Fluid bolus increases plasma hyaluronan concentration compared to follow-up strategy without a bolus in oliguric intensive care unit patients.

Fluid therapy is a fundamental part of supportive therapy in critical care. However, it is also a suspected risk for endothelial glycocalyx degradation which is associated with poor clinical outcomes. This secondary analysis of RESPONSE randomized trial compares the effect of follow-up strategy (FU) on endothelial biomarkers to that of 500 ml crystalloid fluid bolus (FB) in oliguric, hemodynamically optimized intensive care unit (ICU) patients. 130 adult subjects were enrolled in two Finnish ICUs from January 2017 to November 2020. Blood and urine samples of 63 patients in FU group and 67 patients in FB group were collected before and after the intervention and analyzed using enzyme-linked immunosorbent assays. Single fluid bolus, given after median of 3887 ml (interquartile range 2842; 5359 ml) resuscitation fluids in the preceding 24 h, increased plasma hyaluronan concentration compared to the follow-up strategy (difference in medians 29.2 ng/ml with 95% CI [14.5ng/ml; 55.5ng/ml], P < 0.001). No treatment effect was detected in the plasma levels of syndecan-1, , angiopoietin-2, angiopoietin receptors Tie2 and Tie1, or in soluble thrombomodulin in the adjusted median regression analysis. The increase in hyaluronan was independent of its simultaneous renal clearance but correlated moderately with the increase in endothelium-specific Tie1. The follow-up strategy did not show consistent endothelium-sparing effect but protected against hyaluronan increase. The mechanisms and consequences of hyaluronan fluctuations need further clarification. Trial registration: clinicaltrials.gov, NCT02860572. Registered 1 August 2016, https://www.clinicaltrials.gov/study/NCT02860572?term=NCT02860572&rank=1.

A protocol for an international, multicentre pharmacokinetic study for Screening Antifungal Exposure in Intensive Care Units: The SAFE-ICU study.

Objective: To describe whether contemporary dosing of antifungal drugs achieves therapeutic exposures in critically ill patients that are associated with optimal outcomes. Adequate antifungal therapy is a key determinant of survival of critically ill patients with fungal infections. Critical illness can alter an antifungal agents' pharmacokinetics, increasing the risk of inappropriate antifungal exposure that may lead to treatment failure and/or toxicity. Design setting and participants: This international, multicentre, observational pharmacokinetic study will comprise adult critically ill patients prescribed antifungal agents including fluconazole, voriconazole, posaconazole, isavuconazole, caspofungin, micafungin, anidulafungin, and amphotericin B for the treatment or prophylaxis of invasive fungal disease. A minimum of 12 patients are targeted for enrolment for each antifungal agent, across 12 countries and 30 intensive care units to perform descriptive pharmacokinetics. Pharmacokinetic sampling will occur during two dosing intervals (occasions): firstly, between days 1 and 3, and secondly, between days 4 and 7 of the antifungal course, collecting three samples per occasion. Patients' demographic and clinical data will be collected. Main outcome measures: The primary endpoint of the study is attainment of pharmacokinetic/pharmacodynamic target exposures that are associated with optimal efficacy. Thirty-day mortality will also be measured. Results and conclusions: This study will describe whether contemporary antifungal drug dosing achieves drug exposures associated with optimal outcomes. Data will also be used for the development of antifungal dosing algorithms for critically ill patients. Optimised drug dosing should be considered a priority for improving clinical outcomes for critically ill patients with fungal infections.

Non-interventional follow-up versus fluid bolus in RESPONSE to oliguria in hemodynamically stable critically ill patients: a randomized controlled pilot trial.

