Association between Net Ultrafiltration Rate and Renal Recovery among Critically Ill Adults with Acute Kidney Injury Receiving Continuous Renal Replacement Therapy: An Observational Cohort Study.

INTRODUCTION: Higher net ultrafiltration (UFNET) rates are associated with mortality among critically ill patients with acute kidney injury (AKI) and treated with continuous renal replacement therapy (CRRT). OBJECTIVE: The aim of the study was to discover whether UFNET rates are associated with renal recovery and independence from renal replacement therapy (RRT). METHODS: Retrospective cohort study using data from the Randomized Evaluation of Normal versus Augmented Level of Renal Replacement Therapy trial that enrolled 1,433 critically ill patients with AKI and treated with CRRT between December 2005 and November 2008 across 35 intensive care units in Australia and New Zealand. We examined the association between UFNET rate and time to independence from RRT by day 90 using competing risk regression after accounting for mortality. The UFNET rate was defined as the volume of fluid removed per hour adjusted for patient body weight. RESULTS AND CONCLUSIONS: Median age was 67.3 (interquartile range [IQR], 57-76.3) years, 64.4% were male, median Acute Physiology and Chronic Health Evaluation-III score was 100 (IQR, 84-118), and 634 (44.2%) died by day 90. Kidney recovery occurred in 755 patients (52.7%). Using tertiles of UFNET rates, 3 groups were defined: high, >1.75; middle, 1.01-1.75; and low, <1.01 mL/kg/h. Proportion of patients alive and independent of RRT among the groups were 47.8 versus 57.2 versus 53.0%; p = 0.01. Using competing risk regression, higher UFNET rate tertile compared with middle (cause-specific hazard ratio [csHR], 0.79, 95% CI, 0.66-0.95; subdistribution hazard ratio [sHR], 0.80, 95% CI, 0.67-0.97) and lower (csHR, 0.69, 95% CI, 0.56-0.85; sHR, 0.78, 95% CI 0.64-0.95) tertiles were associated with a longer time to independence from RRT. Every 1.0 mL/kg/h increase in rate was associated with a lower probability of kidney recovery (csHR, 0.81, 95% CI, 0.74-0.89; and sHR, 0.87, 95% CI, 0.80-0.95). Using the joint model, longitudinal increases in UFNET rates were also associated with a lower renal recovery (ß = -0.29, p < 0.001). UFNET rates >1.75 mL/kg/h compared with rates 1.01-1.75 and <1.01 mL/kg/h were associated with a longer duration of dependence on RRT. Randomized clinical trials are required to confirm this UFNET rate-outcome relationship.

Murine sepsis phenotypes and differential treatment effects in a randomized trial of prompt antibiotics and fluids.

BACKGROUND: Clinical and biologic phenotypes of sepsis are proposed in human studies, yet it is unknown whether prognostic or drug response phenotypes are present in animal models of sepsis. Using a biotelemetry-enhanced, murine cecal ligation and puncture (CLP) model, we determined phenotypes of polymicrobial sepsis prior to physiologic deterioration, and the association between phenotypes and outcome in a randomized trial of prompt or delayed antibiotics and fluids. METHODS: We performed a secondary analysis of male C57BL/6J mice in two observational cohorts and two randomized, laboratory animal experimental trials. In cohort 1, mice (n = 118) underwent biotelemetry-enhanced CLP, and we applied latent class mixed models to determine optimal number of phenotypes using clinical data collected between injury and physiologic deterioration. In cohort 2 (N = 73 mice), inflammatory cytokines measured at 24 h after deterioration were explored by phenotype. In a subset of 46 mice enrolled in two trials from cohort 1, we tested the association of phenotypes with the response to immediate (0 h) vs. delayed (2 to 4 h) antibiotics or fluids initiated after physiologic deterioration. RESULTS: Latent class mixture modeling derived a two-class model in cohort 1. Class 2 (N = 97) demonstrated a shorter time to deterioration (mean SD 7.3 (0.9) vs. 9.7 (3.2) h, p < 0.001) and lower heart rate at 7 h after injury (mean (SD) 564 (55) vs. 626 (35) beats per minute, p < 0.001). Overall mortality was similar between phenotypes (p = 0.75). In cohort 2 used for biomarker measurement, class 2 mice had greater plasma concentrations of IL6 and IL10 at 24 h after CLP (p = 0.05). In pilot randomized trials, the effects of sepsis treatment (immediate vs. delayed antibiotics) differed by phenotype (p = 0.03), with immediate treatment associated with greater survival in class 2 mice only. Similar differential treatment effect by class was observed in the trial of immediate vs. delayed fluids (p = 0.02). CONCLUSIONS: We identified two sepsis phenotypes in a murine cecal ligation and puncture model, one of which is characterized by faster deterioration and more severe inflammation. Response to treatment in a randomized trial of immediate versus delayed antibiotics and fluids differed on the basis of phenotype.

