Fluid management in patients with acute kidney injury - A post-hoc analysis of the FINNAKI study.

PURPOSE: Whether positive fluid balance among patients with acute kidney injury (AKI) stems from decreased urine output, overzealous fluid administration, or both is poorly characterized. MATERIALS AND METHODS: This was a post hoc analysis of the prospective multicenter observational Finnish Acute Kidney Injury study including 824 AKI and 1162 non-AKI critically ill patients. RESULTS: We matched 616 AKI (diagnosed during the three first intensive care unit (ICU) days) and non-AKI patients using propensity score. During the three first ICU days, AKI patients received median [IQR] of 11.4 L [8.0-15.2]L fluids and non-AKI patients 10.2 L [7.5-13.7]L, p < 0.001 while the fluid output among AKI patients was 4.7 L [3.0-7.2]L and among non-AKI patients 5.8 L [4.1-8.0]L, p < 0.001. In AKI patients, the median [IQR] cumulative fluid balance was 2.5 L [-0.2-6.0]L compared to 0.9 L [-1.4-3.6]L among non-AKI patients, p < 0.001. Among the 824 AKI patients, smaller volumes of fluid input with a multivariable OR of 0.90 (0.88-0.93) and better fluid output (multivariable OR 1.12 (1.07-1.18)) associated with enhanced change of resolution of AKI. CONCLUSIONS: AKI patients received more fluids albeit having lower fluid output compared to matched critically ill non-AKI patients. Smaller volumes of fluid input and higher fluid output were associated with better AKI recovery.

Early prolonged neutrophil activation in critically ill patients with sepsis.

We hypothesised that plasma concentrations of biomarkers of neutrophil activation and pro-inflammatory cytokines differ according to the phase of rapidly evolving sepsis. In an observational study, we measured heparin-binding protein (HBP), myeloperoxidase (MPO), IL-6 and IL-8 in 167 sepsis patients on intensive care unit admission. We prospectively used the emergence of the first sepsis-associated organ dysfunction (OD) as a surrogate for the sepsis phase. Fifty-five patients (of 167, 33%) developed the first OD > 1 h before, 74 (44%) within ± 1 h, and 38 (23%) > 1 h after intensive care unit admission. HBP and MPO were elevated at a median of 12 h before the first OD, remained high up to 24 h, and were not associated with sepsis phase. IL-6 and IL-8 rose and declined rapidly close to OD emergence. Elevation of neutrophil activation markers HBP and MPO was an early event in the evolution of sepsis, lasting beyond the subsidence of the pro-inflammatory cytokine reaction. Thus, as sepsis biomarkers, HBP and MPO were not as prone as IL-6 and IL-8 to the effect of sample timing.

Two subphenotypes of septic acute kidney injury are associated with different 90-day mortality and renal recovery.

BACKGROUND: The pathophysiology of septic acute kidney injury is inadequately understood. Recently, subphenotypes for sepsis and AKI have been derived. The objective of this study was to assess whether a combination of comorbidities, baseline clinical data, and biomarkers could classify meaningful subphenotypes in septic AKI with different outcomes. METHODS: We performed a post hoc analysis of the prospective Finnish Acute Kidney Injury (FINNAKI) study cohort. We included patients admitted with sepsis and acute kidney injury during the first 48 h from admission to intensive care (according to Kidney Disease Improving Global Outcome criteria). Primary outcomes were 90-day mortality and renal recovery on day 5. We performed latent class analysis using 30 variables obtained on admission to classify subphenotypes. Second, we used logistic regression to assess the association of derived subphenotypes with 90-day mortality and renal recovery on day 5. RESULTS: In total, 301 patients with septic acute kidney injury were included. Based on the latent class analysis, a two-class model was chosen. Subphenotype 1 was assigned to 133 patients (44%) and subphenotype 2 to 168 patients (56%). Increased levels of inflammatory and endothelial injury markers characterized subphenotype 2. At 90 days, 29% of patients in subphenotype 1 and 41% of patients in subphenotype 2 had died. Subphenotype 2 was associated with a lower probability of short-term renal recovery and increased 90-day mortality. CONCLUSIONS: In this post hoc analysis, we identified two subphenotypes of septic acute kidney injury with different clinical outcomes. Future studies are warranted to validate the suggested subphenotypes of septic acute kidney injury.

