Michael G.S. Shashaty

Automated, electronic alerts for acute kidney injury: a single-blind, parallel-group, randomised controlled trial

BACKGROUND Acute kidney injury often goes unrecognised in its early stages when effective treatment options might be available. We aimed to determine whether an automated electronic alert for acute kidney injury would reduce the severity of such injury and improve clinical outcomes in patients in hospital. METHODS In this investigator-masked, parallel-group, randomised controlled trial, patients were recruited from the hospital of the University of Pennsylvania in Philadelphia, PA, USA. Eligible participants were adults aged 18 years or older who were in hospital with stage 1 or greater acute kidney injury as defined by Kidney Disease Improving Global Outcomes creatinine-based criteria. Exclusion criteria were initial hospital creatinine 4·0 mg/dL (to convert to μmol/L, multiply by 88·4) or greater, fewer than two creatinine values measured, inability to determine the covering provider, admission to hospice or the observation unit, previous randomisation, or end-stage renal disease. Patients were randomly assigned (1:1) via a computer-generated sequence to receive an acute kidney injury alert (a text-based alert sent to the covering provider and unit pharmacist indicating new acute kidney injury) or usual care, stratified by medical versus surgical admission and intensive care unit versus non-intensive care unit location in blocks of 4-8 participants. The primary outcome was a composite of relative maximum change in creatinine, dialysis, and death at 7 days after randomisation. All analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01862419. FINDINGS Between Sept 17, 2013, and April 14, 2014, 23,664 patients were screened. 1201 eligible participants were assigned to the acute kidney injury alert group and 1192 were assigned to the usual care group. Composite relative maximum change in creatinine, dialysis, and death at 7 days did not differ between the alert group and the usual care group (p=0·88), or within any of the four randomisation strata (all p>0·05). At 7 days after randomisation, median maximum relative change in creatinine concentrations was 0·0% (IQR 0·0-18·4) in the alert group and 0·6% (0·0-17·5) in the usual care group (p=0·81); 87 (7·2%) patients in the alert group and 70 (5·9%) patients in usual care group had received dialysis (odds ratio 1·25 [95% CI 0·90-1·74]; p=0·18); and 71 (5·9%) patients in the alert group and 61 (5·1%) patients in the usual care group had died (1·16 [0·81-1·68]; p=0·40). INTERPRETATION An electronic alert system for acute kidney injury did not improve clinical outcomes among patients in hospital. FUNDING Penn Center for Healthcare Improvement and Patient Safety.

False-Positive Rate of AKI Using Consensus Creatinine–Based Criteria

BACKGROUND AND OBJECTIVES Use of small changes in serum creatinine to diagnose AKI allows for earlier detection but may increase diagnostic false-positive rates because of inherent laboratory and biologic variabilities of creatinine. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We examined serum creatinine measurement characteristics in a prospective observational clinical reference cohort of 2267 adult patients with AKI by Kidney Disease Improving Global Outcomes creatinine criteria and used these data to create a simulation cohort to model AKI false-positive rates. We simulated up to seven successive blood draws on an equal population of hypothetical patients with unchanging true serum creatinine values. Error terms generated from laboratory and biologic variabilities were added to each simulated patients true serum creatinine value to obtain the simulated measured serum creatinine for each blood draw. We determined the proportion of patients who would be erroneously diagnosed with AKI by Kidney Disease Improving Global Outcomes creatinine criteria. RESULTS Within the clinical cohort, 75.0% of patients received four serum creatinine draws within at least one 48-hour period during hospitalization. After four simulated creatinine measurements that accounted for laboratory variability calculated from assay characteristics and 4.4% of biologic variability determined from the clinical cohort and publicly available data, the overall false-positive rate for AKI diagnosis was 8.0% (interquartile range =7.9%-8.1%), whereas patients with true serum creatinine ≥1.5 mg/dl (representing 21% of the clinical cohort) had a false-positive AKI diagnosis rate of 30.5% (interquartile range =30.1%-30.9%) versus 2.0% (interquartile range =1.9%-2.1%) in patients with true serum creatinine values <1.5 mg/dl (P<0.001). CONCLUSIONS Use of small serum creatinine changes to diagnose AKI is limited by high false-positive rates caused by inherent variability of serum creatinine at higher baseline values, potentially misclassifying patients with CKD in AKI studies.

