Persistent Acute Kidney Injury is Associated with Poor Outcomes and Increased Hospital Cost in Vascular Surgery.

BACKGROUND: Postoperative acute kidney injury (AKI) is common after major surgery and is associated with increased morbidity, mortality, and cost. Additionally, there are recent studies demonstrating that time to renal recovery may have a substantial impact on clinical outcomes. We hypothesized that patients with delayed renal recovery after major vascular surgery will have increased complications, mortality, and hospital cost. METHODS: A single-center retrospective cohort of patients undergoing nonemergent major vascular surgery between 6/1/2014 and 10/1/2020 was analyzed. Development of postoperative AKI (defined using Kidney Disease Improving Global Outcomes (KDIGO) criteria: >50% or > 0.3 mg/dl absolute increase in serum creatinine relative to reference after surgery and before discharge) was evaluated. Patients were divided into 3 groups: no AKI, rapidly reversed AKI (<48 hours), and persistent AKI (≥48 hours). Multivariable generalized linear models were used to evaluate the association between AKI groups and postoperative complications, 90-day mortality, and hospital cost. RESULTS: A total of 1,881 patients undergoing 1,980 vascular procedures were included. Thirty five percent of patients developed postoperative AKI. Patients with persistent AKI had longer intensive care unit and hospital stays, as well as more mechanical ventilation days. In multivariable logistic regression analysis, persistent AKI was a major predictor of 90-day mortality (odds ratio 4.1, 95% confidence interval 2.4-7.1). Adjusted average cost was higher for patients with any type of AKI. The incremental cost of having any AKI ranged from $3,700 to $9,100, even after adjustment for comorbidities and other postoperative complications. The adjusted average cost for patients stratified by type of AKI was higher among patients with persistent AKI compared to those with no or rapidly reversed AKI. CONCLUSIONS: Persistent AKI after vascular surgery is associated with increased complications, mortality, and cost. Strategies to prevent and aggressively treat AKI, specifically persistent AKI, in the perioperative setting are imperative to optimize care for this population.

Postoperative Overtriage to an Intensive Care Unit Is Associated With Low Value of Care.

OBJECTIVE: We test the hypothesis that for low-acuity surgical patients, postoperative intensive care unit (ICU) admission is associated with lower value of care compared with ward admission. BACKGROUND: Overtriaging low-acuity patients to ICU consumes valuable resources and may not confer better patient outcomes. Associations among postoperative overtriage, patient outcomes, costs, and value of care have not been previously reported. METHODS: In this longitudinal cohort study, postoperative ICU admissions were classified as overtriaged or appropriately triaged according to machine learning-based patient acuity assessments and requirements for immediate postoperative mechanical ventilation or vasopressor support. The nearest neighbors algorithm identified risk-matched control ward admissions. The primary outcome was value of care, calculated as inverse observed-to-expected mortality ratios divided by total costs. RESULTS: Acuity assessments had an area under the receiver operating characteristic curve of 0.92 in generating predictions for triage classifications. Of 8592 postoperative ICU admissions, 423 (4.9%) were overtriaged. These were matched with 2155 control ward admissions with similar comorbidities, incidence of emergent surgery, immediate postoperative vital signs, and do not resuscitate order placement and rescindment patterns. Compared with controls, overtraiged admissions did not have a lower incidence of any measured complications. Total costs for admission were $16.4K for overtriage and $15.9K for controls ( P =0.03). Value of care was lower for overtriaged admissions [2.9 (2.0-4.0)] compared with controls [24.2 (14.1-34.5), P <0.001]. CONCLUSIONS: Low-acuity postoperative patients who were overtriaged to ICUs had increased total costs, no improvements in outcomes, and received low-value care.

Clinical Trajectories of Acute Kidney Injury in Surgical Sepsis: A Prospective Observational Study.

