IFN-ß Improves Sepsis-related Alveolar Macrophage Dysfunction and Postseptic Acute Respiratory Distress Syndrome-related Mortality.

IFN-ß is reported to improve survival in patients with acute respiratory distress syndrome (ARDS), possibly by preventing sepsis-induced immunosuppression, but its therapeutic nature in ARDS pathogenesis is poorly understood. We investigated the therapeutic effects of IFN-ß for postseptic ARDS to better understand its pathogenesis in mice. Postseptic ARDS was reproduced in mice by cecal ligation and puncture to induce sepsis, followed 4 days later by intratracheal instillation of Pseudomonas aeruginosa to cause pneumonia with or without subcutaneous administration of IFN-ß 1 day earlier. Sepsis induced prolonged increases in alveolar TNF-α and IL-10 concentrations and innate immune reprogramming; specifically, it reduced alveolar macrophage (AM) phagocytosis and KC (CXCL1) secretion. Ex vivo AM exposure to TNF-α or IL-10 duplicated cytokine release impairment. Compared with sepsis or pneumonia alone, pneumonia after sepsis was associated with blunted alveolar KC responses and reduced neutrophil recruitment into alveoli despite increased neutrophil burden in lungs (i.e., "incomplete alveolar neutrophil recruitment"), reduced bacterial clearance, increased lung injury, and markedly increased mortality. Importantly, IFN-ß reversed the TNF-α/IL-10-mediated impairment of AM cytokine secretion in vitro, restored alveolar innate immune responsiveness in vivo, improved alveolar neutrophil recruitment and bacterial clearance, and consequently reduced the odds ratio for 7-day mortality by 85% (odds ratio, 0.15; 95% confidence interval, 0.03-0.82; P = 0.045). This mouse model of sequential sepsis → pneumonia infection revealed incomplete alveolar neutrophil recruitment as a novel pathogenic mechanism for postseptic ARDS, and systemic IFN-ß improved survival by restoring the impaired function of AMs, mainly by recruiting neutrophils to alveoli.

Public access defibrillation and outcomes after pediatric out-of-hospital cardiac arrest.

BACKGROUND: Use of automated external defibrillators (AEDs) has been recommended for pediatric out-of-hospital cardiac arrest (OHCA). However, there are no conclusive studies that elucidated the effectiveness of public-access defibrillation (PAD) in children. METHODS: This was a nationwide, population-based, propensity score-matched study of pediatric OHCA in Japan from 2011 to 2012, based on data from the All-Japan Utstein Registry. We included pediatric OHCA patients (aged 1-17 years) who received bystander cardiopulmonary resuscitation. The primary outcome was a favorable neurological state 1 month after OHCA (defined as a CPC score of 1-2). RESULTS: A total of 1193 patients were included in the final cohort; 57 received PAD and 1136 did not. Among 1193 patients, 188 (15.8%) survived with a favorable neurological status 1 month after OHCA. The odds of neurologically favorable survival were significantly higher for patients receiving PAD after adjusting for potential confounders: propensity score matching, OR 3.17 (95% CI 1.40-7.17), and multivariable logistic regression modeling, ORadjusted 5.10 (95% CI 2.01-13.70). Similar findings were observed for the secondary outcomes (i.e., neurologically favorable survival with a CPC score of 1, one-month survival, and prehospital return of spontaneous circulation). In subgroup analyses, there were no significant differences in neurologically favorable survival between the PAD group and non-PAD group in the unwitnessed cohort (ORadjusted 7.76 [0.75-81.90]) or the non-cardiac etiology cohort (ORadjusted 6.65 [0.64-66.24]). CONCLUSIONS: PAD was associated with an increased chance of neurologically favorable survival in pediatric OHCA (aged 1-17 years) who received bystander CPR, except for in cases of unwitnessed or non-cardiac etiology.

Effect of rescue breathing by lay rescuers for out-of-hospital cardiac arrest caused by respiratory disease: a nationwide, population-based, propensity score-matched study.

