Trajectory pattern of serially measured acute kidney injury biomarkers in critically ill patients: a prospective observational study.

BACKGROUND: The clinical value of the trajectory of temporal changes in acute kidney injury (AKI) biomarkers has not been well established among intensive care unit (ICU) patients. METHODS: This is a single-center, prospective observational study, performed at a mixed ICU in a teaching medical institute in Tokyo, Japan. Adult ICU patients with an arterial line and urethral catheter were enrolled from September 2014 to March 2015. Patients who stayed in the ICU for less than 48 h and patients with known end-stage renal disease were excluded from the study. Blood and urine samples were collected for measurement of AKI biomarkers at 0, 12, 24, and 48 h after ICU admission. The primary outcome was major adverse kidney events (MAKE) at discharge, defined as a composite of death, dialysis dependency, and persistent loss of kidney function (≥ 25% decline in eGFR). RESULTS: The study included 156 patients. Serum creatinine-based estimated glomerular filtration rate (eGFR), plasma neutrophil gelatinase-associated lipocalin (NGAL), and urinary liver-type fatty acid-binding protein (uL-FABP) were serially measured and each variable was classified into three groups based on group-based trajectory modeling analysis. While the trajectory curves moved parallel to each other (i.e., "low," "middle," and "high") for eGFR and plasma NGAL, the uL-FABP curves showed distinct trajectory patterns and moved in different directions ("low and constant," "high and exponential decrease," and "high and exponential increase"). These trajectory patterns were significantly associated with MAKE. MAKE occurred in 16 (18%), 16 (40%), and 9 (100%) patients in the "low and constant," "high and exponential decrease," and "high and exponential increase" groups, respectively, based on uL-FABP levels (p-value < 0.001). The initial value and the 12-h change in uL-FABP were both significantly associated with MAKE, even after adjusting for eGFR [Odds ratio (95% confidence interval): 1.45 (1.17-1.83) and 1.43 (1.12-1.88) for increase of initial value and 12-h change of log-transformed uL-FABP by 1 point, respectively]. CONCLUSIONS: Trajectory pattern of serially measured urinary L-FABP was significantly associated with MAKE in ICU patients.

Tachycardia and Acute Kidney Injury among Critically Ill Patients with Sepsis: A Prospective Observational Study.

INTRODUCTION: Tachycardia caused by sympathetic overactivity impairs myocardial function and raises septic patients' mortality. This study examined whether tachycardia is associated with acute kidney injury (AKI) period-prevalence among critically ill patients with and without sepsis. METHODS: In 328 patients (119 sepsis and 209 non-sepsis) admitted to our intensive care unit (ICU), we assessed heart rate at ICU admission, plasma neutrophil gelatinase-associated lipocalin (NGAL) and N-terminal pro-B-type natriuretic peptide, and urinary L-type fatty acid-binding protein and N-acetyl-ß-d-glucosaminidase (NAG) at 0 and 48 h after admission. Tachycardia was defined as a heart rate above 100 beats/min. RESULTS: Tachycardia was independently correlated with AKI prevalence during the first week after ICU admission in the septic patients, but not in the non-septic patients. A dose-dependent increase in AKI period-prevalence was observed across ascending heart rate ranges. Furthermore, we discovered a dose-dependent increase in renal biomarker-positive patients regarding plasma NGAL and urinary NAG over increasing heart rate ranges 48 h after admission. CONCLUSION: The findings revealed an independent relationship between tachycardia and AKI prevalence during the first week of ICU in septic patients. Heart rate was found to have a dose-dependent effect on AKI prevalence and renal insult monitored by biomarkers.

Impact of renal dysfunction on the diagnosis of acute pancreatitis using urinary trypsinogen-2: A retrospective study.