OBJECTIVE: To characterize endothelial function, inflammation, and immunosuppression in surgical patients with distinct clinical trajectories of AKI and to determine the impact of persistent kidney injury and renal non-recovery on clinical outcomes, resource utilization, and long-term disability and survival. SUMMARY OF BACKGROUND DATA: AKI is associated with increased healthcare costs and mortality. Trajectories that account for duration and recovery of AKI have not been described for sepsis patients, who are uniquely vulnerable to renal dysfunction. METHODS: This prospective observational study included 239 sepsis patients admitted and enrolled between January 2015 and July 2017. Kidney Disease: Improving Global Outcomes (KDIGO) and Acute Disease Quality Initiative (ADQI) criteria were used to classify subjects as having no AKI, rapidly reversed AKI, persistent AKI with renal recovery, or persistent AKI without renal recovery. Serial biomarker profiles, clinical outcomes, resource utilization, and long-term physical performance status and survival were compared among AKI trajectories. RESULTS: Sixty-two percent of the study population developed AKI. Only one-third of AKI episodes rapidly reversed within 48 hours; the remaining had persistent AKI, among which 57% did not have renal recovery by discharge. One-year survival and proportion of subjects fully active 1 year after sepsis was lowest among patients with persistent AKI compared with other groups. Long-term mortality hazard rates were 5-fold higher for persistent AKI without renal recovery compared with no AKI. CONCLUSIONS: Among critically ill surgical sepsis patients, persistent AKI and the absence of renal recovery are associated with distinct early and sustained immunologic and endothelial biomarker signatures and decreased long-term physical function and survival.

Early Biomarker Signatures in Surgical Sepsis.

INTRODUCTION: Sepsis has complex, time-sensitive pathophysiology and important phenotypic subgroups. The objective of this study was to use machine learning analyses of blood and urine biomarker profiles to elucidate the pathophysiologic signatures of subgroups of surgical sepsis patients. METHODS: This prospective cohort study included 243 surgical sepsis patients admitted to a quaternary care center between January 2015 and June 2017. We applied hierarchical clustering to clinical variables and 42 blood and urine biomarkers to identify phenotypic subgroups in a development cohort. Clinical characteristics and short-term and long-term outcomes were compared between clusters. A naïve Bayes classifier predicted cluster labels in a validation cohort. RESULTS: The development cohort contained one cluster characterized by early organ dysfunction (cluster I, n = 18) and one cluster characterized by recovery (cluster II, n = 139). Cluster I was associated with higher Acute Physiologic Assessment and Chronic Health Evaluation II (30 versus 16, P < 0.001) and SOFA scores (13 versus 5, P < 0.001), greater prevalence of chronic cardiovascular and renal disease (P < 0.001) and septic shock (78% versus 17%, P < 0.001). Cluster I had higher mortality within 14 d of sepsis onset (11% versus 1.5%, P = 0.001) and within 1 y (44% versus 20%, P = 0.032), and higher incidence of chronic critical illness (61% versus 30%, P = 0.001). The Bayes classifier achieved 95% accuracy and identified two clusters that were similar to development cohort clusters. CONCLUSIONS: Machine learning analyses of clinical and biomarker variables identified an early organ dysfunction sepsis phenotype characterized by inflammation, renal dysfunction, endotheliopathy, and immunosuppression, as well as poor short-term and long-term clinical outcomes.

Lipid Profiles of Urinary Extracellular Vesicles Released during the Inactive and Active Phases of Aged Male Mice with Spontaneous Hypertension.

Hypertension remains a major problem, especially in the elderly, as it increases the risk for cardiovascular, coronary artery, cerebrovascular, and kidney diseases. Extracellular vesicles (EVs) play a role in the aging process and contribute to pathophysiology. Our goal was to examine differences in lipid profiles of urinary EVs (uEVs) collected during the inactive and active phases of aged mice and investigate whether these EVs regulate the density of lipid rafts in mouse cortical collecting duct (mpkCCD) principal cells. Here, we demonstrate the epithelial sodium channel (ENaC) inhibitor benzyl amiloride reduced systolic blood pressure in aged male mice during the inactive and active phases. Lipidomics data demonstrate differential enrichment of lipids between the two groups. For example, there are more phosphatidylethanolamine plasmalogens, particularly in the form of alkyl phosphatidylethanolamines, that are enriched in active phase uEVs compared to inactive phase uEVs from the same mice. Amiloride-sensitive transepithelial current increased more in mpkCCD cells challenged with uEVs from the active phase group. Moreover, more ENaC alpha protein was distributed to lipid raft fractions of mpkCCD cells challenged with active phase uEVs. Taken together, the identification of bioactive lipids associated with lipid rafts that are enriched in EVs released during the active phase of aged mice may offer clues to help understand lipid raft organization in recipient principal cells after EV uptake and increased renal ENaC activity, leading to a time-of-day dependent regulation of blood pressure in an aging model.

