Clustering ICU patients with sepsis based on the patterns of their circulating biomarkers: A secondary analysis of the CAPTAIN prospective multicenter cohort study.

BACKGROUND: Although sepsis is a life-threatening condition, its heterogeneous presentation likely explains the negative results of most trials on adjunctive therapy. This study in patients with sepsis aimed to identify subgroups with similar immune profiles and their clinical and outcome correlates. METHODS: A secondary analysis used data of a prospective multicenter cohort that included patients with early assessment of sepsis. They were described using Predisposition, Insult, Response, Organ failure sepsis (PIRO) staging system. Thirty-eight circulating biomarkers (27 proteins, 11 mRNAs) were assessed at sepsis diagnosis, and their patterns were determined through principal component analysis (PCA). Hierarchical clustering was used to group the patients and k-means algorithm was applied to assess the internal validity of the clusters. RESULTS: Two hundred and three patients were assessed, of median age 64.5 [52.0-77.0] years and SAPS2 score 55 [49-61] points. Five main patterns of biomarkers and six clusters of patients (including 42%, 21%, 17%, 9%, 5% and 5% of the patients) were evidenced. Clusters were distinguished according to the certainty of the causal infection, inflammation, use of organ support, pro- and anti-inflammatory activity, and adaptive profile markers. CONCLUSIONS: In this cohort of patients with suspected sepsis, we individualized clusters which may be described with criteria used to stage sepsis. As these clusters are based on the patterns of circulating biomarkers, whether they might help to predict treatment responsiveness should be addressed in further studies. TRIAL REGISTRATION: The CAPTAIN study was registered on clinicaltrials.gov on June 22, 2011, # NCT01378169.

Challenging the Ex Vivo Lung Perfusion Procedure With Continuous Dialysis in a Pig Model.

BACKGROUND: Normothermic ex vivo lung perfusion (EVLP) increases the pool of donor lungs by requalifying marginal lungs refused for transplantation through the recovery of macroscopic and functional properties. However, the cell response and metabolism occurring during EVLP generate a nonphysiological accumulation of electrolytes, metabolites, cytokines, and other cellular byproducts which may have deleterious effects both at the organ and cell levels, with impact on transplantation outcomes. METHODS: We analyzed the physiological, metabolic, and genome-wide response of lungs undergoing a 6-h EVLP procedure in a pig model in 4 experimental conditions: without perfusate modification, with partial replacement of fluid, and with adult or pediatric dialysis filters. RESULTS: Adult and pediatric dialysis stabilized the electrolytic and metabolic profiles while maintaining acid-base and gas exchanges. Pediatric dialysis increased the level of IL-10 and IL-6 in the perfusate. Despite leading to modification of the perfusate composition, the 4 EVLP conditions did not affect the gene expression profiles, which were associated in all cases with increased cell survival, cell proliferation, inflammatory response and cell movement, and with inhibition of bleeding. CONCLUSIONS: Management of EVLP perfusate by periodic replacement and continuous dialysis has no significant effect on the lung function nor on the gene expression profiles ex vivo. These results suggest that the accumulation of dialyzable cell products does not significantly alter the lung cell response during EVLP, a finding that may have impact on EVLP management in the clinic.

Circulating biomarkers may be unable to detect infection at the early phase of sepsis in ICU patients: the CAPTAIN prospective multicenter cohort study.