AIM: Early diagnosis of acute pancreatitis is crucial, and urinary trypsinogen has been recently reported as a useful biomarker for diagnosing acute pancreatitis. We aimed to evaluate the impact of renal dysfunction on the diagnostic performance of urinary trypsinogen-2 for acute pancreatitis. METHODS: We conducted a retrospective study using the clinical data of patients who visited the Department of Emergency and Critical Care at the University of Tokyo Hospital between 1 October, 2021, and 30 June, 2022. Patients with available data on qualitative urinary trypsinogen-2 levels were identified. We compared the urinary trypsinogen-2 levels among patients who were clinically diagnosed with acute pancreatitis. We further stratified the patients according to renal function parameters, such as serum creatinine level, blood urea nitrogen level, and estimated glomerular filtration rate, and evaluated the performance of urinary trypsinogen-2 as a biomarker for acute pancreatitis. RESULTS: Within 9 months, 35 patients were identified. Of them, 22 patients showed positive results and 13 showed negative results on the urinary trypsinogen-2 test. The sensitivity, specificity, positive predictive value, and negative predictive value were 0.80, 0.40, 0.18, and 0.92, respectively. Based on the blood urea nitrogen level and estimated glomerular filtration rate, the prevalence of false-positive results was significantly higher in patients with reduced renal function than in those with normal renal function. CONCLUSION: In patients with reduced renal function, the urinary trypsinogen-2 qualitative test results might be interpreted with caution when used for diagnosing acute pancreatitis.

Changes in carbon dioxide production and oxygen uptake evaluated using indirect calorimetry in mechanically ventilated patients with sepsis.

BACKGROUND: Several clinical guidelines recommend monitoring blood lactate levels and central venous oxygen saturation for hemodynamic management of patients with sepsis. We hypothesized that carbon dioxide production (VCO2) and oxygen extraction (VO2) evaluated using indirect calorimetry (IC) might provide additional information to understand the dynamic metabolic changes in sepsis. METHODS: Adult patients with sepsis who required mechanical ventilation in the intensive care unit (ICU) of our hospital between September 2019 and March 2020 were prospectively enrolled. Sepsis was diagnosed according to Sepsis-3. Continuous measurement of VCO2 and VO2 using IC for 2 h was conducted within 24 h after tracheal intubation, and the changes in VCO2 and VO2 over 2 h were calculated as the slopes by linear regression analysis. Furthermore, temporal lactate changes were evaluated. The primary outcome was 28-day survival. RESULTS: Thirty-four patients with sepsis were enrolled, 26 of whom survived 76%. Significant differences in the slope of VCO2 (- 1.412 vs. - 0.446) (p = 0.012) and VO2 (- 2.098 vs. - 0.851) (p = 0.023) changes were observed between non-survivors and survivors. Of note, all eight non-survivors and 17 of the 26 survivors showed negative slopes of VCO2 and VO2 changes. For these patients, 17 survivors had a median lactate of - 2.4% changes per hour (%/h), whereas non-survivors had a median lactate of 2.6%/hr (p = 0.023). CONCLUSIONS: The non-survivors in this study showed temporal decreases in both VCO2 and VO2 along with lactate elevation. Monitoring the temporal changes in VCO2 and VO2 along with blood lactate levels may be useful in predicting the prognosis of sepsis.

Pulse oximetry-based capillary refilling evaluation predicts postoperative outcomes in liver transplantation: a prospective observational cohort study.