Metabolomic Profiling for Diagnosis and Prognostication in Surgery: A Scoping Review.

OBJECTIVE: This review assimilates and critically evaluates available literature regarding the use of metabolomic profiling in surgical decision-making. BACKGROUND: Metabolomic profiling is performed by nuclear magnetic resonance spectroscopy or mass spectrometry of biofluids and tissues to quantify biomarkers (ie, sugars, amino acids, and lipids), producing diagnostic and prognostic information that has been applied among patients with cardiovascular disease, inflammatory bowel disease, cancer, and solid organ transplants. METHODS: PubMed was searched from 1995 to 2019 to identify studies investigating metabolomic profiling of surgical patients. Articles were included and assimilated into relevant categories per PRISMA-ScR guidelines. Results were summarized with descriptive analytical methods. RESULTS: Forty-seven studies were included, most of which were retrospective studies with small sample sizes using various combinations of analytic techniques and types of biofluids and tissues. Results suggest that metabolomic profiling has the potential to effectively screen for surgical diseases, suggest diagnoses, and predict outcomes such as postoperative complications and disease recurrence. Major barriers to clinical adoption include a lack of high-level evidence from prospective studies, heterogeneity in study design regarding tissue and biofluid procurement and analytical methods, and the absence of large, multicenter metabolome databases to facilitate systematic investigation of the efficacy, reproducibility, and generalizability of metabolomic profiling diagnoses and prognoses. CONCLUSIONS: Metabolomic profiling research would benefit from standardization of study design and analytic approaches. As technologies improve and knowledge garnered from research accumulates, metabolomic profiling has the potential to provide personalized diagnostic and prognostic information to support surgical decision-making from preoperative to postdischarge phases of care.

Advances in artificial intelligence and deep learning systems in ICU-related acute kidney injury.

PURPOSE OF REVIEW: Acute kidney injury (AKI) affects nearly 60% of all patients admitted to ICUs. Large volumes of clinical, monitoring and laboratory data produced in ICUs allow the application of artificial intelligence analytics. The purpose of this article is to assimilate and critically evaluate recently published literature regarding artificial intelligence applications for predicting, diagnosing and subphenotyping AKI among critically ill patients. RECENT FINDINGS: Among recent studies regarding artificial intelligence implementations for predicting, diagnosing and subphenotyping AKI among critically ill patients, there are many promising models, but few had external validation, clinical interpretability and high predictive performance. Deep learning techniques leveraging multimodal clinical data show great potential to provide continuous, accurate, early predictions of AKI risk, which could be implemented clinically to optimize preventive and early therapeutic management strategies. SUMMARY: Use of consensus criteria, standard definitions and common data models could facilitate access to machine learning-ready data sets for external validation. The lack of interpretability, explainability, fairness and transparency of artificial intelligence models hinder their entrustment and clinical implementation; compliance with standardized reporting guidelines can mitigate these challenges.

Improved ability to achieve target trough levels with liquid versus capsule tacrolimus in kidney transplant patients with HIV on protease inhibitor- or cobicistat-based regimens.

HIV + patients are commonly accepted for kidney transplantation. However, patients on protease inhibitor (PI)- or cobicistat (cobi)-based regimens have trouble achieving optimal tacrolimus (Tac) levels. Our study compared the ability to achieve target levels using liquid versus immediate-release capsule Tac in kidney transplant patients with HIV on PI- or cobi-based regimens. The study included four kidney transplant patients who were converted to liquid Tac due to inability to achieve acceptable drug levels on the capsule formulation. Tac trough levels were analyzed retrospectively to compare target levels before and after conversion. The individual patient time in the therapeutic range (TTR) was calculated using Rosendaal's linear interpolation method, and the difference between before and after conversion TTR was determined. In combined data, 44.63% of all Tac trough levels were within the target range after conversion to liquid Tac compared to 22.07% prior to conversion (P < .001). Furthermore, 3.31% and 7.44% of Tac trough levels were lower than 3 ng/mL or higher than 12 ng/mL, respectively, after conversion compared to 11.72% (P = .0564) and 24.14% (P < .0001) prior to conversion. The overall mean TTR was 45.1% after conversion to liquid Tac compared to 16.2% prior to conversion (P = .097). Finally, the coefficient of variation for Tac trough levels was 42.6 after conversion compared to 56.4 prior to conversion. A significantly improved ability to achieve target trough Tac levels was achieved with liquid Tac extemporaneous versus capsule formulation in kidney transplant patients with HIV taking a PI- or cobi-based regimen.

