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.

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.

Outcomes of Argatroban Treatment in Patients With Atherothrombotic Stroke: Observational Nationwide Study in Japan.

BACKGROUND AND PURPOSE: Argatroban, a selective thrombin inhibitor, is recommended for the use in patients with atherothrombotic stroke by the Japanese Guidelines for the Management of Patients with Acute Ischemic Stroke. We performed a nationwide Japanese study to investigate whether argatroban improved early stroke outcomes in patients with acute atherothrombotic stroke. METHODS: This retrospective observational study, using the Diagnosis Procedure Combination database in Japan, included patients who were hospitalized from July 1, 2010, to March 31, 2012, with a diagnosis of atherothrombotic stroke within 1 day of stroke onset. Patients were divided into 2 groups: those receiving argatroban on admission (argatroban group), and those who did not receive argatroban during hospitalization (control group). To balance the baseline characteristics and concomitant treatments during hospitalization between the 2 groups, one-to-one propensity-score matching analyses were performed. The main outcomes were the modified Rankin Scale score at discharge and the occurrence of hemorrhagic complications during hospitalization. An ordinal logistic regression analysis evaluated the association between argatroban use and modified Rankin Scale at discharge. RESULTS: After propensity-score matching, 2289 pairs of patients were analyzed. There were no significant differences in modified Rankin Scale at discharge between the argatroban and the control groups (adjusted odds ratio, 1.01; 95% confidence interval, 0.88-1.16). The occurrence of hemorrhagic complications did not differ significantly between the argatroban and the control groups (3.5% versus 3.8%; P=0.58). CONCLUSIONS: The present study suggested that argatroban was safe, but had no added benefit in early outcomes after acute atherothrombotic stroke.

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.

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.

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.

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.

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.

Regulation of Mitochondrial Dynamics by Dynamin-Related Protein-1 in Acute Cardiorenal Syndrome.

Experimental evidence has clarified distant organ dysfunctions induced by AKI. Crosstalk between the kidney and heart, which has been recognized recently as cardiorenal syndrome, appears to have an important role in clinical settings, but the mechanisms by which AKI causes cardiac injury remain poorly understood. Both the kidney and heart are highly energy-demanding organs that are rich in mitochondria. Therefore, we investigated the role of mitochondrial dynamics in kidney-heart organ crosstalk. Renal ischemia reperfusion (IR) injury was induced by bilateral renal artery clamping for 30 min in 8-week-old male C57BL/6 mice. Electron microscopy showed a significant increase of mitochondrial fragmentation in the heart at 24 h. Cardiomyocyte apoptosis and cardiac dysfunction, evaluated by echocardiography, were observed at 72 h. Among the mitochondrial dynamics regulating molecules, dynamin-related protein 1 (Drp1), which regulates fission, and mitofusin 1, mitofusin 2, and optic atrophy 1, which regulate fusion, only Drp1 was increased in the mitochondrial fraction of the heart. A Drp1 inhibitor, mdivi-1, administered before IR decreased mitochondrial fragmentation and cardiomyocyte apoptosis significantly and improved cardiac dysfunction induced by renal IR. This study showed that renal IR injury induced fragmentation of mitochondria in a fission-dominant manner with Drp1 activation and subsequent cardiomyocyte apoptosis in the heart. Furthermore, cardiac dysfunction induced by renal IR was improved by Drp1 inhibition. These data suggest that mitochondrial fragmentation by fission machinery may be a new therapeutic target in cardiac dysfunction induced by AKI.

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.

Current state of continuous renal replacement therapy for acute kidney injury in Japanese intensive care units in 2011: analysis of a national administrative database.

BACKGROUND: Nationwide data for the prevalence and outcomes of patients receiving continuous renal replacement therapy (CRRT) in intensive care units (ICUs) are scarce. This study assessed the status of CRRT in Japanese ICUs using a nationwide administrative claim database. METHODS: Data were extracted from the Japanese Diagnosis Procedure Combination database for 2011. From a cohort of critically ill patients aged 12 years or older who were admitted to ICUs for 3 days or longer, acute kidney injury (AKI) patients treated with CRRT were identified. The period prevalence of CRRT and in-hospital mortality were calculated. Logistic regression analysis identified factors associated with in-hospital mortality. RESULTS: Of 165 815 ICU patients, 6478 (3.9%) received CRRT for AKI. The most frequent admission diagnosis category was diseases of the circulatory system (n = 3074). The overall in-hospital mortality rate of the CRRT-treated AKI patients was 50.6%. Clustering patients into four groups by background revealed the lowest in-hospital mortality rate of 41.5% for the cardiovascular surgery group (n = 1043) compared with 53.5% for the nonsurgical cardiovascular group (n = 2031), 51.7% for the sepsis group (n = 1863) and 51.6% for other cases (n = 1541). Multiple logistic regression analysis showed a significant association of these four group classifications with in-hospital mortality in addition to age, hospital characteristics (type and volume), time from hospital admission to CRRT initiation and interventions performed on the day of CRRT initiation. CONCLUSIONS: Using a large Japanese nationwide database, this study revealed remarkably high in-hospital mortality of CRRT-treated AKI patients, although the period prevalence of CRRT for AKI in ICUs was low.