The importance of respiratory care in cardiopulmonary resuscitation may vary depending on the cause of cardiac arrest. No previous study has investigated the effects of rescue breathing performed by a lay rescuer on the outcomes of patients with out-of-hospital cardiac arrest (OHCA) caused by intrinsic respiratory diseases. The aim of this study was to investigate whether rescue breathing performed by a lay rescuer is associated with outcomes after respiratory disease-related OHCA. In a nationwide, population-based, propensity score-matched study in Japan, among adult patients with OHCA caused by respiratory disease who received bystander cardiopulmonary resuscitation from January 1, 2005 to December 31, 2010, we compared patients with rescue breathing to those without rescue breathing. The primary outcome was neurologically favorable survival 1 month after OHCA. Of the eligible 14,781 patients, 4970 received rescue breathing from a lay rescuer and 9811 did not receive rescue breathing. In a propensity score-matched cohort (4897 vs. 4897 patients), the neurologically favorable survival rate was similar between patients with and without rescue breathing from a lay rescuer [0.9 vs. 0.7 %; OR 1.23 (95 % CI 0.79-1.93)]. Additionally, in subgroup analyses, rescue breathing was not associated with neurological outcome regardless of the type of rescuer [family member: adjusted OR 0.83 (95 % CI 0.39-1.70); or non-family member: adjusted OR 1.91 (95 % CI 0.79-5.35)]. Even among patients with OHCA caused by respiratory disease, rescue breathing performed by a lay rescuer was not associated with neurological outcomes, regardless of the type of lay rescuer.

Conventional Versus Compression-Only Versus No-Bystander Cardiopulmonary Resuscitation for Pediatric Out-of-Hospital Cardiac Arrest.

BACKGROUND: Conventional cardiopulmonary resuscitation (CPR) (chest compression and rescue breathing) has been recommended for pediatric out-of-hospital cardiac arrest (OHCA) because of the asphyxial nature of the majority of pediatric cardiac arrest events. However, the clinical effectiveness of additional rescue breathing (conventional CPR) compared with compression-only CPR in children is uncertain. METHODS: This nationwide population-based study of pediatric OHCA patients was based on data from the All-Japan Utstein Registry. We included all pediatric patients who experienced OHCA in Japan from January 1, 2011, to December 31, 2012. The primary outcome was a favorable neurological state 1 month after OHCA defined as a Glasgow-Pittsburgh Cerebral Performance Category score of 1 to 2 (corresponding to a Pediatric Cerebral Performance Category score of 1-3). Outcomes were compared with logistic regression with uni- and multivariable modeling in the overall cohort and for a propensity-matched subset of patients. RESULTS: A total of 2157 patients were included; 417 received conventional CPR, 733 received compression-only CPR, and 1007 did not receive any bystander CPR. Among these patients, 213 (9.9%) survived with a favorable neurological status 1 month after OHCA, including 108/417 (25.9%) for conventional, 68/733 (9.3%) for compression-only, and 37/1007 (3.7%) for no-bystander CPR. In unadjusted analyses, conventional CPR was superior to compression-only CPR in neurologically favorable survival (odds ratio [OR] 3.42, 95% confidence interval [CI] 2.45-4.76; P<0.0001), with a trend favoring conventional CPR that was no longer statistically significant after multivariable adjustment (ORadjusted 1.52, 95% CI 0.93-2.49), and with further attenuation of the difference in a propensity-matched subset (OR 1.20, 95% CI 0.81-1.77). Both conventional and compression-only CPR were associated with higher odds for neurologically favorable survival compared with no-bystander CPR (ORadjusted 5.01, 95% CI 2.98-8.57, and ORadjusted 3.29, 95% CI 1.93-5.71), respectively. CONCLUSIONS: In this population-based study of pediatric OHCA in Japan, both conventional and compression-only CPR were associated with superior outcomes compared with no-bystander CPR. Unadjusted outcomes with conventional CPR were superior to compression-only CPR, with the magnitude of difference attenuated and no longer statistically significant after statistical adjustments. These findings support randomized clinical trials comparing conventional versus compression-only CPR in children, with conventional CPR preferred until such controlled comparative data are available, and either method preferred over no-bystander CPR.

Impact of clinical context on acute kidney injury biomarker performances: differences between neutrophil gelatinase-associated lipocalin and L-type fatty acid-binding protein.