Neutrophil activation in septic acute kidney injury: A post hoc analysis of the FINNAKI study.

BACKGROUND: Inflammation, reflected by high plasma interleukin-6 concentration, is associated with acute kidney injury (AKI) in septic patients. Neutrophil activation has pathophysiological significance in experimental septic AKI. We hypothesized that neutrophil activation is associated with AKI in critically ill sepsis patients. METHODS: We measured plasma (n = 182) and urine (n = 118) activin A (a rapidly released cytosolic neutrophil protein), interleukin-8 (a chemotactic factor for neutrophils), myeloperoxidase (a neutrophil biomarker released in tissues), and interleukin-6 on intensive care unit admission (plasma and urine) and 24 hours later (plasma) in sepsis patients manifesting their first organ dysfunction between 24 hours preceding admission and the second calendar day in intensive care unit. AKI was defined by the Kidney Disease: Improving Global Outcomes criteria. RESULTS: Plasma admission interleukin-8 (240 [60-971] vs 50 [19-164] pg/mL, P < .001) and activin A (845 [554-1895] vs 469 [285-862] pg/mL, P < .001) were but myeloperoxidase (169 [111-300] vs 144 [88-215] ng/mL, P = .059) was not higher among patients with AKI compared with those without. Urine admission interleukin-8 (50.4 [19.8-145.3] vs 9.5 [2.7-28.7] ng/mL, P < .001) and myeloperoxidase (7.7 [1.5-12.6] vs 1.9 [0.4-6.9] ng/mL, P < .001) were but activin A (9.7 [1.4-42.6] vs 4.0 [0.0-33.0] ng/mL, P = .064) was not higher in AKI than non-AKI patients. Urine myeloperoxidase correlated with urine interleukin-8 (R = .627, P < .001) but not with plasma myeloperoxidase (R = .131, P = .158). CONCLUSION: Interleukin-8 in plasma and urine was associated with septic AKI. Elevated plasma activin A indicates intravascular neutrophil activation in septic AKI. Concomitant plasma and urine myeloperoxidase measurements suggest neutrophil accumulation into injured kidneys.

Burden of acute kidney injury and 90-day mortality in critically ill patients.

BACKGROUND: Mortality rates associated with acute kidney injury (AKI) vary among critically ill patients. Outcomes are often not corrected for severity or duration of AKI. Our objective was to analyse whether a new variable, AKI burden, would outperform 1) presence of AKI, 2) highest AKI stage, or 3) AKI duration in predicting 90-day mortality. METHODS: Kidney Diseases: Improving Global Outcomes (KDIGO) criteria using creatinine, urine output and renal replacement therapy were used to diagnose AKI. AKI burden was defined as AKI stage multiplied with the number of days that each stage was present (maximum five), divided by the maximum possible score yielding a proportion. The AKI burden as a predictor of 90-day mortality was assessed in two independent cohorts (Finnish Acute Kidney Injury, FINNAKI and Simple Intensive Care Studies I, SICS-I) by comparing four multivariate logistic regression models that respectively incorporated either the presence of AKI, the highest AKI stage, the duration of AKI, or the AKI burden. RESULTS: In the FINNAKI cohort 1096 of 2809 patients (39%) had AKI and 90-day mortality of the cohort was 23%. Median AKI burden was 0.17 (IQR 0.07-0.50), 1.0 being the maximum. The model including AKI burden (area under the receiver operator curve (AUROC) 0.78, 0.76-0.80) outperformed the models using AKI presence (AUROC 0.77, 0.75-0.79, p = 0.026) or AKI severity (AUROC 0.77, 0.75-0.79, p = 0.012), but not AKI duration (AUROC 0.77, 0.75-0.79, p = 0.06). In the SICS-I, 603 of 1075 patients (56%) had AKI and 90-day mortality was 28%. Median AKI burden was 0.19 (IQR 0.08-0.46). The model using AKI burden performed better (AUROC 0.77, 0.74-0.80) than the models using AKI presence (AUROC 0.75, 0.71-0.78, p = 0.001), AKI severity (AUROC 0.76, 0.72-0.79. p = 0.008) or AKI duration (AUROC 0.76, 0.73-0.79, p = 0.009). CONCLUSION: AKI burden, which appreciates both severity and duration of AKI, was superior to using only presence or the highest stage of AKI in predicting 90-day mortality. Using AKI burden or other more granular methods may be helpful in future epidemiological studies of AKI.

