organ Failure Assessment score greater than or equal to 2 at admission was independently associated with diagnostic error (odds ratio, 5.73; 95% CI, 1.72-19.01). CONCLUSIONS: Diagnostic errors may be an underappreciated source of ICU-related harm. Women and higher acuity patients appear to be at increased risk for such errors. Further research is merited to define the scope of error-associated harm and to clarify risk factors for diagnostic errors among the critically ill.

Population Pharmacokinetic and Pharmacodynamic Analysis of GLPG1690, an Autotaxin Inhibitor, in Healthy Volunteers and Patients with Idiopathic Pulmonary Fibrosis.

BACKGROUND AND OBJECTIVES: GLPG1690 is an autotaxin inhibitor in development for the treatment of idiopathic pulmonary fibrosis. Several publications suggested a role of autotaxin in the control of disease-affected lung function and of lysophosphatidic acid in lung remodeling processes. The aim of the current article was to describe the exposure-response relationship of GLPG1690 and further develop a rational basis to support dose selection for clinical trials in patients with idiopathic pulmonary fibrosis. METHODS: Two trials were conducted in healthy volunteers: in the first trial, GLPG1690 was administered as single doses from 20 mg up to 1500 mg, and subsequently in multiple daily doses of 300-1000 mg. In a second trial, the interaction of rifampin with 600 mg of GLPG1690 was evaluated. A third trial was conducted in patients with idiopathic pulmonary fibrosis administered 600 mg of GLPG1690 once daily for 12 weeks. The exposure-response (lysophosphatidic acid C18:2 reduction) relationship of GLPG1690 was first described using non-linear mixed-effects modeling and the model was subsequently deployed to simulate a lysophosphatidic acid C18:2 reduction as a biomarker of autotaxin inhibition in the dose range from 50 to 1000 mg once or twice daily. RESULTS: The population pharmacokinetics and lysophosphatidic acid C18:2 response of GLPG1690 were adequately described by a combined population pharmacokinetic and pharmacokinetic/pharmacodynamic model. Dose, formulation, rifampin co-administration, health status (healthy volunteer vs. patient with idiopathic pulmonary fibrosis), and baseline lysophosphatidic acid C18:2 were identified as covariates in the model. The effect of dose on systemic clearance indicated that GLPG1690 followed a more than dose-proportional increase in exposure over the simulated dose range of 50-1000 mg once daily. Model-based simulations showed reductions in lysophosphatidic acid C18:2 of at least 80% with doses greater or equal to 200 mg once daily. CONCLUSION: Based on these results, 200 and 600 mg once-daily doses were selected for future clinical trials in patients with idiopathic pulmonary fibrosis.

Computed Tomography Bronchus Sign and the Diagnostic Yield of Guided Bronchoscopy for Peripheral Pulmonary Lesions. A Systematic Review and Meta-Analysis.

RATIONALE: Indeterminate peripheral pulmonary lesions (PPLs) often require tissue diagnosis. If nonsurgical biopsy techniques are considered, deciding between bronchoscopic transbronchial versus computed tomography-guided transthoracic biopsy can be difficult. The former has a low diagnostic yield with a low complication risk, whereas the latter has a better diagnostic yield but a higher complication rate. Investigators have looked at various lesion characteristics that can predict the diagnostic yield of guided bronchoscopic biopsies. Although consensus exists that larger size and proximity to the hilum increase the diagnostic yield, there is ongoing debate about the association between computed tomography bronchus sign (air-filled bronchus in close proximity of the lesion as seen on computed tomography imaging) and the diagnostic yield of guided bronchoscopic modalities. OBJECTIVES: To perform a meta-analysis and systematic review, determining the association between computed tomography bronchus sign and the diagnostic yield of guided bronchoscopy for PPLs. METHODS: MEDLINE, Embase, Scopus, and Google Scholar were searched in January 2018 for guided bronchoscopy studies that had assessed the impact of computed tomography bronchus sign on the diagnostic yield. The quality of included studies was assessed using Quality Assessment of Diagnostic Accuracy Studies-2 tool. Meta-analysis was performed using MedCalc (version 18). Odds ratios were used to compare yield of lesions with and without bronchus sign. Random effects model was used when significant heterogeneity was observed (I2 > 40%). RESULTS: For 2,199 lesions with computed tomography bronchus sign, the overall weighted diagnostic yield was 74.1% (95% confidence interval, 68.3-79.5%). For 971 lesions without computed tomography bronchus sign, the overall weighted diagnostic yield was 49.6% (95% confidence interval, 39.6-59.5%). The odds ratio for successfully diagnosing a lesion with computed tomography bronchus sign was 3.4 (95% confidence interval, 2.4-5.0). Possible sources of heterogeneity in the meta-analysis included differences in study designs, guidance modalities, and cancer prevalence. The odds ratio for successfully diagnosing a lesion with computed tomography bronchus sign was relatively lower for prospective studies. CONCLUSIONS: PPLs with computed tomography bronchus sign are more likely to be diagnosed with guided bronchoscopy than the lesions without computed tomography bronchus sign. Clinicians should consider this, along with the lesion size and distance from the hilum, when contemplating guided bronchoscopy for PPLs.