Application of acute kidney injury (AKI) biomarkers with consideration of nonrenal conditions and systemic severity has not been sufficiently determined. Herein, urinary neutrophil gelatinase-associated lipocalin (NGAL), L-type fatty acid-binding protein (L-FABP) and nonrenal disorders, including inflammation, hypoperfusion and liver dysfunction, were evaluated in 249 critically ill patients treated at our intensive care unit. Distinct characteristics of NGAL and L-FABP were revealed using principal component analysis: NGAL showed linear correlations with inflammatory markers (white blood cell count and C-reactive protein), whereas L-FABP showed linear correlations with hypoperfusion and hepatic injury markers (lactate, liver transaminases and bilirubin). We thus developed a new algorithm by combining urinary NGAL and L-FABP with stratification by the Acute Physiology and Chronic Health Evaluation score, presence of sepsis and blood lactate levels to improve their AKI predictive performance, which showed a significantly better area under the receiver operating characteristic curve [AUC-ROC 0.940; 95% confidential interval (CI) 0.793-0.985] than that under NGAL alone (AUC-ROC 0.858, 95% CI 0.741-0.927, P = 0.03) or L-FABP alone (AUC-ROC 0.837, 95% CI 0.697-0.920, P = 0.007) and indicated that nonrenal conditions and systemic severity should be considered for improved AKI prediction by NGAL and L-FABP as biomarkers.

Ozagrel for Patients With Noncardioembolic Ischemic Stroke: A Propensity Score-Matched Analysis.

BACKGROUND AND PURPOSE: Ozagrel sodium (ozagrel), a thromboxane A2 synthesis inhibitor, is used for ischemic stroke patients in several countries, despite a lack of strict evidence of its benefits. We investigated whether ozagrel was beneficial for patients with atherothrombotic stroke or lacunar infarction. METHODS: This was a retrospective observational study using the Diagnosis Procedure Combination database in Japan. We identified patients with atherothrombotic stroke or lacunar infarction who were admitted to 781 hospitals from July 1, 2010 to March 31, 2012. Propensity score-matched analyses were performed separately for patients with atherothrombotic stroke and those with lacunar infarction, which balanced differences in baseline characteristics between patients who received ozagrel (ozagrel group) and those who did not (control group) in each stroke subtype. The modified Rankin Scale scores at discharge and occurrence of hemorrhagic complications after admission were compared between the ozagrel and control groups. RESULTS: After the propensity score matching, 2726 pairs of patients with atherothrombotic stroke and 1612 pairs of patients with lacunar infarction were analyzed. Ordinal logistic regression analyses showed that ozagrel use was not significantly associated with modified Rankin Scale score at discharge in patients with atherothrombotic stroke (odds ratio: .99; 95% confidence interval: .88-1.11) or in those with lacunar infarction (odds ratio: 1.00; 95% confidence interval: .87-1.16). The occurrence of hemorrhagic complications did not differ significantly between the ozagrel and control groups. CONCLUSION: The present study suggested that ozagrel was safe to use but did not improve functional outcomes in patients with atherothrombotic or lacunar infarction.

Effect of prehospital epinephrine on out-of-hospital cardiac arrest: a report from the national out-of-hospital cardiac arrest data registry in Japan, 2011-2012.