PURPOSE: Sepsis and non-septic systemic inflammatory response syndrome (SIRS) are the same syndromes, differing by their cause, sepsis being secondary to microbial infection. Microbiological tests are not enough to detect infection early. While more than 50 biomarkers have been proposed to detect infection, none have been repeatedly validated. AIM: To assess the accuracy of circulating biomarkers to discriminate between sepsis and non-septic SIRS. METHODS: The CAPTAIN study was a prospective observational multicenter cohort of 279 ICU patients with hypo- or hyperthermia and criteria of SIRS, included at the time the attending physician considered antimicrobial therapy. Investigators collected blood at inclusion to measure 29 plasma compounds and ten whole blood RNAs, and-for those patients included within working hours-14 leukocyte surface markers. Patients were classified as having sepsis or non-septic SIRS blindly to the biomarkers results. We used the LASSO method as the technique of multivariate analysis, because of the large number of biomarkers. RESULTS: During the study period, 363 patients with SIRS were screened, 84 having exclusion criteria. Ninety-one patients were classified as having non-septic SIRS and 188 as having sepsis. Eight biomarkers had an area under the receiver operating curve (ROC-AUC) over 0.6 with a 95% confidence interval over 0.5. LASSO regression identified CRP and HLA-DRA mRNA as being repeatedly associated with sepsis, and no model performed better than CRP alone (ROC-AUC 0.76 [0.68-0.84]). CONCLUSIONS: The circulating biomarkers tested were found to discriminate poorly between sepsis and non-septic SIRS, and no combination performed better than CRP alone.

Complications of regional citrate anticoagulation: accumulation or overload?

Regional citrate anticoagulation (RCA) is now recommended over systemic heparin for continuous renal replacement therapy in patients without contraindications. Its use is likely to increase throughout the world. However, in the absence of citrate blood level monitoring, the diagnosis of citrate accumulation, the most feared complication of RCA, remains relatively complex. It is therefore commonly mistaken with other conditions. This review aims at providing clarifications on RCA-associated acid-base disturbances and their management at the bedside. In particular, the authors wish to propose a clear distinction between citrate accumulation and net citrate overload.

Haemodialysis catheters in the intensive care unit.

Ten to 15% of critically ill patients need renal replacement therapy (RRT) for severe acute kidney injury. The dialysis catheter is critical for RRT quality and efficiency. Catheters have several properties that must be optimized to promote RRT success. The distal tip has to be located in a high blood flow location, which means central venous territory. Therefore, catheters are mostly inserted into the right internal jugular vein or in femoral veins. External diameter should vary from 12 to 16 Fr in order to ensure adequate blood flow inside the catheter. Lumen shapes are theoretically designed to limit thrombotic risk with low turbulences and frictional forces against the internal wall. With low aspiration pressure, distal tip shape has to deliver sufficient blood flow, while limiting recirculation rate. Catheter material should be biocompatible. Despite in vitro data, no strong evidence supports the use of coated catheters in the ICU in order to reduce infectious risk. Antibiotic "lock" solutions are not routinely recommended. Ultrasound guidance for catheterization significantly decreases mechanical complications. Clinicians should select the optimal catheter according to patient body habitus, catheter intrinsic properties and RRT modality to be used.

Acute kidney injury in the perioperative period and in intensive care units (excluding renal replacement therapies).

Acute kidney injury (AKI) is a syndrome that has progressed a great deal over the last 20 years. The decrease in urine output and the increase in classical renal biomarkers, such as blood urea nitrogen and serum creatinine, have largely been used as surrogate markers for decreased glomerular filtration rate (GFR), which defines AKI. However, using such markers of GFR as criteria for diagnosing AKI has several limits including the difficult diagnosis of non-organic AKI, also called "functional renal insufficiency" or "pre-renal insufficiency". This situation is characterized by an oliguria and an increase in creatininemia as a consequence of a reduction in renal blood flow related to systemic haemodynamic abnormalities. In this situation, "renal insufficiency" seems rather inappropriate as kidney function is not impaired. On the contrary, the kidney delivers an appropriate response aiming to recover optimal systemic physiological haemodynamic conditions. Considering the kidney as insufficient is erroneous because this suggests that it does not work correctly, whereas the opposite is occurring, because the kidney is healthy even in a threatening situation. With current definitions of AKI, normalization of volaemia is needed before defining AKI in order to avoid this pitfall.

[Perioperative acute kidney injury and failure]. / Insuffisance et agression rénales aiguës périopératoires.