BACKGROUND: Fluid bolus therapy is a common intervention to improve urine output. Data concerning the effect of a fluid bolus on oliguria originate mainly from observational studies and remain controversial regarding the actual benefit of such therapy. We compared the effect of a follow-up approach without fluid bolus to a 500 mL fluid bolus on urine output in hemodynamically stable critically ill patients with oliguria at least for 2 h (urine output < 0.5 mL/kg/h) in randomized setting. METHODS: We randomized 130 patients in 1:1 fashion to receive either (1) non-interventional follow-up (FU) for 2 h or (2) 500 mL crystalloid fluid bolus (FB) administered over 30 min. The primary outcome was the proportion of patients who doubled their urine output, defined as 2-h urine output post-randomization divided by urine output 2 h pre-randomization. The outcomes were adjusted for the stratification variables (presence of sepsis or AKI) using two-tailed regression. Obtained odds ratios were converted to risk ratios (RR) with 95% confidence intervals (CI). The between-group difference in the continuous variables was compared using mean or median regression and expressed with 95% CIs. RESULTS: Altogether 10 (15.9%) of 63 patients in the FU group and 22 (32.8%) of 67 patients in FB group doubled their urine output during the 2-h period, RR (95% CI) 0.49 (0.23-0.71), P = 0.026. Median [IQR] change in individual urine output 2 h post-randomization compared to 2 h pre-randomization was - 7 [- 19 to 17] mL in the FU group and 19[0-53] mL in the FB group, median difference (95% CI) - 23 (- 36 to - 10) mL, P = 0.001. Median [IQR] duration of oliguria in the FU group was 4 [2-8] h and in the FB group 2 [0-6] h, median difference (95%CI) 2 (0-4) h, P = 0.038. Median [IQR] cumulative fluid balance on study day was lower in the FU group compared to FB group, 678 [518-1029] mL versus 1071 [822-1505] mL, respectively, median difference (95%CI) - 387 (- 635 to - 213) mL, P < 0.001. CONCLUSIONS: Follow-up approach to oliguria compared to administering a fluid bolus of 500 mL crystalloid in oliguric patients improved urine output less frequently but lead to lower cumulative fluid balance. Trial registration clinical. TRIALS: gov, NCT02860572. Registered 9 August 2016.

End of life decisions in immunocompromised patients with acute respiratory failure.

PURPOSE: To identify patient, disease and organizational factors associated with decisions to forgo life-sustaining therapies (DFLSTs) in critically ill immunocompromised patients admitted to the intensive care unit (ICU) for acute respiratory failure. MATERIAL AND METHODS: We performed a secondary analysis of the international EFRAIM prospective study, which enrolled 1611 immunocompromised patients with acute respiratory failure admitted to 68 ICUs in 16 countries between October 2015 and June 2016. Multivariate logistic analysis was performed to identify independent predictors of DFLSTs. RESULTS: The main causes of immunosuppression were hematological malignancies (50%) and solid tumor (38%). Patients had a median age of 63 yo (54-71). A pulmonologist was involved in the patient management in 38% of cases. DFLSTs had been implemented in 28% of the patients. The following variables were independently associated with DFLSTs: 1) patient-related: older age (OR 1.02 per one year increase, 95% confidence interval(CI) 1.01-1.03,P < 0.001), poor performance status (OR 2.79, 95% CI 1.98-3.93, P < 0.001); 2) disease-related: shock (OR 2.00, 95% CI 1.45-2.75, P < 0.001), liver failure (OR 1.59, 95% CI 1.14-2.21, P = 0.006), invasive mechanical ventilation (OR 1.79, 95% CI 1.31-2.46, P < 0.001); 3) organizational: having a pulmonologist involved in patient management (OR 1.85, 95% CI 1.36-2.52, P < 0.001), and the presence of a critical care outreach services (OR 1.63, 95% CI 1.11-2.38, P = 0.012). CONCLUSIONS: A DFLST is made in one in four immunocompromised patient admitted to the ICU for acute respiratory failure. Involving a pulmonologist in patient's management is associated with less non beneficial care.

Occurrence and Risk Factors of Infected Pancreatic Necrosis in Intensive Care Unit-Treated Patients with Necrotizing Severe Acute Pancreatitis.

BACKGROUND: In patients with severe acute pancreatitis (SAP), infected pancreatic necrosis (IPN) is associated with a worsened outcome. We studied risk factors and consequences of IPN in patients with necrotizing SAP. METHODS: The study consisted of a retrospective cohort of 163 consecutive patients treated for necrotizing SAP at a university hospital intensive care unit (ICU) between 2010 and 2018. RESULTS: All patients had experienced at least one persistent organ failure and approximately 60% had multiple organ failure within the first 24 h from admission to the ICU. Forty-seven (28.8%) patients had IPN within 90 days. Independent risk factors for IPN were more extensive anatomical spread of necrotic collections (unilateral paracolic or retromesenteric (OR 5.7, 95% CI 1.5-21.1) and widespread (OR 21.8, 95% CI 6.1-77.8)) compared to local collections around the pancreas, postinterventional pancreatitis (OR 13.5, 95% CI 2.4-76.5), preceding bacteremia (OR 4.8, 95% CI 1.3-17.6), and preceding open abdomen treatment for abdominal compartment syndrome (OR 3.6, 95% CI 1.4-9.3). Patients with IPN had longer ICU and overall hospital lengths of stay, higher risk for necrosectomy, and higher readmission rate to ICU. CONCLUSIONS: Wide anatomical spread of necrotic collections, postinterventional etiology, preceding bacteremia, and preceding open abdomen treatment were identified as independent risk factors for IPN.