Heparin-binding protein (HBP) improves prediction of sepsis-related acute kidney injury.

BACKGROUND: Sepsis-related acute kidney injury (AKI) accounts for major morbidity and mortality among the critically ill. Heparin-binding protein (HBP) is a promising biomarker in predicting development and prognosis of severe sepsis and septic shock that has recently been proposed to be involved in the pathophysiology of AKI. The objective of this study was to investigate the added predictive value of measuring plasma HBP on admission to the intensive care unit (ICU) regarding the development of septic AKI. METHODS: We included 601 patients with severe sepsis or septic shock from the prospective, observational FINNAKI study conducted in seventeen Finnish ICUs during a 5-month period (1 September 2011-1 February 2012). The main outcome measure was the development of KDIGO AKI stages 2-3 from 12 h after admission up to 5 days. Statistical analysis for the primary endpoint included construction of a clinical risk model, area under the receiver operating curve (ROC area), category-free net reclassification index (cfNRI) and integrated discrimination improvement (IDI) with 95% confidence intervals (95% CI). RESULTS: Out of 511 eligible patients, 101 (20%) reached the primary endpoint. The addition of plasma HBP to a clinical risk model significantly increased ROC area (0.82 vs. 0.78, p = 0.03) and risk classification scores: cfNRI 62.0% (95% CI 40.5-82.4%) and IDI 0.053 (95% CI 0.029-0.075). CONCLUSIONS: Plasma HBP adds predictive value to known clinical risk factors in septic AKI. Further studies are warranted to compare the predictive performance of plasma HBP to other novel AKI biomarkers.

Evolution of Blood Lactate and 90-Day Mortality in Septic Shock. A Post Hoc Analysis of the FINNAKI Study.

Hyperlactatemia predicts mortality in patients with sepsis and septic shock, and its normalization is a potential treatment goal. We investigated the association of blood lactate and its changes over time with 90-day mortality in septic shock. We performed a post hoc analysis of 513 septic shock patients with admission blood lactate measurements in the prospective, observational, multicenter FINNAKI study. Repetitive lactate measurements were available in 496 patients for analyses of change in lactate values during intensive care unit stay.The 90-day mortality for all patients was 33.3%. Patients with admission lactate >2 mmol/L had higher 90-day mortality than those with admission lactate ≤2 mmol/L (43.4% vs. 22.6%, P < 0.001). Patients with persistent hyperlactatemia (>2 mmol/L) at ≥72 h had higher 90-day mortality compared with those with a lactate value of ≤2.0 mmol/L (52.0% vs. 24.3%, P < 0.001). Time-weighted mean lactate values were higher in non-survivors than in survivors, (median [IQR] 2.05 [1.38-4.22] mmol/L vs. 1.29 [0.98-1.77] mmol/L, P < 0.001). Time to normalization of lactate was comparable for 90-day non-survivors and survivors (median [IQR] 17.0 [3.5-43.5] vs. 15.0 [5.0-35.0] h, P = 0.67). In separate models, time-weighted mean lactate, lactate value at ≥72 h, and hyperlactatemia at ≥72 h were independently associated with 90-day mortality, but admission lactate and time to normalization of lactate were not. These findings may inform future clinical trials using combined surrogate endpoints for mortality in septic shock patients.

Goal-directed fluid management in free flap surgery for cancer of the head and neck.