Ratio of urine and blood urea nitrogen concentration predicts the response of tolvaptan in congestive heart failure.

AIM: This study was conducted to evaluate the performance of the ratio of urine and blood urea nitrogen concentration (UUN/BUN) as a new predictive factor for the response of an arginine vasopressin receptor 2 antagonist tolvaptan (TLV) in decompensated heart failure patients. METHODS: This study enrolled 70 decompensated heart failure patients who were administered TLV at University of Tokyo Hospital. We collected the data of clinical parameters including UUN/BUN before administering TLV. Two different outcomes were defined as follows: having over 300 mL increase in urine volume on the first day (immediate urine output response) and having any decrease in body weight within one week after starting TLV treatment (subsequent clinical response). RESULTS: Among the 70 enrolled patients, 37 patients (52.9%) showed immediate urine output response; 51 patients (72.9%) showed a subsequent clinical response of body weight decrease. Receiver operating characteristics (ROC) analysis showed good prediction by UUN/BUN for the immediate response (AUC-ROC 0.86 [0.75-0.93]) and a significantly better prediction by UUN/BUN for the subsequent clinical response compared with urinary osmolality (AUC-ROC 0.78 [0.63-0.88] vs. 0.68 [0.52-0.80], P < 0.05). CONCLUSIONS: We demonstrated that a clinical parameter of UUN/BUN can predict the response of TLV even when measured before TLV administration. UUN/BUN might enable identification of good responders for this new drug.

A healthy young woman with massive hemorrhagic ascites.

Retrograde menstruation is the backward movement of menstrual fluids. The underlying mechanisms remain unknown. The converse current itself is benign, but the result can be abdominal pain caused by peritoneal irritation and, eventually, endometriosis. The case was of a 25-year-old woman with lower abdominal pain accompanied by significant hemoperitoneum. Physical examination and inspection using abdominal ultrasonography and computed tomography failed to reveal a differential diagnosis. Detailed history taking revealed sexual activities during her menstrual period, which allowed for a diagnosis of retrograde menstruation. These findings emphasize the importance of extensive history taking.

The contributions of emergency physicians to out-of-hospital cardiopulmonary arrest: an analysis of the national Utstein Registry data.

BACKGROUND: Emergency physicians are likely to play an important role in the "chain of survival." The relationship between the number of emergency physicians and out-of-hospital cardiopulmonary arrest (OHCA) prognosis is not well understood. OBJECTIVE: We assessed the impact of the number of emergency physicians on the outcomes of OHCA. METHODS: In a nationwide, population-based, observational study, we enrolled 120,721 adults aged ≥ 18 years with OHCA, from January 1, 2010 to December 31, 2010. We used the countrywide Utstein Registry database coupled with health statistics data surveyed by the Ministry of Health, Labour and Welfare. The primary endpoint was favorable neurological outcomes 1 month after OHCA. RESULTS: During the study period, OHCA occurred in 25,580 people (21.2%) in an area with the number of emergency physicians/100,000 population < 1.5, in 62,299 people (51.6%) in an area with ≥ 1.5 and < 3.0 emergency physicians/100,000 population, in 30,948 people (25.6%) in an area with ≥ 3.0 and < 4.5 emergency physicians/100,000 population, and in 1894 people (1.6%) in an area with ≥ 4.5 emergency physicians/100,000 population. Patient prognosis became more favorable as the number of emergency physicians increased (1-month survival: 5.08% vs. 5.81% vs. 5.90% vs. 8.82%, p < 0.0001; and favorable neurological outcomes: 2.64% vs. 2.84% vs. 3.23% vs. 3.54%, p < 0.0001; for emergency physicians/100,000 population of < 1.5, ≥ 1.5 and < 3.0, ≥ 3.0 and < 4.5, and ≥ 4.5, respectively). The adjusted odds ratio for favorable neurological outcomes per increase of one emergency physician/100,000 population was 1.06 (95% confidence interval 1.01-1.11, p = 0.0163). CONCLUSION: An increased number of emergency physicians/100,000 population is likely to be associated with improved outcomes.

Effective pre-hospital care for out-of-hospital cardiac arrest caused by respiratory disease.