Net ultrafiltration intensity and mortality in critically ill patients with fluid overload.

BACKGROUND: Although net ultrafiltration (UFNET) is frequently used for treatment of fluid overload in critically ill patients with acute kidney injury, the optimal intensity of UFNET is unclear. Among critically ill patients with fluid overload receiving renal replacement therapy (RRT), we examined the association between UFNET intensity and risk-adjusted 1-year mortality. METHODS: We selected patients with fluid overload ≥ 5% of body weight prior to initiation of RRT from a large academic medical center ICU dataset. UFNET intensity was calculated as the net volume of fluid ultrafiltered per day from initiation of either continuous or intermittent RRT until the end of ICU stay adjusted for patient hospital admission body weight. We stratified UFNET as low (≤ 20 ml/kg/day), moderate (> 20 to ≤ 25 ml/kg/day) or high (> 25 ml/kg/day) intensity. We adjusted for age, sex, body mass index, race, surgery, baseline estimated glomerular filtration rate, oliguria, first RRT modality, pre-RRT fluid balance, duration of RRT, time to RRT initiation from ICU admission, APACHE III score, mechanical ventilation use, suspected sepsis, mean arterial pressure on day 1 of RRT, cumulative fluid balance during RRT and cumulative vasopressor dose during RRT. We fitted logistic regression for 1-year mortality, Gray's survival model and propensity matching to account for indication bias. RESULTS: Of 1075 patients, the distribution of high, moderate and low-intensity UFNET groups was 40.4%, 15.2% and 44.2% and 1-year mortality was 59.4% vs 60.2% vs 69.7%, respectively (p = 0.003). Using logistic regression, high-intensity compared with low-intensity UFNET was associated with lower mortality (adjusted odds ratio 0.61, 95% CI 0.41-0.93, p = 0.02). Using Gray's model, high UFNET was associated with decreased mortality up to 39 days after ICU admission (adjusted hazard ratio range 0.50-0.73). After combining low and moderate-intensity UFNET groups (n = 258) and propensity matching with the high-intensity group (n = 258), UFNET intensity > 25 ml/kg/day compared with ≤ 25 ml/kg/day was associated with lower mortality (57% vs 67.8%, p = 0.01). Findings were robust to several sensitivity analyses. CONCLUSIONS: Among critically ill patients with ≥ 5% fluid overload and receiving RRT, UFNET intensity > 25 ml/kg/day compared with ≤ 20 ml/kg/day was associated with lower 1-year risk-adjusted mortality. Whether tolerating intensive UFNET is just a marker for recovery or a mediator requires further research.

Outcomes of Biologic Use in Asian Compared with Non-Hispanic White Adult Psoriasis Patients from the CorEvitas Psoriasis Registry.