BACKGROUND: Goal-directed fluid management using stroke volume variation (SVV) analysis is not well studied in free flap reconstruction surgery in patients with head and neck cancer. METHODS: Patients operated due to cancer of the head and neck with free flap reconstruction during 2008-2010 and 2012-2014 in Oulu University Hospital were retrospectively evaluated to determine the impact of SVV-guided fluid management on perioperative fluid balance, postoperative complications and hospital length of stay (LOS). RESULTS: A total of 104 patients were included in the study and in 48 of them SVV was used to guide intraoperative fluid management. The SVV-guided fluid management led to significant reduction in intraoperative fluid load (6070 mL vs. 8185 mL) and hospital length of stay (11.5 vs. 14.0 days). There was no difference in the number of postoperative complications between the groups. CONCLUSIONS: The SVV-guided fluid management reduces fluid administration in free flap reconstruction surgery with head and neck cancer.

Vitamin D deficiency at admission is not associated with 90-day mortality in patients with severe sepsis or septic shock: Observational FINNAKI cohort study.

Introduction Low levels of vitamin D have been associated with increased mortality in patients that are critically ill. This study explored whether vitamin D levels were associated with 90-day mortality in severe sepsis or septic shock. Methods Plasma vitamin D levels were measured on admission to the intensive care unit (ICU) in a prospective multicentre observational study. Results 610 patients with severe sepsis were included; of these, 178 (29%) had septic shock. Vitamin D deficiency (<50 nmol/L) was present in 333 (55%) patients. The 90-day mortality did not differ among patients with or without vitamin D deficiency (28.3% vs. 28.5%, p = 0.789). Diabetes was more common among patients deficient compared to those not deficient in vitamin D (30% vs. 18%, p < 0.001). Hospital-acquired infections at admission were more prevalent in patients with a vitamin D deficiency (31% vs. 16%, p < 0.001). A multivariable adjusted Cox regression model showed that low vitamin D levels could not predict 90-day mortality (<50 nmol/L: hazard ratio (HR) 0.99 (95% CI: 0.72-1.36), p > 0.9; and <25 nmol/L: HR 0.44 (95% CI: 0.22-0.87), p = 0.018). Conclusions Vitamin D deficiency detected upon ICU admission was not associated with 90-day mortality in patients with severe sepsis or septic shock. Key messages In severe sepsis and septic shock, a vitamin D deficiency upon ICU admission was not associated with increased mortality. Compared to patients with sufficient vitamin D, patients with deficient vitamin D more frequently exhibited diabetes, elevated C-reactive protein levels, and hospital-acquired infections upon ICU admission, and they more frequently developed acute kidney injury.

Predicting one-year mortality of critically ill patients with early acute kidney injury: data from the prospective multicenter FINNAKI study.

INTRODUCTION: No predictive models for long-term mortality in critically ill patients with acute kidney injury (AKI) exist. We aimed to develop and validate two predictive models for one-year mortality in patients with AKI based on data (1) on intensive care unit (ICU) admission and (2) on the third day (D3) in the ICU. METHODS: This substudy of the FINNAKI study comprised 774 patients with early AKI (diagnosed within 24 hours of ICU admission). We selected predictors a priori based on previous studies, clinical judgment, and differences between one-year survivors and non-survivors in patients with AKI. We validated the models internally with bootstrapping. RESULTS: Of 774 patients, 308 (39.8%, 95% confidence interval (CI) 36.3 to 43.3) died during one year. Predictors of one-year mortality on admission were: advanced age, diminished premorbid functional performance, co-morbidities, emergency admission, and resuscitation or hypotension preceding ICU admission. The area under the receiver operating characteristic curve (AUC) (95% CI) for the admission model was 0.76 (0.72 to 0.79) and the mean bootstrap-adjusted AUC 0.75 (0.74 to 0.75). Advanced age, need for mechanical ventilation on D3, number of co-morbidities, higher modified SAPS II score, the highest bilirubin value by D3, and the lowest base excess value on D3 remained predictors of one-year mortality on D3. The AUC (95% CI) for the D3 model was 0.80 (0.75 to 0.85) and by bootstrapping 0.79 (0.77 to 0.80). CONCLUSIONS: The prognostic performance of the admission data-based model was acceptable, but not good. The D3 model for one-year mortality performed fairly well in patients with early AKI.