BACKGROUND: The relationship between pre-hospital care and the prognosis of out-of-hospital cardiac arrest (OHCA) caused by respiratory disease is unclear. This study aimed to assess the impact of pre-hospital care on the prognosis of OHCA caused by respiratory disease. METHODS: In a nationwide, population-based, observational study, we enrolled 121,081 adults aged ≥18 years who experienced OHCA from January 1, 2010, to December 31, 2010. The primary endpoint was favourable neurological outcomes. RESULTS: Of the 120,256 eligible adult OHCA patients, 7,071 (5.9%) experienced OHCA caused by respiratory disease. Of these 7,071 patients, 3,911 (55.3%) received no cardiopulmonary resuscitation (CPR), 2,403 (34.0%) received chest-compression-only CPR, and 757 (10.7%) received conventional CPR by a bystander. There was no significant difference between the three types of bystander CPR with regard to the neurological outcome (no CPR: OR 0.68, 95%CI 0.39-1.24, p=0.1951; chest-compression-only CPR: OR 0.68, 95%CI 0.37-1.29, p=0.2295; and conventional CPR: as a reference). Pre-hospital administration of epinephrine (OR 0.37, 95%CI 0.13-0.85, p=0.0170) and the implementation of advanced airway management (OR 0.32, 95%CI 0.19-0.52, p<0.0001) were associated with poor neurological outcomes. CONCLUSIONS: Even in OHCA caused by respiratory disease, not only pre-hospital epinephrine administration but also pre-hospital advanced airway management and rescue breathing in bystander CPR may not be critical.

The high-mobility group protein B1-Toll-like receptor 4 pathway contributes to the acute lung injury induced by bilateral nephrectomy.

Acute lung injury and acute kidney injury are severe complications in critically ill patients and synergistically increase mortality in intensive care units. Organ cross-talk between the kidney and the lung has been implicated recently as amplifying injury in each organ. Here we sought to identify a possible mechanism of acute kidney injury-induced acute lung injury using a mouse bilateral nephrectomy model. Toll-like receptor 4 (TLR4)-mutant C3H/HeJ mice were more resistant to lung injury including neutrophil infiltration, increased neutrophil elastase activity, and vascular permeability caused by bilateral nephrectomy compared with TLR4-wild-type C3H/HeN mice 6 h after surgery. High-mobility group protein B1 (HMGB1) is one agonist for TLR4. Its blood concentrations were increased significantly by bilateral nephrectomy. Blockade of HMGB1 by neutralizing antibody reduced neutrophil infiltration in TLR4-wild-type C3H/HeN but not in TLR4-mutant C3H/HeJ mice. However, HMGB1 blockade in a renal ischemia reperfusion model reduced pulmonary neutrophil infiltration independent from TLR4. Thus, an enhanced HMGB1-TLR4 pathway contributes to lung injury induced by bilateral nephrectomy and the other HMGB1-dependent pathway exists in pulmonary neutrophil infiltration caused by renal ischemia reperfusion. Targeting the HMGB1-TLR4 pathway might enable development of a new therapeutic strategy to improve the outcomes of severely ill patients with both acute lung and acute kidney injury.

Postoperative polymyxin B hemoperfusion and mortality in patients with abdominal septic shock: a propensity-matched analysis.

OBJECTIVES: To examine the effect of postoperative polymyxin B hemoperfusion on mortality in patients with abdominal septic shock triggered by lower gastrointestinal tract perforation, identifying subpopulations of patients who may benefit from this treatment. DESIGN: Propensity-matched analysis. SETTING: We used a nationwide inpatient database in Japan. PATIENTS: We included patients who are 18 years old or older hospitalized during a period of 34 months between July 2007 and October 2011, who had open abdominal surgery on the day of admission (day 0) for perforation of lower gastrointestinal tract, and who required noradrenaline and/or dopamine. We excluded patients who died on day 0 or 1 and patients starting polymyxin B hemoperfusion on day 2 or later. MEASUREMENTS AND MAIN RESULTS: The main outcome was 28-day mortality. Of 2,925 eligible patients, 642 received one or two polymyxin B hemoperfusion sessions, starting the first one on day 0 or 1. Propensity score matching created a matched cohort of 1,180 patients (590 pairs with and without polymyxin B hemoperfusion). The 28-day mortality was 17.1% (101 of 590) in the polymyxin B hemoperfusion group and 16.3% (96 of 590) in the control group (p = 0.696). Subgroup analyses by number of polymyxin B hemoperfusion sessions (one or two), timing of polymyxin B hemoperfusion initiation (day 0 or 1), the use of noradrenaline, and number of dysfunctional organs (one to six) did not show any significant difference in 28-day mortality between the groups. Multiple logistic did not show a significant association between the use of polymyxin B hemoperfusion and 28-day mortality (adjusted odds ratio, 1.10; 95% CI, 0.80-1.51; p = 0.569). Age, end-stage renal disease requiring maintenance hemodialysis, the use of noradrenaline, and number of dysfunctional organs were positively associated with 28-day mortality. CONCLUSIONS: In this retrospective study, postoperative polymyxin B hemoperfusion did not show any survival benefit for the overall study population or any of the studied subgroups of patients with abdominal septic shock. A large multicentered prospective randomized trial is warranted to identify the true role of polymyxin B hemoperfusion in sepsis caused by Gram-negative bacteria.