INTRODUCTION: Real-world data are limited comparing Asian and White patients with psoriasis using biologic therapy. This study compared the 6-month effectiveness of biologic therapy between Asian and White plaque patients with psoriasis in the CorEvitas Psoriasis Registry. METHODS: Analyses included biologic initiations and 6-month follow-up visits from self-identified Asian (n = 293) and White (n = 2314) patients in the USA/Canada (4/2015-4/2020). Outcomes included: Psoriasis Area Severity Index (PASI) 75, disease activity measures [body surface area (BSA) ≤ 1, BSA ≤ 3, PASI90, PASI100, Investigator's Global Assessment (IGA) 0/1], and patient-reported outcomes [Dermatology Life Quality Index (DLQI) 0/1, itch, fatigue, skin pain, EuroQoL visual analog scale (EQ-VAS), patient global assessment, Work Productivity Activity and Impairment (WPAI) domains]. Unadjusted regression models were used to calculate odds ratios (OR) and 95% confidence intervals (CI) for achievement of binary outcomes and difference in mean change in continuous outcomes (ß, 95% CI) at 6 months, followed by adjustment for age, sex, body mass index, alcohol, smoking, health insurance, education, comorbidities, scalp psoriasis morphology, psoriatic arthritis, biologic class, previous biologics, and baseline outcome value. RESULTS: Asians had lower proportions of women (32.8% versus 49.1%) and obesity (27.3% versus 54.5%), and higher proportions on Medicaid (19.9% versus 8.8%), graduated college (50.9% versus 40.1%) and never smoked (67.1% versus 44.1%). In unadjusted analyses, Asians had 52% higher odds of achieving PASI75 versus White patients (OR 1.52; 95% CI 1.15, 2.02). After adjustment, the association was attenuated (OR 1.11; 0.81, 1.52). Secondary outcomes experienced similar patterns except for DLQI: Asians had 33% lower odds of achieving DLQI 0/1 in both the unadjusted (OR 0.67; 0.50, 0.90) and adjusted (OR 0.67; 0.49, 0.92) models. CONCLUSION: Unadjusted differences in biologic therapy effectiveness between Asians compared with White patients were likely explained by differences in demographic, lifestyle, and psoriatic disease characteristics between groups. However, Asians still experienced lesser improvements in skin-related quality of life, even after adjustment.

Association of Practitioner Interfacility Triage Performance With Outcomes for Severely Injured Patients With Fee-for-Service Medicare Insurance.

Importance: Despite evidence that treatment of severely injured patients at trauma centers is associated with reduced mortality, nearly half of all such patients are treated at nontrauma centers (undertriaged). Little is known about whether interfacility undertriage occurs because of practitioner decision-making or institutional and regional factors. Objectives: To assess the associations between variation in triage practitioners at nontrauma centers and between practitioner-level variation and patient outcomes after injury. Design, Setting, and Participants: This retrospective cohort study used Medicare claims data from severely injured patients presenting to nontrauma centers and the practitioners who evaluated them in the emergency department from January 1, 2010, to October 15, 2015. Data analysis was performed from January 15, 2018, to March 21, 2019. Main Outcomes and Measures: Proportion of variation in undertriage associated with practitioners, practitioner rates of undertriage, practitioner characteristics associated with undertriage, and 30-day case-fatality rate. Results: A total of 124 008 severely injured patients (mean [SD] age, 81 [8.4] years; 67 253 [54.2%] female) and the 25 376 practitioners (5564 [21.9%] female) who evaluated the patients in the emergency department of nontrauma centers were included in the study. Undertriage occurred among 85 403 patients (68.9%), with 40.6% of total variation associated with practitioners, 37.8% with hospitals, and 6.7% with regions. Compared with physicians with National Provider Identification (NPI) enumeration before 2007, those with an NPI enumerated between 2007 and 2010 had an undertriage risk ratio (RR) of 0.98 (95% CI, 0.97-0.99), and those with an NPI enumerated after 2010 had an undertriage RR of 0.96 (95% CI, 0.94-0.99). Hospitals with neurosurgeons had an undertriage RR of 1.51 (95% CI, 1.45-1.57) compared with those that did not; hospitals with spine surgeons had an undertriage RR of 1.10 (95% CI, 1.06-1.13); hospitals with general surgeons had an undertriage RR of 1.13 (95% CI, 1.09-1.17). Compared with practitioners who undertriaged 25% or less of patients, a statistically significant increase was found in the odds of death for patients treated by practitioners with a triage rate of less than 25% to 50% (odds ratio [OR], 1.08; 95% CI, 1.05-1.20) and less than 50% to 75% undertriage (OR, 1.12; 95% CI, 1.09-1.26) but not undertriage at greater than 75% (OR, 1.03, 95% CI, 1.00-1.18). In sensitivity analyses to adjust for unmeasured confounding, the association between triage practices and the case fatality rate became monotonic; compared with patients treated by practitioners with an undertriage rate of 25% or less, the odds of case fatality were 1.13 (95% CI, 1.05-1.21; P = .001) among patients treated by practitioners with undertriage rates less than 25% to 50%, 1.22 (95% CI, 1.13-1.32; P < .001) for patients treated by practitioners with undertriage rates less than 50% to 75%, and 1.20 (95% CI, 1.10-1.30; P < .001) for patients treated by practitioners with undertriage rates greater than 75%. Conclusions and Relevance: The findings suggest that individual practitioner practices are an important source of variation in triage and represent a potential locus of intervention to reduce preventable deaths after injury.