Continuous intravenous infusion of enoxaparin controls thrombin formation more than standard subcutaneous administration in critically ill patients. A sub-study of the ENOKSI thromboprophylaxis RCT.

INTRODUCTION: Standard subcutaneous low-molecular-weight heparin (LMWH) thromboprophylaxis yields low anti-factor Xa activity in patients in the intensive care unit (ICU). The aim of the study was to assess coagulation status in ICU patients randomized to receive enoxaparin thromboprophylaxis either as a standard subcutaneous bolus (SCB) or continuous intravenous infusion (CII) for 3 consecutive days after the initiation of LMWH thromboprophylaxis. MATERIALS AND METHODS: Thirty-eight patients were studied by conventional coagulation variables: prothrombin fragment F 1+2 (F 1+2) representing FXa inhibition and antithrombin (AT). Additionally, 18 patients were analyzed by the thrombin generation assay-calibrated automated thrombogram (TGA-CAT). Blood samples were collected before the initiation of the LMWH thromboprophylaxis (ie, baseline), at 51 h, and at 72 h. RESULTS: At beginning, no differences in coagulation biomarkers were observed. The levels of F 1+2 were significantly lower at 51 and 72 h in the CII group than in the SCB group. AT levels increased during the follow-up in the CII group, unlike in the SCB group. TGA-CAT was poor in some patients overall. In a subset of patients at 51 h lag time (4.3 vs 7.5 min, respectively, P < 0.05) and time to peak (7.7 vs 14.3 min, respectively, P < 0.05) were prolonged in the SCB group. At 72 h, however, peak thrombin was lower in the CII than in the SCB group: 271 vs 356 nM, respectively (P < 0.05). CONCLUSIONS: Enoxaparin thromboprophylaxis administered by CII inhibited more prominently FXa and preserved better the AT level, compared with standard subcutaneous care.

ICU-acquired pneumonia in immunosuppressed patients with acute hypoxemic respiratory failure: A post-hoc analysis of a prospective international cohort study.

OBJECTIVE: Intensive Care Units (ICU) acquired Pneumonia (ICU-AP) is one of the most frequent nosocomial infections in critically ill patients. Our aim was to determine the effects of having an ICU-AP in immunosuppressed patients with acute hypoxemic respiratory failure. DESIGN: Post-hoc analysis of a multinational, prospective cohort study in 16 countries. SETTINGS: ICU. PATIENTS: Immunosuppressed patients with acute hypoxemic respiratory failure. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: The original cohort had 1611 and in this post-hoc analysis a total of 1512 patients with available data on hospital mortality and occurrence of ICU-AP were included. ICU-AP occurred in 158 patients (10.4%). Hospital mortality was higher in patients with ICU-AP (14.8% vs. 7.1% p < 0.001). After adjustment for confounders and centre effect, use of vasopressors (Odds Ratio (OR) 2.22; 95%CI 1.46-3.39) and invasive mechanical ventilation at day 1 (OR 2.12 vs. high flow oxygen; 95%CI 1.07-4.20) were associated with increased risk of ICU-AP while female gender (OR 0.63; 95%CI 0.43-94) and chronic kidney disease (OR 0.43; 95%CI 0.22-0.88) were associated with decreased risk of ICU-AP. After adjustment for confounders and centre effect, ICU-AP was independently associated with mortality (Hazard Ratio 1.48; 95%CI 14.-1.91; P = 0.003). CONCLUSIONS: The attributable mortality of ICU-AP has been repetitively questioned in immunosuppressed patients with acute respiratory failure. This manuscript found that ICU-AP represents an independent risk factor for hospital mortality.

The Effect of Renal Replacement Therapy and Antibiotic Dose on Antibiotic Concentrations in Critically Ill Patients: Data From the Multinational Sampling Antibiotics in Renal Replacement Therapy Study.

BACKGROUND: The optimal dosing of antibiotics in critically ill patients receiving renal replacement therapy (RRT) remains unclear. In this study, we describe the variability in RRT techniques and antibiotic dosing in critically ill patients receiving RRT and relate observed trough antibiotic concentrations to optimal targets. METHODS: We performed a prospective, observational, multinational, pharmacokinetic study in 29 intensive care units from 14 countries. We collected demographic, clinical, and RRT data. We measured trough antibiotic concentrations of meropenem, piperacillin-tazobactam, and vancomycin and related them to high- and low-target trough concentrations. RESULTS: We studied 381 patients and obtained 508 trough antibiotic concentrations. There was wide variability (4-8-fold) in antibiotic dosing regimens, RRT prescription, and estimated endogenous renal function. The overall median estimated total renal clearance (eTRCL) was 50 mL/minute (interquartile range [IQR], 35-65) and higher eTRCL was associated with lower trough concentrations for all antibiotics (P < .05). The median (IQR) trough concentration for meropenem was 12.1 mg/L (7.9-18.8), piperacillin was 78.6 mg/L (49.5-127.3), tazobactam was 9.5 mg/L (6.3-14.2), and vancomycin was 14.3 mg/L (11.6-21.8). Trough concentrations failed to meet optimal higher limits in 26%, 36%, and 72% and optimal lower limits in 4%, 4%, and 55% of patients for meropenem, piperacillin, and vancomycin, respectively. CONCLUSIONS: In critically ill patients treated with RRT, antibiotic dosing regimens, RRT prescription, and eTRCL varied markedly and resulted in highly variable antibiotic concentrations that failed to meet therapeutic targets in many patients.