Repulsive guidance cue semaphorin 3A in urine predicts the progression of acute kidney injury in adult patients from a mixed intensive care unit.

BACKGROUNDS: Predicting the development of acute kidney injury (AKI) in the critical care setting is challenging. Although several biomarkers showed somewhat satisfactory performance for detecting established AKI even in a heterogeneous disease-oriented population, identification of new biomarkers that predict the development of AKI accurately is urgently required. METHODS: A single-center prospective observational cohort study was undertaken to evaluate for the first time the reliability of the newly identified biomarker semaphorin 3A for AKI diagnosis in heterogeneous intensive care unit populations. In addition to five urinary biomarkers of L-type fatty acid-binding protein (L-FABP), neutrophil gelatinase-associated lipocalin (NGAL), IL-18, albumin and N-acetyl-ß-d-glucosaminidase (NAG), urinary semaphorin 3A was measured at intensive care unit (ICU) admission. RESULTS AND CONCLUSION: Three hundred thirty-nine critically ill adult patients were recruited for this study. Among them, 131 patients (39%) were diagnosed with AKI by the RIFLE criteria and 66 patients were diagnosed as AKI at post-ICU admission (later-onset AKI). Eighty-four AKI patients showed worsening severity during 1 week observation (AKI progression). Although L-FABP, NGAL and IL-18 showed significantly higher area under the curve (AUC)-receiver operating characteristic (ROC) values than semaphorin 3A in detecting established AKI, semaphorin 3A was able to detect later-onset AKI and AKI progression with similar AUC-ROC values compared with the other five biomarkers [AUC-ROC (95% CI) for established AKI 0.64 (0.56-0.71), later-onset AKI 0.71 (0.64-0.78), AKI progression 0.71 (0.64-0.77)]. Urinary semaphorin 3A was not increased in non-progressive established AKI, while the other biomarkers were elevated regardless of further progression. Finally, sepsis did not have any impact on semaphorin 3A while the other urinary biomarkers were increased with sepsis. Semaphorin 3A is a new biomarker of AKI which may have a distinct predictive use for AKI progression when compared with other AKI biomarkers.

Mortality prediction by acute kidney injury biomarkers in comparison with serum creatinine.

OBJECTIVES: To investigate the performance of acute kidney injury (AKI) biomarkers for mortality prediction. MATERIALS AND METHODS: Cutoff values of urinary L-type fatty acid-binding protein (L-FABP) and N-acetyl-ß-d-glucosaminidase (NAG) for AKI diagnosis in ICU were determined in the derivation cohort. The performance of these AKI biomarkers for mortality prediction was evaluated in the validation cohort with stratification of serum-creatinine based AKI diagnosis. RESULTS: Mortality in the AKI patients diagnosed by serum creatinine was increased remarkably when urinary L-FABP and NAG were positive. CONCLUSIONS: These AKI biomarkers can specifically detect high-risk patients among creatinine-base diagnosed AKI.

Perioperative plasma neutrophil gelatinase-associated lipocalin measurement in patients who undergo left ventricular assist device implantation surgery.

BACKGROUND: Perioperative complication of end-organ injury including acute kidney injury (AKI) is a frequent and severe problem for patients undergoing left ventricular assist device (LVAD) implantation. This study evaluated an emerging AKI biomarker, plasma neutrophil gelatinase-associated lipocalin (NGAL), in a LVAD implantation cohort. METHODS AND RESULTS: Of 31 LVAD implantation patients enrolled to this study, 17 (55%) patients were diagnosed as having AKI. Six AKI patients showed severe AKI requiring renal replacement therapy (RRT). Plasma NGAL values in the AKI-with-RRT group (n=6) were significantly higher than that in other patients, although the AKI-without-RRT (n=11) group showed a similar level of plasma NGAL to that of the non-AKI group (n=14). Multiple logistic regression analysis revealed that plasma NGAL measured at pre-operation and central venous pressure at pre-operation and 12 h after surgery independently discriminated against postoperative RRT requirement. In the AKI-with-RRT group, plasma NGAL decreased before termination of RRT in 4 patients who eventually showed renal recovery, although no decline of plasma NGAL was observed in 2 patients who showed no recovery of renal function. Removal of blood NGAL by continuous hemodiafiltration was shown to be 70-75% lower than that of creatinine. CONCLUSIONS: Measurement of perioperative plasma NGAL is useful for predicting severe AKI requiring RRT and renal recovery in patients who have had LVAD implantation surgery. Further investigation is necessary to confirm these findings because this study examined a low number of patients.