BACKGROUND: Capillary refill time (CRT) is a non-invasive technique to evaluate tissue perfusion, and quantitative CRT (Q-CRT) adapted to pulse oximetry was developed with patients with sepsis and compared to blood lactate and sepsis scores. In post liver transplantation, large amounts of fluid administration are necessary for maintaining tissue perfusion to grafted liver against intravascular hypovolemia. This study aimed to evaluate whether Q-CRT can predict poor outcomes by detecting peripheral tissue perfusion abnormality in patients with liver transplantations who were treated with massive fluid administration. METHODS: In this single-center prospective cohort study, we enrolled adult patients with liver transplantations between June 2018 and July 2019. Measurement of Q-CRT was conducted at intensive care units (ICU) admission and postoperative day 1 (POD1). RESULTS: A total of 33 patients with liver transplantations were enrolled. Significant correlations of Q-CRT and ΔAb, a tissue oxygen delivery parameter calculated by pulse oximetry data, at ICU admission with the postoperative outcomes such as length of ICU and hospital stay and total amount of ascitic fluid discharge were observed. Quantitative CRT and ΔAb at ICU admission were significantly associated with these postoperative outcomes, even after adjusting preoperative and operative factors (MELD score and bleeding volume, respectively). However, quantitative CRT and ΔAb at POD1 and changes from ICU admission to POD1 failed to show significant associations. CONCLUSIONS: Q-CRT values were significantly associated with postoperative outcomes in liver transplantation. Although the mechanisms of this association need to be clarified further, Q-CRT may enable identification of high-risk patients that need intensive postoperative managements.

Organ system network analysis and biological stability in critically ill patients.

BACKGROUND: Continuous coordination among organ systems is necessary to maintain biological stability in humans. Organ system network analysis in addition to organ-oriented medicine is expected to improve patient outcomes. However, organ system networks remain beyond clinical application with little evidence for their importance on homeostatic mechanisms. This proof-of-concept study examined the impact of organ system networks on systemic stability in severely ill patients. METHODS: Patients admitted to the intensive care unit of the University of Tokyo Hospital with one representative variable reflecting the condition of each of the respiratory, cardiovascular, renal, hepatic, coagulation, and inflammatory systems were enrolled. Relationships among the condition of individual organ systems, inter-organ connections, and systemic stability were evaluated between non-survivors and survivors whose organ system conditions were matched to those of the non-survivors (matched survivors) as well as between non-survivors and all survivors. We clustered these six organ systems using principal component analysis and compared the dispersion of the principal component scores of each cluster using the Ansari-Bradley test to evaluate systemic stability involving multiple organ systems. Inter-organ connections were evaluated using Spearman's rank test. RESULTS: Among a total of 570 enrolled patients, 91 patients died. The principal component analysis yielded the respiratory-renal-inflammatory and cardiovascular-hepatic-coagulation system clusters. In the respiratory-renal-inflammatory cluster, organ systems were connected in both the survivors and the non-survivors. The principal component scores of the respiratory-renal-inflammatory cluster were dispersed similarly (stable cluster) in the non-survivors, the matched survivors, and the total survivors irrespective of the severity of individual organ system dysfunction. Conversely, in the cardiovascular-hepatic-coagulation cluster, organ systems were connected only in the survivors, and the principal component scores of the cluster were significantly dispersed (unstable cluster) in the non-survivors compared to the total survivors (P = 0.002) and the matched survivors (P = 0.004). CONCLUSIONS: This study demonstrated that systemic instability was closely associated with network disruption among organ systems irrespective of their dysfunction severity. Organ system network analysis is necessary to improve outcomes in severely ill patients.

Modest Impact of Serial Measurements of Acute Kidney Injury Biomarkers in an Adult Intensive Care Unit.

BACKGROUND/AIMS: Acute kidney injury (AKI) biomarkers have been developed with the aim of being able to detect kidney damage earlier than the detection process based on serum creatinine levels. However, single time-point measurements appear to furnish insufficient information for detecting and predicting AKI in intensive care unit patients who are frequently affected by multiple and transient/persistent renal insults. We evaluated whether serial measurements enable the prediction of AKI outcomes in such patients. METHODS: Serial measurements of AKI biomarkers, including plasma and urinary neutrophil gelatinase-associated lipocalin, urinary L-type fatty acid-binding protein, and urinary N-acethyl-ß-D-glucosaminidase, at intensive care unit (ICU) admission (d1) and 24 h later (d2) were performed for critically ill adult patients in a mixed ICU. We assessed whether each biomarker could predict newly developed AKI, recovery from AKI, worsening of AKI, and hospital mortality. RESULTS: Among the enrolled 272 patients, 33 were determined to show newly developed AKI after ICU admission, 58 showed worsening of AKI, 57 recovered from AKI, and 38 died in the hospital. ROC analysis showed that biomarkers at day 2 provided no significant additional benefit in predicting the above-mentioned AKI outcomes compared with those at day 1. However, net reclassification improvement analysis demonstrated that adding day 2 biomarkers to the clinical model comprising clinical variables along with day 1 biomarkers significantly improved the prediction of these AKI outcomes. CONCLUSION: Serial measurement of AKI biomarkers used in clinical models could contribute to the prediction of AKI outcomes in a heterogeneous cohort of adult mixed ICU patients, although its reliability seemed to be modest.