Association of Net Ultrafiltration Rate With Mortality Among Critically Ill Adults With Acute Kidney Injury Receiving Continuous Venovenous Hemodiafiltration: A Secondary Analysis of the Randomized Evaluation of Normal vs Augmented Level (RENAL) of Renal Replacement Therapy Trial.

Importance: Net ultrafiltration (NUF) is frequently used to treat fluid overload among critically ill patients, but whether the rate of NUF affects outcomes is unclear. Objective: To examine the association of NUF with survival among critically ill patients with acute kidney injury being treated with continuous venovenous hemodiafiltration. Design, Setting, and Participants: The Randomized Evaluation of Normal vs Augmented Level (RENAL) of Renal Replacement Therapy trial was conducted between December 30, 2005, and November 28, 2008, at 35 intensive care units in Australia and New Zealand among critically ill adults with acute kidney injury who were being treated with continuous venovenous hemodiafiltration. This secondary analysis began in May 2018 and concluded in January 2019. Exposures: Net ultrafiltration rate, defined as the volume of fluid removed per hour adjusted for patient body weight. Main Outcomes and Measures: Risk-adjusted 90-day survival. Results: Of 1434 patients, the median (interquartile range) age was 67.3 (56.9-76.3) years; 924 participants (64.4%) were male; median (interquartile range) Acute Physiology and Chronic Health Evaluation III score was 100 (84-118); and 634 patients (44.2%) died. Using tertiles, 3 groups were defined: high, NUF rate greater than 1.75 mL/kg/h; middle, NUF rate from 1.01 to 1.75 mL/kg/h; and low, NUF rate less than 1.01 mL/kg/h. The high-tertile group compared with the low-tertile group was not associated with death from day 0 to 6. However, death occurred in 51 patients (14.7%) in the high-tertile group vs 30 patients (8.6%) in the low-tertile group from day 7 to 12 (adjusted hazard ratio [aHR], 1.51; 95% CI, 1.13-2.02); 45 patients (15.3%) in the high-tertile group vs 25 patients (7.9%) in the low-tertile group from day 13 to 26 (aHR, 1.52; 95% CI, 1.11-2.07); and 48 patients (19.2%) in the high-tertile group vs 29 patients (9.9%) in the low-tertile group from day 27 to 90 (aHR, 1.66; 95% CI, 1.16-2.39). Every 0.5-mL/kg/h increase in NUF rate was associated with increased mortality (3-6 days: aHR, 1.05; 95% CI, 1.00-1.11; 7-12 days: aHR, 1.08; 95% CI, 1.02-1.15; 13-26 days: aHR, 1.11; 95% CI, 1.04-1.18; 27-90 days: aHR, 1.13; 95% CI, 1.05-1.22). Using longitudinal analyses, increase in NUF rate was associated with lower survival (ß = .056; P < .001). Hypophosphatemia was more frequent among patients in the high-tertile group compared with patients in the middle-tertile group and patients in the low-tertile group (high: 308 of 477 patients at risk [64.6%]; middle: 293 of 472 patients at risk [62.1%]; low: 247 of 466 patients at risk [53.0%]; P < .001). Cardiac arrhythmias requiring treatment occurred among all groups: high, 176 patients (36.8%); middle: 175 patients (36.5%); and low: 147 patients (30.8%) (P = .08). Conclusions and Relevance: Among critically ill patients, NUF rates greater than 1.75 mL/kg/h compared with NUF rates less than 1.01 mL/kg/h were associated with lower survival. Residual confounding may be present from unmeasured risk factors, and randomized clinical trials are required to confirm these findings. Trial Registration: ClinicalTrials.gov identifier: NCT00221013.