Perioperative period is very likely to lead to acute renal failure because of anesthesia (general or perimedullary) and/or surgery which can cause acute kidney injury. Characterization of acute renal failure is based on serum creatinine level which is imprecise during and following surgery. Studies are based on various definitions of acute renal failure with different thresholds which skewed their comparisons. The RIFLE classification (risk, injury, failure, loss, end stage kidney disease) allows clinicians to distinguish in a similar manner between different stages of acute kidney injury rather than using a unique definition of acute renal failure. Acute renal failure during the perioperative period can mainly be explained by iatrogenic, hemodynamic or surgical causes and can result in an increased morbi-mortality. Prevention of this complication requires hemodynamic optimization (venous return, cardiac output, vascular resistance), discontinuation of nephrotoxic drugs but also knowledge of the different steps of the surgery to avoid further degradation of renal perfusion. Diuretics do not prevent acute renal failure and may even push it forward especially during the perioperative period when venous retourn is already reduced. Edema or weight gain following surgery are not correlated with the vascular compartment volume, much less with renal perfusion. Treatment of perioperative acute renal failure is similar to other acute renal failure. Renal replacement therapy must be mastered to prevent any additional risk of hemodynamic instability or hydro-electrolytic imbalance.

Predictive performance of urine neutrophil gelatinase-associated lipocalin for dialysis requirement and death following cardiac surgery in neonates and infants.

BACKGROUND AND OBJECTIVES: Urine neutrophil gelatinase-associated lipocalin (uNGAL) has been shown to accurately predict and allow early detection of AKI, as assessed by an increase in serum creatinine in children and adults. The present study explores the accuracy of uNGAL for the prediction of severe AKI-related outcomes in neonates and infants undergoing cardiac surgery: dialysis requirement and/or death within 30 days. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Prospective, observational cohort study conducted in a tertiary referral pediatric cardiac intensive care unit, including 75 neonates and 125 infants undergoing surgery with cardiopulmonary bypass between August 1, 2010, and May 31, 2011. Urine samples were collected before surgery and at median of five time points within 48 hours of bypass. Urine NGAL was quantified as absolute concentration, creatinine-normalized concentration, and absolute excretion rate, and a clusterization algorithm was applied to the individual uNGAL kinetics. The accuracy for the prediction of the outcome was assessed using receiver-operating characteristic areas, likelihood ratios, diagnostic odds ratios, net reclassification index, integrated reclassification improvement, and number needed to screen. RESULTS: A total of 1176 urine samples were collected. Of all patients, 8% required dialysis and 4% died. Three clusters of uNGAL kinetics were identified, including patients with significantly different outcomes. The uNGAL level peaked between 1 and 3 hours of bypass and remained high in half of all patients who required dialysis or died. The uNGAL levels measured within 24 hours of bypass accurately predicted the outcome and performed best after normalization to creatinine, with varying cutoffs according to the time elapsed since bypass. The number needed to screen to correctly identify the risk of dialysis or death in one patient varied between 1.5 and 2.6 within 12 hours of bypass. CONCLUSIONS: uNGAL is a valuable predictive tool of dialysis requirement and death in neonates and infants with AKI after cardiac surgery.

Limitations of early serum creatinine variations for the assessment of kidney injury in neonates and infants with cardiac surgery.

BACKGROUND: Changes in kidney function, as assessed by early and even small variations in serum creatinine (ΔsCr), affect survival in adults following cardiac surgery but such associations have not been reported in infants. This raises the question of the adequate assessment of kidney function by early ΔsCr in infants undergoing cardiac surgery. METHODOLOGY: The ability of ΔsCr within 2 days of surgery to assess the severity of kidney injury, accounted for by the risk of 30-day mortality, was explored retrospectively in 1019 consecutive neonates and infants. Patients aged ≤ 10 days were analyzed separately because of the physiological improvement in glomerular filtration early after birth. The Kml algorithm, an implementation of k-means for longitudinal data, was used to describe creatinine kinetics, and the receiver operating characteristic and the reclassification methodology to assess discrimination and the predictive ability of the risk of death. RESULTS: Three clusters of ΔsCr were identified: in 50% of all patients creatinine decreased, in 41.4% it increased slightly, and in 8.6% it rose abruptly. Mortality rates were not significantly different between the first and second clusters, 1.6% [0.0-4.1] vs 5.9% [1.9-10.9], respectively, in patients aged ≤ 10 days, and 1.6% [0.5-3.0] vs 3.8% [1.9-6.0] in older ones. Mortality rates were significantly higher when creatinine rose abruptly, 30.3% [15.1-46.2] in patients aged ≤ 10 days, and 15.1% [5.9-25.5] in older ones. However, only 41.3% of all patients who died had an abrupt increase in creatinine. ΔsCr improved prediction in survivors, but not in patients who died, and did not improve discrimination over a clinical mortality model. CONCLUSIONS: The present results suggest that a postoperative decrease in creatinine represents the normal course in neonates and infants with cardiac surgery, and that early creatinine variations lack sensitivity for the assessment of the severity of kidney injury.