PURPOSE: The effect of prehospital epinephrine on neurological outcome in out-of-hospital cardiac arrest (OHCA) is still controversial. We sought to determine whether prehospital epinephrine administration was associated with improved outcomes in adult OHCA. METHODS: A nationwide, population-based, propensity score-matched study of OHCA patients from January 1, 2011, to December 31, 2012, in Japan was conducted. We included adult OHCA patients treated by emergency medical service personnel without an excessive delay. The primary outcome was neurologically favorable survival 1 month after OHCA. RESULTS: A total of 237,068 patients (16,616 with a shockable rhythm and 220,452 with a non-shockable rhythm) were included in the final cohort. A total of 4024 out of the 16,616 shockable OHCAs and 29,393 out of the 220,452 non-shockable OHCAs received prehospital epinephrine. In the propensity score-matched cohort, prehospital epinephrine was associated with a decreased chance of neurologically favorable survival (shockable OHCA 7.6 vs. 17.9 %, OR 0.38 [95%CI 0.33-0.43]; non-shockable OHCA 0.6 vs. 1.2 %, OR 0.47 [95%CI 0.39-0.56]). In the subgroup analyses, prehospital epinephrine was significantly associated with poor neurological outcome in all subgroups. In the ancillary analyses, although the neurological outcome was worse as the number of epinephrine doses increased or the time to epinephrine increased, patients had a greater chance of a favorable neurological outcome only when a single dose of epinephrine was administered within 15 min of the emergency call in shockable OHCA. CONCLUSIONS: Among adult OHCA patients, prehospital epinephrine was associated with a decreased chance of neurologically favorable survival. Situations in which prehospital epinephrine is effective may be extremely limited.

Association of Heart Rate with N-Terminal Pro-B-Type Natriuretic Peptide in Septic Patients: A Prospective Observational Cohort Study.

BACKGROUND: Excessive sympathetic stress has multiple adverse effects during critical illness including sepsis. Recent studies showed that heart rate control had a significant effect on reducing mortality in septic shock patients. Furthermore, elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels in septic patients were reportedly associated with adverse outcome. However, no study has evaluated the relationship between hemodynamic profiles of septic patients and the circulating cardiac biomarker. Our objective was to determine whether hemodynamic profiles, specifically tachycardia and new-onset atrial fibrillation (AF), were associated with NT-proBNP elevation in septic patients. METHODS: We consecutively enrolled patients admitted to our intensive care unit (ICU). NT-proBNP levels, heart rate, and rhythm at ICU admission were measured, and all clinical and laboratory data were prospectively collected. Tachycardia was defined as a heart rate of above 100 bpm. RESULTS: Ninety-five patients out of 267 patients (35.6%) were diagnosed as sepsis. Of these septic patients, 47 presented with tachycardia and 6 developed new-onset AF. Multivariate Cox regression analysis revealed that tachycardia was an independent predictor of 28-day overall survival in septic patients (hazard ratio, 4.22; 95% confidence interval, 1.10-27.72; P < 0.05), but not in nonseptic patients. Multivariate linear regression analysis demonstrated that the presence of tachycardia was an independent determinant of NT-proBNP elevation (P < 0.05) in septic patients, but not in nonseptic patients. CONCLUSIONS: Tachycardia was significantly and independently associated with NT-proBNP elevation and lower survival rate in septic patients, although no association was observed in nonseptic patients. Increased NT-proBNP in sepsis with tachycardia might predict poor outcomes in ICU.

Epidemiology, Risk Factors, and Outcomes of Out-of-Hospital Cardiac Arrest Caused by Stroke: A Population-Based Study.

Limited information is available regarding stroke-related out-of-hospital cardiac arrest (OHCA). We aimed to assess the clinical characteristics of stroke-related OHCA and to identify the factors associated with patient outcomes.We conducted a nationwide population-based study of adult OHCA patients in Japan from January 1, 2006 to December 31, 2009. We examined the epidemiology, risk factors, and outcomes of stroke-related OHCA compared with cardiogenic OHCA. The primary outcome was neurologically favorable survival.Of the 243,140 eligible patients, 18,682 (7.7%) were diagnosed with stroke-related OHCA. Compared to OHCA with a presumed cardiac etiology, stroke-related OHCA patients had a greater chance of prehospital return of spontaneous circulation (ROSC) (9.9% vs 5.9%, P < 0.0001) but a reduced chance of 1-month survival (3.6% vs 4.9%, P < 0.0001) or favorable neurological outcomes (1.2% vs 2.6%, P < 0.0001). After adjusting for a variety of confounding factors, the prehospital ROSC rates were higher (adjusted OR 2.47, 95% confidence interval [CI] 2.34-2.62), but the neurologically favorable survival rates were lower (adjusted OR 0.66, 95%CI 0.57-0.76), among the stroke-related OHCA patients. In stroke-related OHCA cases, having a younger age, witness, and shockable 1st documented rhythm were associated with improved outcomes. Men had more favorable neurological outcomes. Seasonal or circadian factors had no critical impact on favorable neurological outcomes. Prehospital advanced life support techniques (i.e., epinephrine administration or advanced airway management) were not associated with favorable neurological outcomes.Although stroke-related OHCA had lower 1-month survival rates and poorer neurological outcomes than cardiogenic OHCA, the rates were not considered to be medically futile. Characteristically, sex differences might impact neurologically favorable survival.