Acute respiratory failure in immunocompromised patients: outcome and clinical features according to neutropenia status.

BACKGROUND: The impact of neutropenia in critically ill immunocompromised patients admitted in a context of acute respiratory failure (ARF) remains uncertain. The primary objective was to assess the prognostic impact of neutropenia on outcomes of these patients. Secondary objective was to assess etiology of ARF according to neutropenia. METHODS: We performed a post hoc analysis of a prospective multicenter multinational study from 23 ICUs belonging to the Nine-I network. Between November 2015 and July 2016, all adult immunocompromised patients with ARF admitted to the ICU were included in the study. Adjusted analyses included: (1) a hierarchical model with center as random effect; (2) propensity score (PS) matched cohort; and (3) adjusted analysis in the matched cohort. RESULTS: Overall, 1481 patients were included in this study of which 165 had neutropenia at ICU admission (11%). ARF etiologies distribution was significantly different between neutropenic and non-neutropenic patients, main etiologies being bacterial pneumonia (48% vs 27% in neutropenic and non-neutropenic patients, respectively). Initial oxygenation strategy was standard supplemental oxygen in 755 patients (51%), high-flow nasal oxygen in 165 (11%), non-invasive ventilation in 202 (14%) and invasive mechanical ventilation in 359 (24%). Before adjustment, hospital mortality was significantly higher in neutropenic patients (54% vs 42%; p = 0.006). After adjustment for confounder and center effect, neutropenia was no longer associated with outcome (OR 1.40, 95% CI 0.93-2.11). Similar results were observed after matching (52% vs 46%, respectively; p = 0.35) and after adjustment in the matched cohort (OR 1.04; 95% CI 0.63-1.72). CONCLUSION: Neutropenia at ICU admission is not associated with hospital mortality in this cohort of critically ill immunocompromised patients admitted for ARF. In neutropenic patients, main ARF etiologies are bacterial and fungal infections.

Respiratory Mechanics and Outcomes in Immunocompromised Patients With ARDS: A Secondary Analysis of the EFRAIM Study.

BACKGROUND: In view of the high mortality rate of immunocompromised patients with ARDS, it is important to identify targets for improvement. RESEARCH QUESTION: This study investigated factors associated with mortality in this specific ARDS population, including factors related to respiratory mechanics (plateau pressure [Pplat,rs], compliance [Crs], and driving pressure [ΔPrs]). STUDY DESIGN AND METHODS: This study consisted of a predefined secondary analysis of the EFRAIM data. Overall, 789 of 1,611 patients met the Berlin criteria for ARDS, and Pplat,rs, ΔPrs, and Crs were available for 494 patients. A hierarchical model was used to assess factors at ARDS onset independently associated with hospital mortality. RESULTS: Hospital mortality was 56.3%. After adjustment, variables independently associated with hospital mortality included ARDS of undetermined etiology (OR, 1.66; 95% CI, 1.01-2.72), need for vasopressors (OR, 1.91; 95% CI, 1.27-2.88), and need for renal replacement therapy (OR, 2.02; 95% CI, 1.37-2.97). ARDS severity according to the Berlin definition, neutropenia on admission, and the type of underlying disease were not significantly associated with mortality. Before adjustment, higher Pplat,rs, higher ΔPrs, and lower Crs were associated with higher mortality. Addition of each of these individual variables to the final hierarchical model revealed a significant association with mortality: ΔPrs (OR, 1.08; 95% CI, 1.05-1.12), Pplat,rs (OR, 1.07; 95% CI, 1.04-1.11), and Crs (OR, 0.97; 95% CI, 0.95-0.98). Tidal volume was not associated with mortality. INTERPRETATION: In immunocompromised patients with ARDS, respiratory mechanics provide additional prognostic information to predictors of hospital mortality. Studies designed to define lung-protective ventilation guided by these physiological variables may be warranted in this specific population.