Do simple screening statistical tools help to detect reporting bias?

BACKGROUND: As a result of reporting bias, or frauds, false or misunderstood findings may represent the majority of published research claims. This article provides simple methods that might help to appraise the quality of the reporting of randomized, controlled trials (RCT). METHODS: This evaluation roadmap proposed herein relies on four steps: evaluation of the distribution of the reported variables; evaluation of the distribution of the reported p values; data simulation using parametric bootstrap and explicit computation of the p values. Such an approach was illustrated using published data from a retracted RCT comparing a hydroxyethyl starch versus albumin-based priming for cardiopulmonary bypass. RESULTS: Despite obvious nonnormal distributions, several variables are presented as if they were normally distributed. The set of 16 p values testing for differences in baseline characteristics across randomized groups did not follow a Uniform distribution on [0,1] (p = 0.045). The p values obtained by explicit computations were different from the results reported by the authors for the two following variables: urine output at 5 hours (calculated p value < 10-6, reported p ≥ 0.05); packed red blood cells (PRBC) during surgery (calculated p value = 0.08; reported p < 0.05). Finally, parametric bootstrap found p value > 0.05 in only 5 of the 10,000 simulated datasets concerning urine output 5 hours after surgery. Concerning PRBC transfused during surgery, parametric bootstrap showed that only the corresponding p value had less than a 50% chance to be inferior to 0.05 (3,920/10,000, p value < 0.05). CONCLUSIONS: Such simple evaluation methods might offer some warning signals. However, it should be emphasized that such methods do not allow concluding to the presence of error or fraud but should rather be used to justify asking for an access to the raw data.

Early initiation of peritoneal dialysis in neonates and infants with acute kidney injury following cardiac surgery is associated with a significant decrease in mortality.

Association between early renal replacement therapy and better survival has been reported in adults with postoperative kidney injury, but not in children undergoing cardiac surgery. We conducted a retrospective cohort study of 146 neonates and infants requiring peritoneal dialysis following cardiac surgery in a tertiary referral hospital. A propensity score was used to limit selection bias due to timing of dialysis, and included baseline and intraoperative characteristics, requirement for postoperative extracorporeal membrane oxygenation, and creatinine clearance variation. Inverse probability of treatment weighting resulted in good balance between groups for all baseline and intraoperative variables. After weighting, 30-day and 90-day mortality were compared between the 109 patients placed on dialysis early, within the first day of surgery, and those with delayed dialysis, commencing on the second day of surgery or later, using logistic regression and survival analysis. Mortality was 28.1% at 30 days, and was 36.3% during follow-up. Early dialysis was associated with a 46.7% decrease in the 30-day and a 43.5% decrease in the 90-day mortality rate when compared with delayed dialysis. All other short-term outcome variables were similar. Thus, initiation of peritoneal dialysis on the day of or the first day following surgery was associated with a significant decrease in mortality in neonates and infants with acute kidney injury.

Factors associated with early graft dysfunction in cystic fibrosis patients receiving primary bilateral lung transplantation.