A pilot study of immunosuppression resumption following BK viremia resolution.

BACKGROUND: Immunosuppression reduction for BK viremia is associated with de novo humoral responses, which are a risk factor for rejection and graft loss. In this pilot project, we tested a protocol of immunosuppression resumption to standard dose after viral clearance for optimal protection against humoral immunity in patients undergoing treatment for BK viremia. METHODS: Thirty-six consecutive kidney transplant recipients who developed BK viremia from 7/1/2014 to 11/18/2016 underwent immunosuppression reduction. After 4 weeks of absent viremia, mycophenolate mofetil (MMF) was increased by 500mg/day every 2 weeks up to standard dosage, followed by increase of tacrolimus trough levels to 5-7 ng/mL. If viremia recurred during the increase, immunosuppression was reduced in this same stepwise fashion, with stepwise increase again after 2 months of negative viremia. RESULTS: Mean tacrolimus trough level (ng/mL) was 8.3 ± 2.7 at viremia onset, 5.3 ± 3.6 at resolution, and 5.6 ± 2.0 at study end date. Mean daily dose (mg) of MMF was 1574 ± 355 at onset, 910 ± 230 at resolution, and 1377 ± 451 at study end date. Only one patient developed low level viremia recurrence (peak 2875 copies/mL) during the period of immunosuppression resumption that ultimately resolved. CONCLUSIONS: The results of our pilot project indicate that following BK viremia resolution, resumption of standard immunosuppression can be achieved safely without BK viremia recurrence. Larger trials with long-term follow up are required to determine whether such an approach improves long-term graft survival.

Added Value of Intraoperative Data for Predicting Postoperative Complications: The MySurgeryRisk PostOp Extension.

BACKGROUND: Models that predict postoperative complications often ignore important intraoperative events and physiological changes. This study tested the hypothesis that accuracy, discrimination, and precision in predicting postoperative complications would improve when using both preoperative and intraoperative data input data compared with preoperative data alone. METHODS: This retrospective cohort analysis included 43,943 adults undergoing 52,529 inpatient surgeries at a single institution during a 5-y period. Random forest machine learning models in the validated MySurgeryRisk platform made patient-level predictions for seven postoperative complications and mortality occurring during hospital admission using electronic health record data and patient neighborhood characteristics. For each outcome, one model trained with preoperative data alone; one model trained with both preoperative and intraoperative data. Models were compared by accuracy, discrimination (expressed as area under the receiver operating characteristic curve), precision (expressed as area under the precision-recall curve), and reclassification indices. RESULTS: Machine learning models incorporating both preoperative and intraoperative data had greater accuracy, discrimination, and precision than models using preoperative data alone for predicting all seven postoperative complications (intensive care unit length of stay >48 h, mechanical ventilation >48 h, neurologic complications including delirium, cardiovascular complications, acute kidney injury, venous thromboembolism, and wound complications), and in-hospital mortality (accuracy: 88% versus 77%; area under the receiver operating characteristic curve: 0.93 versus 0.87; area under the precision-recall curve: 0.21 versus 0.15). Overall reclassification improvement was 2.4%-10.0% for complications and 11.2% for in-hospital mortality. CONCLUSIONS: Incorporating both preoperative and intraoperative data significantly increased the accuracy, discrimination, and precision of machine learning models predicting postoperative complications and mortality.

Preventive care for patients with end-stage kidney disease: crossroads between nephrology and primary care.

Patients with end-stage kidney disease (ESKD) undergoing maintenance hemodialysis (HD) might expect their nephrologists to coordinate all their healthcare needs. We performed a survey among adult patients with ESKD undergoing HD in two outpatient dialysis centers at the University of Florida to identify differences in characteristics between patients with and without primary care providers (PCP) and to explore the association of PCP utilization with adherence to preventive health measures. Of the 132 participants, 89.4% reported having a PCP. This group was more likely to be female, older, and with higher education level. Having a PCP was associated with influenza, pneumococcal, and tetanus/Tdap vaccinations as well as screening for tuberculosis, depression, hypertension, and dyslipidemia. The PCP group had statistically significant higher rates of influenza immunization (89.8% vs 71.4%, P = .04) as well as screening for hypertension (93.2% vs 64.3%, P = .04) and depression (78.8% vs 42.9%, P = .004), compared to the group without PCP, in the multivariable analysis. Having a PCP is associated with higher rates of influenza vaccination and screening for depression and hypertension. These findings could have important implications as far as identifying patients with ESKD at risk for fragmented care and potential gaps in optimal preventive care.