Cardiac Variation of Internal Jugular Vein for the Evaluation of Hemodynamics.

Evaluations of intravascular fluid volume are considered to be one of the most important assessments in emergency and intensive care. Focusing on pulse-induced variation of the internal jugular vein (IJV) area, i.e., cardiac variation, we investigated its correlation with various hemodynamic indices using newly developed software. Software that automatically can track and analyze the IJV during ultrasonography was developed. Eleven healthy patients were subjected to an exercise load to increase their stroke volume (SV) and a dehydration load to decrease their central venous pressure (CVP). The cardiac variation in the area of the IJV, CVP, the SV and the respiratory variation in the inferior vena cava (IVC) were evaluated. The exercise protocol increased the patients' mean SV by 14.5 ± 3.7 mL, and the dehydration protocol caused their mean CVP to fall by 3.75 ± 0.33 cm H2O, which resulted in the collapse index (max IJV area - min IJV area/max IJV area) changing from 0.32 ± 0.04 to 0.44 ± 0.06 and 0.49 ± 0.04, respectively (p < 0.05). The SV exhibited a strong positive correlation with the collapse index (r = 0.59, p = 0.006), and CVP showed a strong positive correlation with the body height-adjusted mean area of the IJV (r = 0.72, p < 0.001). Cardiac variation in the area of the great veins is considered to be induced by venous return to the right atrium under negative pressure. It is possible that intravascular dehydration can be detected and hemodynamic indices, such as CVP and SV, can be estimated by evaluating cardiac variation in the area of the IJV.

Association of initial rhythm with neurologically favorable survival in non-shockable out-of-hospital cardiac arrest without a bystander witness or bystander cardiopulmonary resuscitation.

BACKGROUND: Out-of-hospital cardiac arrest (OHCA) has a predominantly non-shockable rhythm. Non-shockable rhythm, and the absence of a bystander witness or bystander cardiopulmonary resuscitation (CPR) are associated with poor outcomes. However, the association between the type of non-shockable rhythm and outcomes is not well known. OBJECTIVE: To examine the association between the initial rhythm and neurologically favorable outcomes after non-shockable OHCA without a bystander witness or bystander CPR. METHODS: In a nationwide, population-based, cohort study, we analyzed 213,984 adult OHCA patients with a non-shockable rhythm who had neither a bystander witness nor bystander CPR. They were identified through the Japanese national OHCA registry data from January 1, 2005 to December 31, 2010. The primary outcome was neurologically favorable survival. RESULTS: Among 213,984 patients, the initial rhythm was Pulseless Electrical Activity (PEA) in 31,179 patients (14.6%) and Asystole in 182,805 patients (85.4%). The neurological outcome was more favorable in PEA than in Asystole (1.4% vs. 0.2%, p<0.0001). After adjusting for age, sex, etiology of arrest, epinephrine administration, advanced airway management, time from call to contact with patient, and calendar year, PEA was associated with an increased neurologically favorable survival rate (odds ratio 7.86; 95% confidence interval 6.81-9.07). In subgroup analysis stratified by age group (18-64, 65-84, or ≥85years), the neurologically favorable survival rate was ≥1% in PEA, even for patients aged ≥85years, but <1% in Asystole among all age groups. CONCLUSION: PEA and Asystole should not be considered to be identical to non-shockable rhythm, but rather should be clearly distinguished from each other from the perspective of quantitative medical futility.

Potential Survival Benefit of Polymyxin B Hemoperfusion in Septic Shock Patients on Continuous Renal Replacement Therapy: A Propensity-Matched Analysis.