African American race, obesity, and blood product transfusion are risk factors for acute kidney injury in critically ill trauma patients☆

PURPOSE Acute kidney injury (AKI) is a common source of morbidity after trauma. We sought to determine novel risk factors for AKI, by Acute Kidney Injury Network (AKIN) criteria, in critically ill trauma patients. MATERIALS AND METHODS A prospective cohort of 400 patients admitted to the intensive care unit of a level 1 trauma center was followed for the development of AKI over 5 days. RESULTS Acute kidney injury developed in 147 (36.8%) of 400 patients. In multivariable regression analysis, independent risk factors for AKI included African American race (odds ratio [OR], 1.86; 95% confidence interval [CI], 1.08-3.18; P = .024), body mass index of 30 kg/m(2) or greater (OR, 4.72 versus normal body mass index; 95% CI, 2.59-8.61; P < .001), diabetes mellitus (OR, 3.26; 95% CI, 1.30-8.20; P = .012), abdominal Abbreviated Injury Scale score of 4 or more (OR, 3.78; 95% CI, 1.79-7.96; P < .001), and unmatched packed red blood cells administered during resuscitation (OR, 1.13 per unit; 95% CI, 1.04-1.23; P = .004). Acute Kidney Injury Network stages 1, 2, and 3 were associated with hospital mortality rates of 9.8%, 13.7%, and 30.4%, respectively, compared with 3.8% for those without AKI (P < .001). CONCLUSIONS Acute kidney injury in critically ill trauma patients is associated with substantial mortality. The findings of African American race, obesity, and blood product administration as independent risk factors for AKI deserve further study to elucidate underlying mechanisms.

Red Blood Cells Induce Necroptosis of Lung Endothelial Cells and Increase Susceptibility to Lung Inflammation

RATIONALE Red blood cell (RBC) transfusions are associated with increased risk of acute respiratory distress syndrome (ARDS) in the critically ill, yet the mechanisms for enhanced susceptibility to ARDS conferred by RBC transfusions remain unknown. OBJECTIVES To determine the mechanisms of lung endothelial cell (EC) High Mobility Group Box 1 (HMGB1) release following exposure to RBCs and to determine whether RBC transfusion increases susceptibility to lung inflammation in vivo through release of the danger signal HMGB1. METHODS In vitro studies examining human lung EC viability and HMGB1 release following exposure to allogenic RBCs were conducted under static conditions and using a microengineered model of RBC perfusion. The plasma from transfused and nontransfused patients with severe sepsis was examined for markers of cellular injury. A murine model of RBC transfusion followed by LPS administration was used to determine the effects of RBC transfusion and HMGB1 release on LPS-induced lung inflammation. MEASUREMENTS AND MAIN RESULTS After incubation with RBCs, lung ECs underwent regulated necrotic cell death (necroptosis) and released the essential mediator of necroptosis, receptor-interacting serine/threonine-protein kinase 3 (RIP3), and HMGB1. RIP3 was detectable in the plasma of patients with severe sepsis, and was increased with blood transfusion and among nonsurvivors of sepsis. RBC transfusion sensitized mice to LPS-induced lung inflammation through release of the danger signal HMGB1. CONCLUSIONS RBC transfusion enhances susceptibility to lung inflammation through release of HMGB1 and induces necroptosis of lung EC. Necroptosis and subsequent danger signal release is a novel mechanism of injury following transfusion that may account for the increased risk of ARDS in critically ill transfused patients.

Heterogeneous phenotypes of acute respiratory distress syndrome after major trauma.

