Genetic variants in SERPINA4 and SERPINA5, but not BCL2 and SIK3 are associated with acute kidney injury in critically ill patients with septic shock

Background: Acute kidney injury (AKI) is a multifactorial syndrome, but knowledge about its pathophysiology and possible genetic background is limited. Recently the first hypothesis-free genetic association studies have been published to explore individual susceptibility to AKI. We aimed to replicate the previously identified associations between five candidate single nucleotide polymorphisms (SNP) in apoptosis-related genes BCL2, SERPINA4, SERPINA5, and SIK3 and the development of AKI, using a prospective cohort of critically ill patients with sepsis/ septic shock, in Finland. Methods: This is a prospective, observational multicenter study. Of 2567 patients without chronic kidney disease and with genetic samples included in the Finnish Acute Kidney Injury (FINNAKI) study, 837 patients had sepsis and 627 patients had septic shock. AKI was defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria, considering stages 2 and 3 affected (severe AKI), stage 0 unaffected, and stage 1 indecisive. Genotyping was done using iPLEX (TM) Assay (Agena Bioscience). The genotyped SNPs were rs8094315 and rs12457893 in the intron of the BCL2 gene, rs2093266 in the SERPINA4 gene, rs1955656 in the SERPINA5 gene and rs625145 in the SIK3 gene. Association analyses were performed using logistic regression with PLINK software. Results: We found no significant associations between the SNPs and severe AKI in patients with sepsis/ septic shock, even after adjustment for confounders. Among patients with septic shock (252 with severe AKI and 226 without AKI (149 with KDIGO stage 1 excluded)), the SNPs rs2093266 and rs1955656 were significantly (odds ratio 0.63, p = 0.04276) associated with stage 2-3 AKI after adjusting for clinical and demographic variables. Conclusions: The SNPs rs2093266 in the SERPINA4 and rs1955656 in the SERPINA5 were associated with the development of severe AKI (KDIGO stage 2-3) in critically ill patients with septic shock. For the other SNPs, we did not confirm the previously reported associations.Peer reviewe

Intra-abdominal pressure in severe acute pancreatitis

BACKGROUND: Hospital mortality in patients with severe acute pancreatitis (SAP) remains high. Some of these patients develop increased intra-abdominal pressure (IAP) which may contribute to organ dysfunction. The aims of this study were to evaluate the frequency of increased IAP in patients with SAP and to assess the development of organ dysfunction and factors associated with high IAP. METHODS: During 2001–2003 a total of 59 patients with severe acute pancreatitis were treated in the intensive care unit (ICU) of Helsinki University Hospital. IAP was measured by the intravesical route in 37 patients with SAP. Data from these patients were retrospectively reviewed. RESULTS: Maximal IAP, APACHE II score, maximal SOFA score, maximal creatinine, age and maximal lactate were significantly higher in nonsurvivors. There was a significant correlation of the maximal IAP with the maximal SOFA, APACHE II, maximal creatinine, maximal lactate, base deficit and ICU length of stay. Patients were divided into quartiles according to the maximal IAP. Maximal IAP was 7–14, 15–18, 19–24 and 25–33 mmHg and the hospital mortality rate 10%, 12.5%, 22.2% and 50% in groups 1–4, respectively. A statistically significant difference was seen in the maximal SOFA, ICU length of stay, maximal creatinine and lactate values. The mean ICU-free days in groups 1–4 were 45.7, 38.8, 32.0 and 27.5 days, respectively. The difference between groups 1 and 4 was statistically significant. CONCLUSION: In patients with SAP, increased IAP is associated with development of early organ failure reflected in increased mortality and fewer ICU-free days. Frequent measurement of IAP during intensive care is important in optimizing abdominal perfusion pressure and recognizing patients potentially benefitting from decompressive laparotomy

Plasma anti-FXa level as a surrogate marker of the adequacy of thromboprophylaxis in critically ill patients : A systematic review

Background: Critical care patients are prone to venous thromboembolism (VTE) and, thus, pharmacological thromboprophylaxis is generally advised. Low-molecular weight heparins (LMWHs) have become the drug of choice in ICU patients, since their predictable and reproducible dose response. Monitoring their pharmacological effect is not usually necessary except in special occasions (i.e. with obese or renal failure patients), where anti-FXa level measuring is recommended. However, there is neither recommendation of adequate anti-FXa levels in critically ill patients nor is it known whether peak or trough level should be measured. The aim of this systematic review was to evaluate the recommended LMWH doses, and the reasons to monitor anti-FXa levels. Methods: We searched MEDLINE, Scopus, Cochrane Central Register of Controlled Trials and ClinicalTrials.com to identify all potentially relevant studies. Prospective studies done in critically ill patients were included if at least one anti-FXa level (i.e. peak or trough) after any specified LMWH thromboprophylaxis dose was measured. Results: Total 18 eligible studies including 1644 patients were included. There was a wide variation in the median peak anti-FXa levels ( Conclusion: Based on the current literature, no definite conclusions can be drawn on targeted anti-FXa level in critically ill patients when using LMWH thromboprophylaxis. (C) 2016 Elsevier Ltd. All rights reserved.Peer reviewe