Modeling of prolactin response following dopamine D2 receptor antagonists in rats: can it be translated to clinical dosing?

Prolactin release is a side effect of antipsychotic therapy with dopamine antagonists, observed in rats as well as humans. We examined whether two semimechanistic models could describe prolactin response in rats and subsequently be translated to predict pituitary dopamine D2 receptor occupancy and plasma prolactin concentrations in humans following administration of paliperidone or remoxipride. Data on male Wistar rats receiving single or multiple doses of risperidone, paliperidone, or remoxipride was described by two semimechanistic models, the precursor pool model and the agonist-antagonist interaction model. Using interspecies scaling approaches, human D2 receptor occupancy and plasma prolactin concentrations were predicted for a range of clinical paliperidone and remoxipride doses. The predictions were compared with corresponding observations described in literature as well as with predictions from published models developed on human data. The pool model could predict D2 receptor occupancy and prolactin response in humans following single doses of paliperidone and remoxipride. Tolerance of prolactin release was predicted following multiple doses. The interaction model underpredicted both D2 receptor occupancy and prolactin response. Prolactin elevation may be deployed as a suitable biomarker for interspecies translation and can inform the clinical safe and effective dose range of antipsychotic drugs. While the pool model was more predictive than the interaction model, it overpredicted tolerance on multiple dosing. Shortcomings of the translations reflect the need for better mechanistic models.

Controlled trial to improve resident sign-out in a medical intensive care unit.

OBJECTIVE: Poor sign-out or handover of care may lead to preventable patient harm. Critically ill patients in intensive care units (ICU) are complex and prone to rapid clinical deterioration. If clinical deterioration occurs, timeliness of appropriate interventions is essential to prevent or reduce adverse outcomes. Therefore sign-outs need to efficiently transmit key information and provide anticipatory guidance. Interventions to improve resident-to-resident ICU sign-outs have not been well described. We conducted a controlled trial to test the effectiveness of a standardised ICU sign-out process to the usual ICU sign-out. DESIGN: Prospective controlled trial. SETTING: A 26-bed medical intensive care unit (MICU) in an urban tertiary academic medical centre. SUBJECTS: Residents rotating through the MICU. INTERVENTIONS: ICU-specific written sign-out template. METHODS: Residents completed postcall surveys assessing satisfaction with verbal and written sign-outs and incidence of non-routine events. Our main outcome of interest was the occurrence of non-routine events. MAIN RESULTS: Compared with the intervention group, on significantly more nights, night float residents in the control group encountered patients who were sicker than sign-out would have suggested (15.94% vs 43.75%; p<0.0001). On significantly fewer nights, night float residents in the intervention group indicated that either something happened to patients that was unexpected (18.84% vs 36.51%; p=0.023) or they were insufficiently prepared for (4.35% vs 35.94%; p<0.0001). Similarly, on fewer nights, residents in the intervention group indicated that they had to perform interventions that were unplanned or unanticipated (15.9% vs 37.7%; p=0.005). CONCLUSION: A structured sign-out process compared with usual sign-out significantly reduced the occurrence of non-routine events in an academic MICU.

Summary data of potency and parameter information from semi-mechanistic PKPD modeling of prolactin release following administration of the dopamine D2 receptor antagonists risperidone, paliperidone and remoxipride in rats.

We provide the reader with relevant data related to our recently published paper, comparing two mathematical models to describe prolactin turnover in rats following one or two doses of the dopamine D2 receptor antagonists risperidone, paliperidone and remoxipride, "A comparison of two semi-mechanistic models for prolactin release and prediction of receptor occupancy following administration of dopamine D2 receptor antagonists in rats" (Taneja et al., 2016) [1]. All information is tabulated. Summary level data on the in vitro potencies and the physicochemical properties is presented in Table 1. Model parameters required to explore the precursor pool model are presented in Table 2. In Table 3, estimated parameter comparisons for both models are presented, when separate potencies are estimated for risperidone and paliperidone, as compared to a common potency for both drugs. In Table 4, parameter estimates are compared when the drug effect is parameterized in terms of drug concentration or receptor occupancy.