BACKGROUND/AIMS: We assessed the survival benefit of polymyxin B hemoperfusion (PMX) in septic shock patients starting continuous renal replacement therapy (CRRT), who are known to have an increased rate of mortality. METHODS: Adult patients in the Japanese diagnosis procedure combination database satisfying the following criteria were enrolled: hospitalized in 2007-2012; diagnosed as having sepsis; required noradrenaline and/or dopamine; and started CRRT in intensive care unit. Propensity scores for receiving PMX were created from patient and hospital characteristics. RESULTS: Of 3,759 eligible patients, 1,068 received PMX. Propensity-score matching produced a matched cohort of 978 pairs. The 28-day mortality was 40.2% (393/978) in the PMX group and 46.8% (458/978) in the control group (p = 0.003). Logistic regression analysis revealed a significant association between the use of PMX and decreased 28-day mortality (adjusted OR 0.75; 95% CI 0.62-0.91). CONCLUSION: This large retrospective study suggests that septic shock patients starting CRRT may benefit from PMX.

Association of Urinary Neutrophil Gelatinase-Associated Lipocalin With Long-Term Renal Outcomes in ICU Survivors: A Retrospective Observational Cohort Study.

BACKGROUND: Epidemiological studies recently suggested that acute kidney injury (AKI) in intensive care units (ICUs) increases the risk of chronic kidney disease development and progression. However, whether any AKI biomarker can predict long-term renal outcomes in ICU survivors remains unclear. This study was undertaken to elucidate the role of urinary biomarkers for long-term renal outcome prediction after ICU discharge. METHODS: This retrospective observational study examined 495 adult patients who had been admitted to the ICU of the University of Tokyo Hospital. Major adverse kidney events (MAKE): death, incident end-stage renal disease (ESRD), and halving of estimated glomerular filtration rate (eGFR), at hospital discharge and long-term renal outcomes of 30% reduction of eGFR or incident ESRD were evaluated. RESULTS: Among all the enrolled 495 patients, 393 patients were discharged from the hospital without MAKE. Data of eGFR up to two years after ICU discharge were available for 173 patients; 63 patients (36.4%) were positive for long-term renal outcomes. Step-wise logistic regression analysis demonstrated that male sex and urinary neutrophil gelatinase-associated lipocalin (NGAL) measured at ICU admission showed significant associations with long-term renal outcomes. Receiver operating characteristic curve analysis showed the area under the curve of 0.66 (95% confidence interval 0.57-0.74) for prediction of long-term renal outcome by urinary NGAL. CONCLUSION: Urinary NGAL measured at ICU admission was significantly associated with long-term renal outcomes after hospital discharge in MAKE-free ICU survivors. Urinary NGAL measurements at ICU might be useful to identify a high risk population of kidney disease progression after intensive care.

Early lactate clearance for predicting active bleeding in critically ill patients with acute upper gastrointestinal bleeding: a retrospective study.

Not all patients with upper gastrointestinal bleeding (UGIB) require emergency endoscopy. Lactate clearance has been suggested as a parameter for predicting patient outcomes in various critical care settings. This study investigates whether lactate clearance can predict active bleeding in critically ill patients with UGIB. This single-center, retrospective, observational study included critically ill patients with UGIB who met all of the following criteria: admission to the emergency department (ED) from April 2011 to August 2014; had blood samples for lactate evaluation at least twice during the ED stay; and had emergency endoscopy within 6 h of ED presentation. The main outcome was active bleeding detected with emergency endoscopy. Classification and regression tree (CART) analyses were performed using variables associated with active bleeding to derive a prediction rule for active bleeding in critically ill UGIB patients. A total of 154 patients with UGIB were analyzed, and 31.2 % (48/154) had active bleeding. In the univariate analysis, lactate clearance was significantly lower in patients with active bleeding than in those without active bleeding (13 vs. 29 %, P < 0.001). Using the CART analysis, a prediction rule for active bleeding is derived, and includes three variables: lactate clearance; platelet count; and systolic blood pressure at ED presentation. The rule has 97.9 % (95 % CI 90.2-99.6 %) sensitivity with 32.1 % (28.6-32.9 %) specificity. Lactate clearance may be associated with active bleeding in critically ill patients with UGIB, and may be clinically useful as a component of a prediction rule for active bleeding.