Interface design dividing physical findings into medical and trauma findings facilitates clinical document entry in the emergency department: A prospective observational study.

PURPOSE: The interface design and its effect on workflow are key determinants of the usability of electronic medical records (EMRs) in the emergency department (ED). However, whether the overall clinical care can be improved by dividing the interface design of physical findings into medical and trauma findings is unknown. We previously developed an EMR system in which the checkpoints were separated into different sections according to the body part. Herein, we modified this EMR system by remaking the interface design specifically for trauma patients, and evaluated its performance. METHODS: This study was undertaken in a single-center ED between October 2014 and September 2015. In the modified EMR system, all trauma findings are displayed together on the screen, according to the Japan Advanced Trauma Evaluation and Care. We compared the time to final documentation entry and the length of ED stay between the previous (used in the first 6 months) and current systems (used in the latter 6 months). Furthermore, we stratified the patients by triage levels. RESULTS: The study involved 2141 patients (934 and 1207 assessed using the previous and modified EMR systems, respectively). The modified EMR in trauma patients significantly decreased the time to final documentation entry from 131.5 [interquartile range, 86.8-207.3] to 115 [78.8-161] min (p = 0.049). When stratifying trauma patients by triage level, significantly shorter clinical documentation times were observed with the modified EMR system in levels 2 (emergency) and 3 (urgent). CONCLUSIONS: Using different interfaces for trauma findings shortened the time for clinical documentation for trauma patients.

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.

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.

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.

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.

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.

Acute respiratory distress syndrome (ARDS) treated successfully by veno-venous extracorporeal membrane oxygenation (ECMO) in a nearly drowned patient.

This report highlights about one acute respiratory distress syndrome (ARDS) case after near-drowning resuscitated using extracorporeal membrane oxygenation (ECMO). Few cases have been reported about ECMO use for near-drowning and in most of these cases, ECMO was initiated within the first week. However, in our report, we would like to emphasize that seemingly irreversible secondary worsening of ARDS after nearly drowned patient was successfully treated by ECMO use more than 1 week after near-drowning followed by discharge without home oxygen therapy, social support, or any complication. This is probably due to sufficient lung rest for ventilator-associated lung injury during ECMO use. Based on our case's clinical course, intensive care unit physicians must consider ECMO even in the late phase of worsened ARDS after near-drowning.

Sudden cardiac arrest caused by tuberculous pericarditis with hemorrhagic pericardial effusion.

As tuberculosis still exists in Japan, tuberculous pericarditis is a major health issue. Tuberculous pericarditis is difficult to diagnose and leads to poor outcomes when left untreated. We herein report the case of a patient who was admitted to the hospital after undergoing resuscitation for cardiopulmonary arrest. Mycobacterium tuberculosis was detected in his hemorrhagic pericardial fluid and tuberculous pericarditis was diagnosed. The administration of antituberculous medication resulted in marked improvements. A diagnosis of tuberculous pericarditis, in addition to other causes such as malignant tumors, should therefore be considered in the differential diagnosis for cases presenting with hemorrhagic pericardial effusion, even in those involving sudden cardiac arrest.