OBJECTIVES: Primary graft dysfunction (PGD) occurs in 10-25% of cases and remains responsible for significant morbidity and mortality after lung transplantation. Our goal was to explore donor and recipient variables and procedure factors that could be related to early graft failure in cystic fibrosis patients receiving bilateral lung transplantation, the PGD grade being derived from the PaO(2)/FiO(2) ratio measured at the sixth post-operative hour. METHODS: Data from 122 cystic fibrosis patients having undergone lung transplantation in six transplant centres in France were retrospectively analysed. Donor and recipient variables, procedure characteristics and anaesthesia management items were recorded and analysed with regard to the PaO(2)/FiO(2) ratio at the sixth post-operative hour. Recipients were divided into three groups according to this ratio: Grade I PGD, when PaO(2)/FiO(2) >300 mmHg or extubated patients, Grade II, when PaO(2)/FiO(2) = 200-300 mmHg, and Grade III, when PaO(2)/FiO(2) <200 mmHg or extracorporeal membrane oxygenation still required. RESULTS: Forty-eight patients were Grade I, 32 patients Grade II and 42 patients Grade III PGD. Oto's donor score, recipient variables and procedure characteristics were not statistically linked to PaO(2)/FiO(2) at the sixth post-operative hour. Ischaemic time of the last implanted graft and the lactate level at the end of the procedure are the only factors related to Grade III PGD in this group. CONCLUSIONS: Hyperlactataemia most probably reflects the severity of early PGD, which leaves graft ischaemic time as the only factor predicting early PGD in a multicentre population of cystic fibrosis lung graft recipients.

Low social support is associated with an increased risk of postoperative delirium.

STUDY OBJECTIVE: To examine the predictive value of social support in postoperative delirium. DESIGN: Prospective observational study. SETTING: Postoperative recovery room and orthopedic surgery department. PATIENTS: 106 consecutive patients undergoing a planned orthopedic surgery with general anesthesia. MEASUREMENTS: All patients completed questionnaires to assess depressive mood (the Beck Depression Inventory) and social support (Sarason's Social Support Questionnaire) during the preanesthesia visit. Postoperative delirium symptoms were assessed daily using the Memorial Delirium Assessment Scale. Demographic, clinical, and biological data, including anesthesia procedure, were recorded. MAIN RESULTS: Controlling for various potential confounders through multivariate binary logistic regression, postoperative delirium was independently predicted by satisfaction with social support, but neither by depressive mood nor the number of supportive persons. Other significant predictors were the preoperative use of benzodiazepines, age, and type of surgery. CONCLUSION: Patients who report low satisfaction with social support may present with a particular vulnerability to postoperative delirium, even after controlling for physical confounding variables and depressive mood.

Partitioning of exhaled NO in ventilated patients undergoing cardiac surgery.

The change in exhaled NO after cardio-pulmonary bypass remains controversial. The aims were to determine whether exhaled NO sources (alveolar or bronchial) are modified after bypass, and whether mechanical ventilation (MV) settings during bypass modify exhaled NO changes. Thirty-two patients were divided into three groups: without MV during bypass and positive end-expiratory pressure (PEEP) (n=12), dead space MV without PEEP (n=10) and dead space MV with PEEP (n=10). Alveolar NO concentration and bronchial NO flux were calculated before and 1h after surgery using a two-compartment model of NO exchange developed in spontaneous breathing patients. Whereas a significant decrease in bronchial NO was found after bypass in the two groups without PEEP during bypass, this decrease was not observed in patients with dead space ventilation with PEEP. Alveolar NO was not significantly modified whatever the ventilation settings. In conclusion, the impairment of bronchial NO seemed related to airway closure since dead space mechanical ventilation with PEEP prevented its decrease.

Misleading abdominal pain following extracorporeal renal lithotripsy.

INTRODUCTION: Extracorporeal shockwave lithotripsy (ESWL) is a useful technique for the treatment of kidney and urinary tract stones but appears also to cause some extrarenal complications. CASE PRESENTATION: We report the case of a 33-year-old Caucasian man with a history of Crohn's disease who presented septic shock due to a jejunum perforation 6 h following an ESWL for a right ureteral stone. The perforation, which occurred at the exact site of a previous surgical anastomosis, was revealed on a CT scan which found an unusual aspect probably due to cavitation and bubbles formation induced by ESWL. CONCLUSION: This case emphasizes the particular aspect of CT scan and the extrarenal potential danger of the ESWL procedure. Some precautions and dedicated patient information must be taken when used in patients with chronic inflammation of the digestive tract or history of intestinal surgery.