MySurgeryRisk: Development and Validation of a Machine-learning Risk Algorithm for Major Complications and Death After Surgery.

OBJECTIVE: To accurately calculate the risk for postoperative complications and death after surgery in the preoperative period using machine-learning modeling of clinical data. BACKGROUND: Postoperative complications cause a 2-fold increase in the 30-day mortality and cost, and are associated with long-term consequences. The ability to precisely forecast the risk for major complications before surgery is limited. METHODS: In a single-center cohort of 51,457 surgical patients undergoing major inpatient surgery, we have developed and validated an automated analytics framework for a preoperative risk algorithm (MySurgeryRisk) that uses existing clinical data in electronic health records to forecast patient-level probabilistic risk scores for 8 major postoperative complications (acute kidney injury, sepsis, venous thromboembolism, intensive care unit admission >48 hours, mechanical ventilation >48 hours, wound, neurologic, and cardiovascular complications) and death up to 24 months after surgery. We used the area under the receiver characteristic curve (AUC) and predictiveness curves to evaluate model performance. RESULTS: MySurgeryRisk calculates probabilistic risk scores for 8 postoperative complications with AUC values ranging between 0.82 and 0.94 [99% confidence intervals (CIs) 0.81-0.94]. The model predicts the risk for death at 1, 3, 6, 12, and 24 months with AUC values ranging between 0.77 and 0.83 (99% CI 0.76-0.85). CONCLUSIONS: We constructed an automated predictive analytics framework for machine-learning algorithm with high discriminatory ability for assessing the risk of surgical complications and death using readily available preoperative electronic health records data. The feasibility of this novel algorithm implemented in real time clinical workflow requires further testing.

The Development of Chronic Critical Illness Determines Physical Function, Quality of Life, and Long-Term Survival Among Early Survivors of Sepsis in Surgical ICUs.

OBJECTIVES: This study sought to examine mortality, health-related quality of life, and physical function among sepsis survivors who developed chronic critical illness. DESIGN: Single-institution, prospective, longitudinal, observational cohort study assessing 12-month outcomes. SETTING: Two surgical/trauma ICUs at an academic tertiary medical and level 1 trauma center. PATIENTS: Adult critically ill patients that survived 14 days or longer after sepsis onset. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Baseline patient characteristics and function, sepsis severity, and clinical outcomes of the index hospitalization were collected. Follow-up physical function (short physical performance battery; Zubrod; hand grip strength) and health-related quality of life (EuroQol-5D-3L, Short Form-36) were measured at 3, 6, and 12 months. Hospital-free days and mortality were determined at 12 months. We compared differences in long-term outcomes between subjects who developed chronic critical illness (≥ 14 ICU days with persistent organ dysfunction) versus those with rapid recovery. The cohort consisted of 173 sepsis patients; 63 (36%) developed chronic critical illness and 110 (64%) exhibited rapid recovery. Baseline physical function and health-related quality of life did not differ between groups. Those who developed chronic critical illness had significantly fewer hospital-free days (196 ± 148 vs 321 ± 65; p < 0.0001) and reduced survival at 12-months compared with rapid recovery subjects (54% vs 92%; p < 0.0001). At 3- and 6-month follow-up, chronic critical illness patients had significantly lower physical function (3 mo: short physical performance battery, Zubrod, and hand grip; 6 mo: short physical performance battery, Zubrod) and health-related quality of life (3- and 6-mo: EuroQol-5D-3L) compared with patients who rapidly recovered. By 12-month follow-up, chronic critical illness patients had significantly lower physical function and health-related quality of life on all measures. CONCLUSIONS: Surgical patients who develop chronic critical illness after sepsis exhibit high healthcare resource utilization and ultimately suffer dismal long-term clinical, functional, and health-related quality of life outcomes. Further understanding of the mechanisms driving the development and persistence of chronic critical illness will be necessary to improve long-term outcomes after sepsis.