RATIONALE Acute respiratory distress syndrome (ARDS) is a heterogeneous syndrome that can develop at various times after major trauma. OBJECTIVES To identify and characterize distinct phenotypes of ARDS after trauma, based on timing of syndrome onset. METHODS Latent class analyses were used to identify patterns of ARDS onset in a cohort of critically ill trauma patients. Identified patterns were tested for associations with known ARDS risk factors and associations were externally validated at a separate institution. Eleven plasma biomarkers representing pathophysiologic domains were compared between identified patterns in the validation cohort. MEASUREMENTS AND MAIN RESULTS Three patterns of ARDS were identified; class I (52%) early onset on Day 1 or 2, class II (40%) onset on Days 3 and 4, and class III (8%) later onset on Days 4 and 5. Early-onset ARDS was associated with higher Abbreviated Injury Scale scores for the thorax (P < 0.001), lower lowest systolic blood pressure before intensive care unit admission (P = 0.003), and a greater red blood cell transfusion requirement during resuscitation (P = 0.030). In the external validation cohort, early-onset ARDS was also associated with a higher Abbreviated Injury Scale score for the thorax (P = 0.001) and a lower lowest systolic blood pressure before intensive care unit enrollment (P = 0.006). In addition, the early-onset phenotype demonstrated higher plasma levels of soluble receptor for advanced glycation end-products and angiopoietin-2. CONCLUSIONS Degree of hemorrhagic shock and severity of thoracic trauma are associated with an early-onset phenotype of ARDS after major trauma. Lung injury biomarkers suggest a dominant alveolar-capillary barrier injury pattern in this phenotype.

Physiological and management implications of obesity in critical illness.

Obesity is highly prevalent in the United States and is becoming increasingly common worldwide. The anatomic and physiological changes that occur in obese individuals may have an impact across the spectrum of critical illness. Obese patients may be more susceptible to hypoxemia and hypercapnia. During mechanical ventilation, elevated end-expiratory pressures may be required to improve lung compliance and to prevent ventilation-perfusion mismatch due to distal airway collapse. Several studies have shown an increased risk of organ dysfunction such as the acute respiratory distress syndrome and acute kidney injury in obese patients. Predisposition to ventricular hypertrophy and increases in blood volume should be considered in fluid management decisions. Obese patients have accelerated muscle losses in critical illness, making nutrition essential, although the optimal predictive equation to estimate nutritional needs or formulation for obese patients is not well established. Many common intensive care unit medications are not well studied in obese patients, necessitating understanding of pharmacokinetic concepts and consultation with pharmacists. Obesity is associated with higher risk of deep venous thrombosis and catheter-associated bloodstream infections, likely related to greater average catheter dwell times. Logistical issues such as blood pressure cuff sizing, ultrasound assistance for procedures, diminished quality of some imaging modalities, and capabilities of hospital equipment such as beds and lifts are important considerations. Despite the physiological alterations and logistical challenges involved, it is not clear whether obesity has an effect on mortality or long-term outcomes from critical illness. Effects may vary by type of critical illness, obesity severity, and obesity-associated comorbidities.

The impact of documentation of severe acute kidney injury on mortality

Aims: Modification of the mortality risk associated with acute kidney injury (AKI) necessitates recognition of AKI when it occurs. We sought to determine whether formal documentation of AKI in the medical record, assessed by billing codes for AKI, would be associated with improved clinical outcomes. Methods: Retrospective cohort study conducted at three hospitals within a single university health system. Adults without severe underlying kidney disease who suffered in-hospital AKI as defined by a doubling of baseline creatinine (n = 5,438) were included. Those whose AKI was formally documented according to discharge billing codes were compared to those without such documentation in terms of 30-day mortality. Results: Formal documentation of AKI occurred in 2,325 patients (43%). Higher baseline creatinine, higher peak creatinine, medical admission status, and higher Sequential Organ Failure Assessment (SOFA) score were strongly associated with documentation of AKI. After adjustment for severity of disease, formal AKI documentation was associated with reduced 30-day mortality – OR 0.81 (0.68 – 0.96, p = 0.02). Patients with formal documentation were more likely to receive a nephrology consultation (31% vs. 6%, p < 0.001) and fluid boluses (64% vs. 45%, p < 0.001), and had a more rapid discontinuation of angiotensin-converting enzyme inhibitor and angiotensin-receptor blocker medications (HR 2.04, CI 1.69 – 2.46, p < 0.001). Conclusions: Formal documentation of AKI is associated with improved survival after adjustment for illness severity among patients with creatinine-defined AKI.