Genetic predisposition to acute kidney injury - a systematic review

Background: The risk of an individual to develop an acute kidney injury (AKI), or its severity, cannot be reliably predicted by common clinical risk factors. Whether genetic risk factors have an explanatory role poses an interesting question, however. Thus, we conducted a systematic literature review regarding genetic predisposition to AKI or outcome of AKI patients. Methods: We searched Ovid SP (MEDLINE) and EMBASE databases and found 4027 references to AKI. Based on titles and abstracts, we approved 37 articles for further analysis. Nine were published only as abstracts, leaving 28 original articles in the final analysis. We extracted the first author, year of publication, study design, clinical setting, number of studied patients, patients with AKI, ethnicity of patients, studied polymorphisms, endpoints, AKI definition, phenotype, significant findings, and data for quality scoring from each article. We summarized the findings and scored the quality of articles. Results: The articles were quite heterogeneous and of moderate quality (mean 6.4 of 10). Conclusions: Despite different gene polymorphisms with suggested associations with development or severity or outcome of AKI, definitive conclusions would require replication of associations in independent cohort studies and, preferably a hypothesis-free study design.Peer reviewe

A statistical analysis protocol for the time-differentiated target temperature management after out-of-hospital cardiac arrest (TTH48) clinical trial

Background The TTH48 trial aims to determine whether prolonged duration (48 hours) of targeted temperature management (TTM) at 33 (±1) °C results in better neurological outcomes compared to standard duration (24 hours) after six months in comatose out-of-hospital cardiac arrest (OHCA) patients. Methods TTH48 is an investigator-initiated, multicentre, assessor-blinded, randomised, controlled superiority trial of 24 and 48 hours of TTM at 33 (±1) ° C performed in 355 comatose OHCA patients aged 18 to 80 years who were admitted to ten intensive care units (ICUs) in six Northern European countries. The primary outcome of the study is the Cerebral Performance Category (CPC) score observed at six months after cardiac arrest. CPC scores of 1 and 2 are defined as good neurological outcomes, and CPC scores of 3, 4 and 5 are defined as poor neurological outcomes. The secondary outcomes are as follows: mortality within six months after cardiac arrest, CPC at hospital discharge, Glasgow Coma Scale (GCS) score on day 4, length of stay in ICU and at hospital and the presence of any adverse events such as cerebral, circulatory, respiratory, gastrointestinal, renal, metabolic measures, infection or bleeding. With the planned sample size, we have 80% power to detect a 15% improvement in good neurological outcomes at a two-sided statistical significance level of 5%. Discussion We present a detailed statistical analysis protocol (SAP) that specifies how primary and secondary outcomes should be evaluated. We also predetermine covariates for adjusted analyses and pre-specify sub-groups for sensitivity analyses. This pre-planned SAP will reduce analysis bias and add validity to the findings of this trial on the effect of length of TTM on important clinical outcomes after cardiac arrest. Trial registration ClinicalTrials.gov: NCT01689077, 17 September 201

The association of endothelial injury and systemic inflammation with perioperative myocardial infarction

Background Major surgery predisposes to endothelial glycocalyx injury. Endothelial glycocalyx injury associates with cardiac morbidity, including spontaneous myocardial infarction. However, the relation between endothelial glycocalyx injury and the development of perioperative myocardial infarction remains unknown. Methods Fifteen perioperative myocardial infarction patients and 60 propensity-matched controls were investigated in this prospective study. The diagnosis of perioperative myocardial infarction was based on repeated cardiac troponin T measurements, electrocardiographs and recordings of ischaemic signs and symptoms. We measured endothelial glycocalyx markers - soluble thrombomodulin, syndecan-1 and vascular adhesion protein 1 - and an inflammatory marker, namely interleukin-6, preoperatively and 6 h and 24 h postoperatively. We calculated the areas under the receiver operating characteristics curves (AUCs) to compare the performances of the different markers in predicting perioperative myocardial infarction. The highest value of each marker was used in the analysis. Results The interleukin-6 concentrations of perioperative myocardial infarction patients were significantly higher preoperatively and 6 and 24 h postoperatively (P = 0.002, P = 0.002 and P = 0.001, respectively). The AUCs (95% confidence intervals) for the detection of perioperative myocardial infarction were 0.51 (0.34-0.69) for soluble thrombomodulin, 0.63 (0.47-0.79) for syndecan-1, 0.54 (0.37-0.70) for vascular adhesion protein 1 and 0.69 (0.54-0.85) for interleukin-6. Conclusions Systemic inflammation, reflected by interleukin-6, associates with cardiac troponin T release and perioperative myocardial infarction. Circulating interleukin-6 demonstrated some potential to predict perioperative myocardial infarction, whereas endothelial glycocalyx markers did not.Peer reviewe