External Validation of the qSOFA Score in Emergency Department Patients With Pneumonia.

BACKGROUND: Pneumonia is the leading cause of sepsis. In 2016, the 3rd International Consensus Conference for Sepsis released the Quick Sepsis-Related Organ Failure Assessment (qSOFA) to identify risk for poor outcomes in sepsis. OBJECTIVE: We sought to externally validate qSOFA in emergency department (ED) patients with pneumonia and compare the accuracy of qSOFA to systemic inflammatory response syndrome score (SIRS), Confusion, Respiratory Rate and Blood Pressure (CRB), Confusion, Respiratory Rate, Blood Pressure and Age (CRB-65), and DS CRB-65, which is based on the CRB-65 score and includes two additional items-presence of underlying comorbid disease and blood oxygen saturation. METHODS: A subgroup analysis of U.S. Critical Illness and Injury Trials Group (USCIITG-Lung Injury Prevention Study [LIPS]; ClinicalTrials.gov ID: NCT00889772) prospective cohort. The primary outcome was in-hospital mortality. Secondary outcomes were measures of intensive care unit (ICU) utilization. Sensitivity, specificity, and area under the curve (AUC) were reported. RESULTS: From March to August 2009, 5584 patients were enrolled; 713 met inclusion criteria. Median age was 61 years (interquartile range 49-75 years). SIRS criteria had the highest sensitivity for death (89%) and lowest specificity (25%), while CRB had the highest specificity (88%) and lowest sensitivity (31%), followed by qSOFA (80% and 53%, respectively). This trend was maintained for the secondary outcomes. There was no significant difference in the AUC for death using qSOFA (AUC 0.75; 95% confidence interval [CI] 0.66-0.84), SIRS (AUC 0.70; 95% CI 0.61-0.78), CRB (AUC 0.71; 95% CI 0.62-0.80), CRB-65 (AUC 0.71; 95% CI 0.63-0.80), and DS CRB-65 (AUC 0.73; 95% CI 0.64-0.82). CONCLUSIONS: In this multicenter observational study of ED patients hospitalized with pneumonia, we found no significant differences between qSOFA and SIRS for predicting in-hospital death. In addition, several popular pneumonia-specific severity scores performed nearly identically to qSOFA score in predicting death and ICU utilization. Validation is needed in a larger sample.

Human Myeloid-derived Suppressor Cells are Associated With Chronic Immune Suppression After Severe Sepsis/Septic Shock.

OBJECTIVE: We hypothesized that after sepsis in humans, MDSCs will be persistently increased, functionally immunosuppressive, and associated with adverse clinical outcomes. BACKGROUND: Cancer and sepsis have surprisingly similar immunologic responses and equally dismal long term consequences. In cancer, increased myeloid-derived suppressor cells (MDSCs) induce detrimental immunosuppression, but little is known about the role of MDSCs after sepsis. METHODS: Blood was obtained from 74 patients within 12 hours of severe sepsis/septic shock (SS/SS), and at set intervals out to 28 days, and also in 18 healthy controls. MDSCs were phenotyped for cell surface receptor expression and enriched by cell sorting. Functional and genome-wide expression analyses were performed. Multiple logistic regression analysis was conducted to determine if increased MDSC appearance was associated with in-hospital and long-term outcomes. RESULTS: After SS/SS, CD33CD11bHLA-DR MDSCs were dramatically increased out to 28 days (P < 0.05). When co-cultured with MDSCs from SS/SS patients, antigen-driven T-cell proliferation and TH1/TH2 cytokine production were suppressed (P < 0.05). Additionally, septic MDSCs had suppressed HLA gene expression and up-regulated ARG1 expression (P < 0.05). Finally, SS/SS patients with persistent increased percentages of blood MDSCs had increased nosocomial infections, prolonged intensive care unit stays, and poor functional status at discharge (P < 0.05). CONCLUSIONS: After SS/SS in humans, circulating MDSCs are persistently increased, functionally immunosuppressive, and associated with adverse outcomes. This novel observation warrants further studies. As observed in cancer immunotherapy, MDSCs could be a novel component in multimodality immunotherapy targeting detrimental inflammation and immunosuppression after SS/SS to improve currently observed dismal long-term outcomes.