The Long Noncoding RNA Landscape in Hypoxic and Inflammatory Renal Epithelial Injury

Long noncoding RNAs (lncRNAs) are emerging as key species-specific regulators of cellular and disease processes. To identify potential lncRNAs relevant to acute and chronic renal epithelial injury, we performed unbiased whole transcriptome profiling of human proximal tubular epithelial cells (PTECs) in hypoxic and inflammatory conditions. RNA sequencing revealed that the protein-coding and noncoding transcriptomic landscape differed between hypoxia-stimulated and cytokine-stimulated human PTECs. Hypoxia- and inflammation-modulated lncRNAs were prioritized for focused followup according to their degree of induction by these stress stimuli, their expression in human kidney tissue, and whether exposure of human PTECs to plasma of critically ill sepsis patients with acute kidney injury modulated their expression. For three lncRNAs (MIR210HG, linc-ATP13A4-8, and linc-KIAA1737-2) that fulfilled our criteria, we validated their expression patterns, examined their loci for conservation and synteny, and defined their associated epigenetic marks. The lncRNA landscape characterized here provides insights into novel transcriptomic variations in the renal epithelial cell response to hypoxic and inflammatory stress.

ABO Blood Type A Is Associated With Increased Risk of ARDS in Whites Following Both Major Trauma and Severe Sepsis

BACKGROUND ABO glycosyltransferases catalyze antigen modifications on various glycans and glycoproteins and determine the ABO blood types. Blood type A has been associated with increased risk of vascular diseases and differential circulating levels of proteins related to inflammation and endothelial function. The objective of this study was to determine the association of ABO blood types with ARDS risk in patients with major trauma and severe sepsis. METHODS We conducted prospective cohort studies in two populations at an urban tertiary referral, level I trauma center. Critically ill patients (n 5 732) presenting after major trauma were followed for 5 days for ARDS development. Additionally, 976 medical patients with severe sepsis were followed for 5 days for ARDS. Multivariable logistic regression was used to adjust for confounders. RESULTS ARDS developed in 197 of the 732 trauma patients (27%). Blood type A was associated with increased ARDS risk among whites (37% vs 24%; adjusted OR, 1.88; 95% CI, 1.14-3.12; P 5 .014), but not blacks (adjusted OR, 0.61; 95% CI, 0.33-1.13; P=.114). ARDS developed in 222 of the 976 patients with severe sepsis (23%). Blood type A was also associated with an increased ARDS risk among whites (31% vs 21%; adjusted OR, 1.67; 95% CI, 1.08-2.59; P=.021) but, again, not among blacks (adjusted OR, 1.17; 95% CI, 0.59-2.33; P=.652). CONCLUSIONS Blood type A is associated with an increased risk of ARDS in white patients with major trauma and severe sepsis. These results suggest a role for ABO glycans and glycosyltransferases in ARDS susceptibility.

SNP-set analysis replicates acute lung injury genetic risk factors

BackgroundWe used a gene – based replication strategy to test the reproducibility of prior acute lung injury (ALI) candidate gene associations.MethodsWe phenotyped 474 patients from a prospective severe trauma cohort study for ALI. Genomic DNA from subjects’ blood was genotyped using the IBC chip, a multiplex single nucleotide polymorphism (SNP) array. Results were filtered for 25 candidate genes selected using prespecified literature search criteria and present on the IBC platform. For each gene, we grouped SNPs according to haplotype blocks and tested the joint effect of all SNPs on susceptibility to ALI using the SNP-set kernel association test. Results were compared to single SNP analysis of the candidate SNPs. Analyses were separate for genetically determined ancestry (African or European).ResultsWe identified 4 genes in African ancestry and 2 in European ancestry trauma subjects which replicated their associations with ALI. Ours is the first replication of IL6, IL10, IRAK3, and VEGFA associations in non-European populations with ALI. Only one gene – VEGFA – demonstrated association with ALI in both ancestries, with distinct haplotype blocks in each ancestry driving the association. We also report the association between trauma-associated ALI and NFKBIA in European ancestry subjects.ConclusionsPrior ALI genetic associations are reproducible and replicate in a trauma cohort. Kernel - based SNP-set analysis is a more powerful method to detect ALI association than single SNP analysis, and thus may be more useful for replication testing. Further, gene-based replication can extend candidate gene associations to diverse ethnicities.