Dynamic lactate indices as predictors of outcome in critically ill patients

INTRODUCTION: Dynamic changes in lactate concentrations in the critically ill may predict patient outcome more accurately than static indices. We aimed to compare the predictive value of dynamic indices of lactatemia in the first 24 hours of intensive care unit (ICU) admission with the value of more commonly used static indices. METHODS: This was a retrospective observational study of a prospectively obtained intensive care database of 5,041 consecutive critically ill patients from four Australian university hospitals. We assessed the relationship between dynamic lactate values collected in the first 24 hours of ICU admission and both ICU and hospital mortality. RESULTS: We obtained 36,673 lactate measurements in 5,041 patients in the first 24 hours of ICU admission. Both the time weighted average lactate (LACTW₂₄) and the change in lactate (LACΔ₂₄) over the first 24 hours were independently predictive of hospital mortality with both relationships appearing to be linear in nature. For every one unit increase in LACTW₂₄ and LACΔ₂₄ the risk of hospital death increased by 37% (OR 1.37, 1.29 to 1.45; P < 0.0001) and by 15% (OR 1.15, 1.10 to 1.20; P < 0.0001) respectively. Such dynamic indices, when combined with Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, improved overall outcome prediction (P < 0.0001) achieving almost 90% accuracy. When all lactate measures in the first 24 hours were considered, the combination of LACTW₂₄ and LACΔ₂₄ significantly outperformed (P < 0.0001) static indices of lactate concentration, such as admission lactate, maximum lactate and minimum lactate. CONCLUSIONS: In the first 24 hours following ICU admission, dynamic indices of hyperlactatemia have significant independent predictive value, improve the performance of illness severity score-based outcome predictions and are superior to simple static indices of lactate concentration

Urinary cell cycle arrest biomarkers and chitinase 3-like protein 1 (CHI3L1) to detect acute kidney injury in the critically ill : a post hoc laboratory analysis on the FINNAKI cohort

Background Acute kidney injury (AKI) is a frequently occurring syndrome in critically ill patients and is associated with worse outcomes. Biomarkers allow early identification and therapy of AKI which may improve outcomes. Urine chitinase 3-like protein 1 (uCHI3L1) was recently identified as a promising urinary biomarker for AKI. In this multicenter study, we evaluated the diagnostic performance for AKI stage 2 or greater of uCHI3L1 in comparison with the urinary cell cycle arrest biomarkers urinary tissue inhibitor of metalloproteinases-2 (TIMP-2)center dot insulin-like growth factor-binding protein 7 (IGFBP7) measured by NephroCheck Risk (R). Methods Post hoc laboratory study of the prospective observational FINNAKI study. Of this cohort, we included patients with stored admission urine samples and availability of serum creatinine at day 1 of admission. Patients who already had AKI stage 2 or 3 at ICU admission were excluded. AKI was defined and staged according to the KDIGO definition and staging system. The primary endpoint was AKI stage 2 or 3 at day 1. Biomarker performance was assessed by the area under the curve of the receiver operating characteristic curve (AUC). We assessed individual performance and different combinations of urine biomarkers. Results Of 660 included patients, 49 (7.4%) had AKI stages 2-3 at day 1. All urine biomarkers were increased at admission in AKI patients. All biomarkers and most combinations had AUCs <0.700. The combination uCHI3L1 center dot TIMP-2 was best with a fair AUC of 0.706 (0.670, 0.718). uCHI3L1 had a positive likelihood ratio (LR) of 2.25 which was comparable to that of the NephroCheck Risk (R) cutoff of 2.0, while the negative LR of 0.53 was comparable to that of the NephroCheck Risk (R) cutoff of 0.3. Conclusions We found that uCHI3L1 and NephroCheck Risk (R) had a comparable diagnostic performance for diagnosis of AKI stage 2 or greater within a 24-h period in this multicenter FINNAKI cohort. In contrast to initial discovery and validation studies, the diagnostic performance was poor. Possible explanations for this observation are differences in patient populations, proportion of emergency admissions, proportion of functional AKI, rate of developing AKI, and observation periods for diagnosis of AKI.Peer reviewe

Phospholipid composition of packed red blood cells and that of extracellular vesicles show a high resemblance and stability during storage

Red blood cells (RBCs) are stored up to 35-42 days at 2-6 degrees C in blood banks. During storage, the RBC membrane is challenged by energy depletion, decreasing pH, altered cation homeostasis, and oxidative stress, leading to several biochemical and morphological changes in RBCs and to shedding of extracellular vesicles (EVs) into the storage medium. These changes are collectively known as RBC storage lesions. EVs accumulate in stored RBC concentrates and are, thus, transfused into patients. The potency of EVs as bioactive effectors is largely acknowledged, and EVs in RBC concentrates are suspected to mediate some adverse effects of transfusion. Several studies have shown accumulation of lipid raft associated proteins in RBC EVs during storage, whereas a comprehensive phospholipidomic study on RBCs and corresponding EVs during the clinical storage period is lacking. Our mass spectrometric and chromatographic study shows that RBCs maintain their major phospholipid (PL) content well during storage despite abundant vesiculation. The phospholipidomes were largely similar between RBCs and EVs. No accumulation of raft lipids in EVs was seen, suggesting that the primary mechanism of RBC vesiculation during storage might not be raft-based. Nonetheless, a slight tendency of EV PLs for shorter acyl chains was observed.Peer reviewe