The Epidemiology of Chronic Critical Illness After Severe Traumatic Injury at Two Level-One Trauma Centers.

OBJECTIVE: To determine the incidence and risk factors of chronic critical illness after severe blunt trauma. DESIGN: Prospective observational cohort study (NCT01810328). SETTING: Two level-one trauma centers in the United States. PATIENTS: One hundred thirty-five adult blunt trauma patients with hemorrhagic shock who survived beyond 48 hours after injury. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Chronic critical illness was defined as an ICU stay lasting 14 days or more with evidence of persistent organ dysfunction. Three subjects (2%) died within the first 7 days, 107 (79%) exhibited rapid recovery and 25 (19%) progressed to chronic critical illness. Patients who developed chronic critical illness were older (55 vs 44-year-old; p = 0.01), had more severe shock (base deficit, -9.2 vs -5.5; p = 0.005), greater organ failure severity (Denver multiple organ failure score, 3.5 ± 2.4 vs 0.8 ± 1.1; p < 0.0001) and developed more infectious complications (84% vs 35%; p < 0.0001). Chronic critical illness patients were more likely to be discharged to a long-term care setting (56% vs 34%; p = 0.008) than to a rehabilitation facility/home. At 4 months, chronic critical illness patients had higher mortality (16.0% vs 1.9%; p < 0.05), with survivors scoring lower in general health measures (p < 0.005). Multivariate analysis revealed age greater than or equal to 55 years, systolic hypotension less than or equal to 70 mm Hg, transfusion greater than or equal to 5 units packed red blood cells within 24 hours, and Denver multiple organ failure score at 72 hours as independent predictors of chronic critical illness (area under the receiver operating curve, 0.87; 95% CI, 0.75-0.95). CONCLUSIONS: Although early mortality is low after severe trauma, chronic critical illness is a common trajectory in survivors and is associated with poor long-term outcomes. Advancing age, shock severity, and persistent organ dysfunction are predictive of chronic critical illness. Early identification may facilitate targeted interventions to change the trajectory of this morbid phenotype.

The Pattern of Longitudinal Change in Serum Creatinine and 90-Day Mortality After Major Surgery.

OBJECTIVE: Calculate mortality risk that accounts for both severity and recovery of postoperative kidney dysfunction using the pattern of longitudinal change in creatinine. BACKGROUND: Although the importance of renal recovery after acute kidney injury (AKI) is increasingly recognized, the complex association that accounts for longitudinal creatinine changes and mortality is not fully described. METHODS: We used routinely collected clinical information for 46,299 adult patients undergoing major surgery to develop a multivariable probabilistic model optimized for nonlinearity of serum creatinine time series that calculates the risk function for 90-day mortality. We performed a 70/30 cross validation analysis to assess the accuracy of the model. RESULTS: All creatinine time series exhibited nonlinear risk function in relation to 90-day mortality and their addition to other clinical factors improved the model discrimination. For any given severity of AKI, patients with complete renal recovery, as manifested by the return of the discharge creatinine to the baseline value, experienced a significant decrease in the odds of dying within 90 days of admission compared with patients with partial recovery. Yet, for any severity of AKI, even complete renal recovery did not entirely mitigate the increased odds of dying, as patients with mild AKI and complete renal recovery still had significantly increased odds for dying compared with patients without AKI [odds ratio: 1.48 (95% confidence interval: 1.30-1.68)]. CONCLUSIONS: We demonstrate the nonlinear relationship between both severity and recovery of renal dysfunction and 90-day mortality after major surgery. We have developed an easily applicable computer algorithm that calculates this complex relationship.

Acute and Chronic Kidney Disease and Cardiovascular Mortality After Major Surgery.