Variation in the use of renal replacement therapy in patients with septic shock: a substudy of the prospective multicenter observational FINNAKI study.

INTRODUCTION: Indications for renal replacement therapy (RRT) have not been generally standardized and vary among intensive care units (ICUs). We aimed to assess the proportion, indications, and modality of RRT, as well as the association between the proportion of RRT use and 90-day mortality in patients with septic shock in Finnish adult ICUs. METHODS: We identified patients with septic shock from the prospective observational multicenter FINNAKI study conducted between 1 September 2011 and 1 February 2012. We divided the ICUs into high-RRT and low-RRT ICUs according to the median of the proportion of RRT-treated patients with septic shock. Differences in indications, and modality of RRT between ICU groups were assessed. Finally, we performed an adjusted logistic regression analysis to evaluate the possible association of the ICU group (high vs. low-RRT) with 90-day mortality. RESULTS: Of the 726 patients with septic shock, 131 (18.0%, 95% CI 15.2 to 20.9%) were treated with RRT. The proportion of RRT-treated patients varied from 3% up to 36% (median 19%) among ICUs. High-RRT ICUs included nine ICUs (354 patients) and low-RRT ICUs eight ICUs (372 patients). In the high-RRT ICUs patients with septic shock were older (P = 0.04), had more cardiovascular (P <0.001) and renal failures (P = 0.003) on the first day in the ICU, were more often mechanically ventilated, and received higher maximum doses of norepinephrine (0.25 µg/kg/min vs. 0.18 µg/kg/min, P <0.001) than in the low-RRT ICUs. No significant differences in indications for or modality of RRT existed between the ICU groups. The crude 90-day mortality rate for patients with septic shock was 36.2% (95% CI 31.1 to 41.3%) in the high-RRT ICUs compared to 33.9% (95% CI 29.0 to 38.8%) in the low-RRT ICUs, P = 0.5. In an adjusted logistic regression analysis the ICU group (high-RRT or low-RRT ICUs) was not associated with 90-day mortality. CONCLUSIONS: Patients with septic shock in ICUs with a high proportion of RRT had more severe organ dysfunctions and received more organ-supportive treatments. Importantly, the ICU group (high-RRT or low-RRT group) was not associated with 90-day mortality.

Hemodynamic variables and progression of acute kidney injury in critically ill patients with severe sepsis: data from the prospective observational FINNAKI study.

INTRODUCTION: Knowledge of the association of hemodynamics with progression of septic acute kidney injury (AKI) is limited. However, some recent data suggest that mean arterial pressure (MAP) exceeding current guidelines (60-65 mmHg) may be needed to prevent AKI. We hypothesized that higher MAP during the first 24 hours in the intensive care unit (ICU), would be associated with a lower risk of progression of AKI in patients with severe sepsis. METHODS: We identified 423 patients with severe sepsis and electronically recorded continuous hemodynamic data in the prospective observational FINNAKI study. The primary endpoint was progression of AKI within the first 5 days of ICU admission defined as new onset or worsening of AKI by the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. We evaluated the association of hemodynamic variables with this endpoint. We included 53724 10-minute medians of MAP in the analysis. We analysed the ability of time-adjusted MAP to predict progression of AKI by receiver operating characteristic (ROC) analysis. RESULTS: Of 423 patients, 153 (36.2%) had progression of AKI. Patients with progression of AKI had significantly lower time-adjusted MAP, 74.4 mmHg [68.3-80.8], than those without progression, 78.6 mmHg [72.9-85.4], P < 0.001. A cut-off value of 73 mmHg for time-adjusted MAP best predicted the progression of AKI. Chronic kidney disease, higher lactate, higher dose of furosemide, use of dobutamine and time-adjusted MAP below 73 mmHg were independent predictors of progression of AKI. CONCLUSIONS: The findings of this large prospective multicenter observational study suggest that hypotensive episodes (MAP under 73 mmHg) are associated with progression of AKI in critically ill patients with severe sepsis.