Quantitative analysis of high plasma lactate concentration in ED patients after alcohol intake.

INTRODUCTION: Plasma lactate concentration is known to increase after alcohol intake. However, this increase has rarely been analyzed quantitatively in emergency department (ED) settings. Evaluating plasma lactate elevation in ED patients after alcohol intake is important because it can affect patients' evaluation based on the plasma lactate level. METHODS: This study analyzed venous lactate concentrations of 196 continuous patients presented to our ED after alcohol intake. The control group comprised 219 successive ED patients without alcohol intake. Patients who had conditions that might induce lactate elevation were excluded from both groups. RESULTS: Venous lactate concentration was significantly higher in the alcohol intake group (2.83 mmol/L; 95% confidence interval, 2.69-2.96 mmol/L) than in the control group (1.65 mmol/L; 95% confidence interval, 1.53-1.77 mmol/L; P<.05). Lactate concentrations exceeding 3 mmol/L and exceeding 4 mmol/L were found, respectively, in 41.8% and 12.2% of the alcohol intake group compared with in 8.7% and 2.3% of the control group (P<.05). Lactate concentrations do not correlate with patients' level of consciousness. Therefore, a higher plasma ethanol level is apparently unrelated to elevated lactate. DISCUSSION AND CONCLUSION: Analyses show that plasma lactate concentration is significantly higher in ED patients after alcohol intake and to a greater degree than previously reported, even in patients without previously known alcohol-related diseases. Emergency department physicians must be careful when interpreting the lactate level of the patients with alcohol intake.

Apoptosis inhibitor of macrophage protein enhances intraluminal debris clearance and ameliorates acute kidney injury in mice.

Acute kidney injury (AKI) is associated with prolonged hospitalization and high mortality, and it predisposes individuals to chronic kidney disease. To date, no effective AKI treatments have been established. Here we show that the apoptosis inhibitor of macrophage (AIM) protein on intraluminal debris interacts with kidney injury molecule (KIM)-1 and promotes recovery from AKI. During AKI, the concentration of AIM increases in the urine, and AIM accumulates on necrotic cell debris within the kidney proximal tubules. The AIM present in this cellular debris binds to KIM-1, which is expressed on injured tubular epithelial cells, and enhances the phagocytic removal of the debris by the epithelial cells, thus contributing to kidney tissue repair. When subjected to ischemia-reperfusion (IR)-induced AKI, AIM-deficient mice exhibited abrogated debris clearance and persistent renal inflammation, resulting in higher mortality than wild-type (WT) mice due to progressive renal dysfunction. Treatment of mice with IR-induced AKI using recombinant AIM resulted in the removal of the debris, thereby ameliorating renal pathology. We observed this effect in both AIM-deficient and WT mice, but not in KIM-1-deficient mice. Our findings provide a basis for the development of potentially novel therapies for AKI.

IMPACT OF CONTINUOUS RENAL REPLACEMENT THERAPY INTENSITY ON SEPTIC ACUTE KIDNEY INJURY.

The intensity of continuous renal replacement therapy (CRRT) for acute kidney injury (AKI) has been evaluated, but recent randomized clinical trials have failed to demonstrate a beneficial impact of high intensity on the outcomes. High intensity might cause some detrimental results recognized recently as CRRT trauma. This study was undertaken to evaluate the association of CRRT intensity with mortality in a population of AKI patients treated with lower-intensity CRRT in Japan. A retrospective single-center cohort study enrolled 125 AKI patients treated with CRRT in mixed intensive care units of a university hospital in Japan. Subanalysis was conducted for septic and postsurgical AKI. The median value of the prescribed total effluent rate was 20.1 (interquartile range 15.3-27.1) mL/kg/h. Overall, univariate Cox regression analysis indicated no association of the CRRT intensity with the 60-day in-hospital mortality rate (hazard ratio 1.006, 95% confidence interval [CI] 0.991-1.018, P = 0.343). In subanalysis with the septic AKI patients, multivariate analysis revealed two factors associated independently with the 60-day mortality rate: the Sequential Organ Failure Assessment score at initiation of CRRT (hazard ratio 1.152, 95% CI 1.025-1.301, P = 0.0171) and the CRRT intensity (hazard ratio 1.024, 95% CI 1.004-1.042, P = 0.0195). The CRRT intensity was associated significantly with higher 60-day in-hospital mortality in septic AKI, suggesting that unknown detrimental effects of CRRT with high-intensity CRRT might worsen the outcomes in septic AKI patients.