A comparison of two semi-mechanistic models for prolactin release and prediction of receptor occupancy following administration of dopamine D2 receptor antagonists in rats.

We compared the model performance of two semi-mechanistic pharmacokinetic-pharmacodynamic models, the precursor pool model and the agonist-antagonist interaction model, to describe prolactin response following the administration of the dopamine D2 receptor antagonists risperidone, paliperidone or remoxipride in rats. The time course of pituitary dopamine D2 receptor occupancy was also predicted. Male Wistar rats received a single dose (risperidone, paliperidone, remoxipride) or two consecutive doses (remoxipride). Population modeling was applied to fit the pool and interaction models to the prolactin data. The pool model was modified to predict the time course of pituitary D2 receptor occupancy. Unbound plasma concentrations of the D2 receptor antagonists were considered the drivers of the prolactin response. Both models were used to predict prolactin release following multiple doses of paliperidone. Both models described the data well and model performance was comparable. Estimated unbound EC50 for risperidone and paliperidone was 35.1nM (relative standard error 51%) and for remoxipride it was 94.8nM (31%). KI values for these compounds were 11.1nM (21%) and 113nM (27%), respectively. Estimated pituitary D2 receptor occupancies for risperidone and remoxipride were comparable to literature findings. The interaction model better predicted prolactin profiles following multiple paliperidone doses, while the pool model predicted tolerance better. The performance of both models in describing the prolactin profiles was comparable. The pool model could additionally describe the time course of pituitary D2 receptor occupancy. Prolactin response following multiple paliperidone doses was better predicted by the interaction model.

Mesenteric Ischemia.

Acute mesenteric ischemia (AMI) is a rare disease that most commonly affects the elderly. The vague symptoms often lead to delayed diagnosis and consequent high mortality. Physical exam and laboratory findings lack the sensitivity and specificity to exclude AMI, but computed tomography angiography can rapidly and accurately confirm the diagnosis. Survival improves with prompt restoration of perfusion and resection of nonviable bowel. Advances in imaging, operative techniques, and critical care have led to a steady decline in overall mortality; however, long-term survival is limited because of the comorbidities in this patient group.

Abdominal Circulatory Interactions.

The abdominal compartment is separated from the thoracic compartment by the diaphragm. Under normal circumstances, a large portion of the venous return crosses the splanchnic and nonsplanchnic abdominal regions before entering the thorax and the right side of the heart. Mechanical ventilation may affect abdominal venous return independent of its interactions at the thoracic level. Changes in pressure in the intra-abdominal compartment may have important implications for organ function within the thorax, particularly if there is a sustained rise in intra-abdominal pressure. It is important to understand the consequences of abdominal pressure changes on respiratory and circulatory physiology. This article elucidates important abdominal-respiratory-circulatory interactions and their clinical effects.

Biomarker exposure-response relationships as the basis for rational dose selection: Lessons from a simulation exercise using a selective COX-2 inhibitor.

An exposure-response model was used to characterize the pharmacokinetic-pharmacodynamic relationship of GW406381, a COX-2 inhibitor, based on data from ex vivo prostaglandin E2 inhibition collected in a phase 1 study in healthy subjects. The final model was then used to simulate a proof-of-concept study and to explore suitable dosing ranges in case of hepatic dysfunction or metabolic induction. Trough concentrations in the range of IC80 to IC95 were used as target therapeutic concentrations. Symptom relief in a subsequent phase 2b study in 400 patients with rheumatoid arthritis receiving GW406381 was then analysed to support the design of a phase 3 study in which doses in the range between 10 to 400 mg were explored. The exercise also allowed the evaluation of correlations between the biomarker and clinical end point. A 2-compartment model described the pharmacokinetics of GW406381, whereas the pharmacodynamics was described by an Imax model. In patients with normal organ function, the predicted median therapeutic dose was between 100 and 150 mg. The time course of symptom relief was fitted by a Weibull model, with an Imax model describing the drug effect. Simulations showed that dose-response discrimination occurred at doses higher than 150 mg, with predicted 60%-80% target engagement in the dose range of 150-400 mg.

Acute Kidney Injury Requiring Dialysis in Severe Sepsis.