Six-month survival and quality of life of intensive care patients with acute kidney injury.

INTRODUCTION: Acute kidney injury (AKI) has high incidence among the critically ill and associates with dismal outcome. Not only the long-term survival, but also the quality of life (QOL) of patients with AKI is relevant due to substantial burden of care regarding these patients. We aimed to study the long-term outcome and QOL of patients with AKI treated in intensive care units. METHODS: We conducted a predefined six-month follow-up of adult intensive care unit (ICU) patients from the prospective, observational, multi-centre FINNAKI study. We evaluated the QOL of survivors with the EuroQol (EQ-5D) questionnaire. We included all participating sites with at least 70% rate of QOL measurements in the analysis. RESULTS: Of the 1,568 study patients, 635 (40.5%, 95% confidence interval (CI) 38.0-43.0%) had AKI according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria. Of the 635 AKI patients, 224 (35.3%), as compared to 154/933 (16.5%) patients without AKI, died within six months. Of the 1,190 survivors, 959 (80.6%) answered the EQ-5D questionnaire at six months. The QOL (median with Interquartile range, IQR) measured with the EQ-5D index and compared to age- and sex-matched general population was: 0.676 (0.520-1.00) versus 0.826 (0.812-0.859) for AKI patients, and 0.690 (0.533-1.00) versus 0.845 (0.812-0.882) for patients without AKI (P <0.001 in both). The EQ-5D at the time of ICU admission was available for 774 (80.7%) of the six-month respondents. We detected a mean increase of 0.017 for non-AKI and of 0.024 for AKI patients in the EQ-5D index (P = 0.728). The EQ-5D visual analogue scores (median with IQR) of patients with AKI (70 (50-83)) and patients without AKI (75 (60-87)) were not different from the age- and sex-matched general population (69 (68-73) and 70 (68-77)). CONCLUSIONS: The health-related quality of life of patients with and without AKI was already lower on ICU admission than that of the age- and sex-matched general population, and did not change significantly during critical illness. Patients with and without AKI rate their subjective health to be as good as age and sex-matched general population despite statistically significantly lower QOL indexes measured by EQ-5D.

Incidence, risk factors and 90-day mortality of patients with acute kidney injury in Finnish intensive care units: the FINNAKI study.

PURPOSE: We aimed to determine the incidence, risk factors and outcome of acute kidney injury (AKI) in Finnish ICUs. METHODS: This prospective, observational, multi-centre study comprised adult emergency admissions and elective patients whose stay exceeded 24 h during a 5-month period in 17 Finnish ICUs. We defined AKI first by the Acute Kidney Injury Network (AKIN) criteria supplemented with a baseline creatinine and second with the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. We screened the patients' AKI status and risk factors for up to 5 days. RESULTS: We included 2,901 patients. The incidence (95 % confidence interval) of AKI was 39.3 % (37.5-41.1 %). The incidence was 17.2 % (15.8-18.6 %) for stage 1, 8.0 % (7.0-9.0 %) for stage 2 and 14.1 % (12.8-15.4 %) for stage 3 AKI. Of the 2,901 patients 296 [10.2 % (9.1-11.3 %)] received renal replacement therapy. We received an identical classification with the new KDIGO criteria. The population-based incidence (95 % CI) of ICU-treated AKI was 746 (717-774) per million population per year (reference population: 3,671,143, i.e. 85 % of the Finnish adult population). In logistic regression, pre-ICU hypovolaemia, diuretics, colloids and chronic kidney disease were independent risk factors for AKI. Hospital mortality (95 % CI) for AKI patients was 25.6 % (23.0-28.2 %) and the 90-day mortality for AKI patients was 33.7 % (30.9-36.5 %). All AKIN stages were independently associated with 90-day mortality. CONCLUSIONS: The incidence of AKI in the critically ill in Finland was comparable to previous large multi-centre ICU studies. Hospital mortality (26 %) in AKI patients appeared comparable to or lower than in other studies.