OBJECTIVE: The aim of the study was to determine the long-term cardiovascular-specific mortality in patients with acute kidney injury (AKI) or chronic kidney disease (CKD) after major surgery. BACKGROUND: In surgical patients, pre-existing CKD and postoperative AKI are associated with increases in all-cause mortality. METHODS: In a single-center cohort of 51,457 adult surgical patients undergoing major inpatient surgery, long-term cardiovascular-specific mortality was modeled using a multivariable subdistributional hazards model while treating any other cause of death as a competing risk and accounting for the progression to end-stage renal disease (ESRD) after discharge. Pre-existing CKD and ESRD, and postoperative AKI were the main independent predictors. RESULTS: Before the admission, 4% and 8% of the cohort had pre-existing ESRD and CKD not requiring renal replacement therapy, respectively. During hospitalization, 39% developed AKI. At 10-year follow-up, adjusted cardiovascular-specific mortality estimates were 6%, 11%, 12%, 19%, and 27% for patients with no kidney disease, AKI with no CKD, CKD with no AKI, AKI with CKD, and ESRD, respectively (P < 0.001). This association remained after excluding 916 patients who progressed to ESRD after discharge, although it was significantly amplified among them. Compared with patients having no kidney disease, adjusted hazard ratios for cardiovascular mortality were significantly higher among patients with kidney disease, ranging from 1.95 (95% confidence interval, 1.80-2.11) for patients with de novo AKI to 5.70 (95% confidence interval, 5.00-6.49) for patients with pre-existing ESRD. CONCLUSIONS: Both AKI and CKD were associated with higher long-term cardiovascular-specific mortality compared with patients having no kidney disease.

Aged mice are unable to mount an effective myeloid response to sepsis.

The elderly have increased morbidity and mortality following sepsis; however, the cause(s) remains unclear. We hypothesized that these poor outcomes are due in part to defects in innate immunity, rather than to an exaggerated early inflammatory response. Young (6-12 wk) or aged (20-24 mo) mice underwent polymicrobial sepsis, and subsequently, the aged mice had increased mortality and defective peritoneal bacterial clearance compared with young mice. No differences were found in the magnitude of the plasma cytokine responses. Although septic aged mice displayed equivalent or increased numbers of circulating, splenic, and bone marrow myeloid cells, some of these cells exhibited decreased phagocytosis, reactive oxygen species production, and chemotaxis. Blood leukocyte gene expression was less altered in aged versus young mice 1 d after sepsis. Aged mice had a relative inability to upregulate gene expression of pathways related to neutrophil-mediated protective immunity, chemokine/chemokine receptor binding, and responses to exogenous molecules. Expression of most MHC genes remained more downregulated in aged mice at day 3. Despite their increased myeloid response to sepsis, the increased susceptibility of aged mice to sepsis appears not to be due to an exaggerated inflammatory response, but rather, a failure to mount an effective innate immune response.

Long-Term Outcomes for Different Forms of Stress Cardiomyopathy After Surgical Treatment for Subarachnoid Hemorrhage.

BACKGROUND: Stress-induced cardiomyopathy (SCM) after subarachnoid hemorrhage (SAH) includes predominant apical or basal regional left ventricular dysfunction (RLVD) with concomitant changes in electrocardiogram or increase in cardiac enzymes. We hypothesized that difference in outcome is associated with the type of RLVD after SAH. METHODS: We studied a single-center retrospective cohort of SAH patients hospitalized between 2000 and 2010 with follow-up until 2013. We classified patients who had an echocardiogram for clinically indicated reasons according to the predominate location of RLVD as classic SCM-apical form and variant SCM-basal form. A Cox proportional hazard model and logistic regression were used to estimate the risk for death and hospital complications associated with different RLVD after adjustment for propensity to undergo echocardiography given clinical characteristics on admission. RESULTS: Among 715 SAH patients, 28% (200/715) had an echocardiogram for clinical evidence of cardiac dysfunction during hospitalization, the most common being acute left ventricular dysfunction, suspected acute ischemic event, changes in electrocardiogram and cardiac enzymes, and arrhythmia. SCM was present in 59 patients (8% of all cohort and 30% of patients with echocardiogram, respectively) with similar distribution of SCM-basal (25/59) and SCM-apical forms (34/59). SAH patients who had an echocardiogram for clinically indicated reasons had a significantly decreased risk-adjusted long-term survival compared with those without an echocardiogram, regardless of the presence of RLVD. SCM-basal form was associated with cardiac complications (odds ratio, 6.1; 99% confidence interval, 1.8-20.2) and severe sepsis (odds ratio, 5.3; 99% confidence interval, 1.6-17.2). CONCLUSIONS: SAH patients with echocardiogram for a clinically indicated reason have a decreased long-term survival, regardless of the presence of RLVD. The association between severe sepsis and SCM-basal warrants future studies to determine their potential synergistic effect on left ventricular systolic dysfunction among SAH patients.