Organ System Network Disruption in Nonsurvivors of Critically Ill Patients.

OBJECTIVES: As interactions of each organ system have been conceptually known to play an important role during life-threatening conditions, we quantitatively evaluated the organ system interactions in critically ill patients and examined the difference in the organ system network structure between the survivors and the nonsurvivors. DESIGN: Prospective observational study. SETTINGS: An ICU of a university hospital. PATIENTS: Two hundred and eighty-two patients who were admitted to the ICU. INTERVENTIONS: Blood samples were obtained at ICU admission. MEASUREMENTS AND MAIN RESULTS: We analyzed the associations among nine representative laboratory variables of each organ system using network analysis. We compared the network structure of the variables in the 40 nonsurvivors with that in the 40 survivors. Their baseline characteristics, including the degree of organ dysfunction, were matched using propensity score matching method. Network structure was quantitatively evaluated using edge (significant correlation among variables evaluated by the p value), weight (connective strength of edge evaluated by coefficient), and cluster (group with tight connection evaluated by edge betweenness). The number of edges among the nine variables was significantly fewer for the nonsurvivors than for the severity-matched survivors (3 vs 12; p = 0.035). The mean weight of edges was significantly smaller for the nonsurvivors (0.055 vs 0.119; p = 0.007). The nine laboratory variables for the nonsurvivors were divided into a significantly larger number of clusters (7 vs 2; p = 0.001). Statistical conclusions were preserved with Bonferroni multiple comparison procedure. These findings were consistently observed in comparison of the 40 nonsurvivors with all the survivors. CONCLUSIONS: This study, as a preliminary proof-of-concept, quantitatively demonstrated a more disrupted network structure of organ systems in the nonsurvivors compared with that in the survivors. These observations suggest the necessity of assessment for organ system interactions to evaluate critically ill patients.

Erythropoietin concentration in acute kidney injury is associated with insulin-like growth factor-binding protein-1.

AIM: Erythropoietin (EPO) production is stimulated by hypoxia in the kidney. Ischaemic injury plays a crucial role in the pathogenesis of acute kidney injury (AKI). However, EPO concentrations in critically ill patients complicated with AKI have not been evaluated sufficiently. This study was conducted to clarify the factors associated with plasma EPO concentrations in AKI. METHODS: This study prospectively enrolled 98 critically ill adult patients treated at the adult mixed ICU. Plasma EPO, insulin-like growth factor-binding protein-1 (IGFBP-1), neutrophil gelatinase-associated lipocalin (NGAL), interleukin-6 (IL-6) and urinary N-acetyl-ß-D-glucosaminidase (NAG) were measured on ICU admission. RESULTS: Acute kidney injury occurred in 42 (42.9%) patients. Significantly higher plasma EPO in the AKI group was detected than in the non-AKI group (16.13 (9.87-28.47) mIU/mL versus 27.81 (10.16-106.02) mIU/mL, P < 0.05). Plasma IGFBP-1 in the AKI group was also significantly higher than in the non-AKI group (19 208 (8820-50 780) pg/mL versus 63 199 (25 289-147 489) pg/mL, P < 0.05). Plasma EPO concentration was negatively correlated with haemoglobin in the non-AKI group with statistical significance, but not in the AKI group. Multiple logistic regression analysis revealed that plasma EPO in the AKI group was associated significantly with plasma IGFBP-1 and complication of diabetes mellitus, but not the haemoglobin concentration, partial pressure of arterial oxygen (PaO2 ), and IL-6. CONCLUSIONS: Not low arterial oxygen tension, haemoglobin concentration, and inflammation evaluated by IL-6 but plasma IGFBP-1 was significantly associated with plasma EPO concentration in AKI, suggesting an unknown mechanism related to systemic stress conditions for EPO regulation in AKI.