RATIONALE: Understanding the changing incidence and impact of acute kidney injury requiring dialysis in patients with severe sepsis will allow better risk stratification, design of clinical trials, and guide resource allocation. OBJECTIVES: To assess the longitudinal incidence of acute kidney injury requiring dialysis and its impact on mortality in patients with severe sepsis. METHODS: Retrospective cohort study of adults (≥20 yr) hospitalized with severe sepsis from 2000 to 2009 in the United States using a nationally representative database. MEASUREMENTS AND MAIN RESULTS: We calculated the incidences of acute kidney injury requiring dialysis and mortality over time. We used linear regression to assess temporal trends. We used logistic regression to estimate the odds of acute kidney injury requiring dialysis and mortality. Of the estimated 5,257,907 hospitalizations with severe sepsis, 6.1% had acute kidney injury requiring dialysis. The odds of acquiring acute kidney injury requiring dialysis increased by 14% in 2009 compared with 2000. Mortality in patients with acute kidney injury requiring dialysis was higher (43.6% vs. 24.9%; P < 0.001). After multivariable adjustment, odds of mortality declined 61% by the year 2009. Acute kidney injury requiring dialysis remained an independent predictor of mortality in patients with severe sepsis, although its influence on mortality declined with time. CONCLUSIONS: Incidence of acute kidney injury requiring dialysis in patients with severe sepsis has increased over time; conversely, associated mortality has declined. The likelihood of demise from acute kidney injury requiring dialysis in patients with severe sepsis has also declined.

Severe sepsis in hematopoietic stem cell transplant recipients*.

OBJECTIVE: Severe sepsis requires timely management and has high mortality if care is delayed. Hematopoietic stem cell transplant recipients are more likely to be immunocompromised and are predisposed to serious infections. Reports of outcomes of severe sepsis in this population are limited to data from single, tertiary care centers, and national outcomes data are missing. DESIGN: Retrospective analysis of an administrative database. SETTING: Twenty percent of community hospitals in United States, excluding federal hospitals. SUBJECT: Patients with severe sepsis. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: We used International Classification of Diseases, 9th Edition, Clinical Modification codes indicating the presence of sepsis and organ system failure to identify hospitalizations for severe sepsis between 2000 and 2008. We also used International Classification of Diseases, 9th Edition, Clinical Modification codes to identify hematopoietic stem cell transplant recipients. We compared outcomes of hematopoietic stem cell transplant recipients with severe sepsis during engraftment and subsequent admissions with a non-hematopoietic stem cell transplant cohort and excluded solid-organ transplantation from this cohort. We used mixed effect, multivariate logistic regression modeling with propensity score adjustment to examine factors associated with mortality of severe sepsis in hematopoietic stem cell transplant recipients. A total of 21,898 hematopoietic stem cell transplant recipients with severe sepsis were identified. The frequency of severe sepsis in hematopoietic stem cell transplant recipients was five times higher when compared with the non-hematopoietic stem cell transplant cohort. The unadjusted mortality was 32.9% in non-hematopoietic stem cell transplant cohort, which was similar to autologous hematopoietic stem cell transplant recipients (30.1%) and those who did not develop graft-versus-host disease (35%). Mortality was significantly higher in allogeneic transplants (55.1%, p < 0.001) and in those who developed graft-versus-host disease (47.9%, p < 0.001). After adjustment, during engraftment admission, the odds of in-hospital mortality in allogeneic hematopoietic stem cell transplant (odds ratio, 3.81; 95% CI, 2.39-6.07) and autologous hematopoietic stem cell transplant (odds ratio, 1.28; 95% CI, 1.06-1.53) recipients was significantly higher than non-hematopoietic stem cell transplant patients. Similarly, in subsequent admissions, hematopoietic stem cell transplant recipients with graft-versus-host disease (odds ratio, 2.14; 95% CI, 1.88-2.45) and without graft-versus-host disease (odds ratio, 1.35; 95% CI, 1.19-1.54) had significantly higher odds of mortality than non-hematopoietic stem cell transplant patients. Among patients with hematopoietic stem cell transplant, persons with autologous hematopoietic stem cell transplant and those without graft-versus-host disease fared better as compared with their allogeneic and graft-versus-host disease counterparts. CONCLUSIONS: Hematopoietic stem cell transplant recipients are more likely to develop severe sepsis and die following a severe sepsis episode than nontransplant patients. Autologous hematopoietic stem cell transplant recipients and those who do not develop graft-versus-host disease have significantly better outcomes than allogeneic and graft-versus-host disease patients.