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.

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.

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.

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.

Etiologies and Outcomes of Acute Respiratory Failure in Solid Organ Transplant Recipients: Insight Into the EFRAIM Multicenter Cohort.

BACKGROUND: Respiratory complications of solid organ transplant (SOT) are a diagnostic and therapeutic challenge when requiring intensive care unit (ICU) admission. We aimed at describing this challenge in a prospective cohort of SOT recipients admitted in the ICU. METHODS: In this post hoc analysis of an international cohort of immunocompromised patients admitted in the ICU for an acute respiratory failure, we analyzed all SOT recipients and compared their severity, etiologic diagnosis, prognosis, and outcome according to the performance of an invasive diagnostic strategy (encompassing a fiber-optic bronchoscopy and bronchoalveolar lavage), the type of transplanted organ, and the need of invasive ventilation at day 1. RESULTS: Among 1611 patients included in the primary study, 142 were SOT recipients (kidney, n = 73; 51.4%; lung, n = 33; 23.2%; liver, n = 29; 20.4%; heart, n = 7; 4.9%). Lung transplant recipients were younger than other SOT recipients, and severity did not differ across type of received organ. An invasive diagnostic strategy was more frequently performed in lung transplant recipients with a trend toward a higher rate of bacterial etiology in lung than kidney transplant recipients. Overall ICU survival of SOT recipients was 75.4%. Invasive diagnostic strategy, type of transplanted organ, and need of invasive mechanical ventilation at day 1 did not affect ICU prognosis. CONCLUSIONS: ICU management of hypoxemic acute respiratory failure in SOT recipients translated into a low ICU mortality rate, whatever the transplanted organ or the acute respiratory failure cause. The post-ICU burden of acute respiratory failure SOT recipients remains to be investigated.

Noninterventional follow-up vs fluid bolus in RESPONSE to oliguria-The RESPONSE trial protocol and statistical analysis plan.

BACKGROUND: Oliguria is a frequent trigger for administering a fluid bolus, but the effect of fluid bolus in improving urine output is inadequately demonstrated. Here, we summarize the protocol and detailed statistical analysis plan of the randomized, controlled RESPONSE trial comparing follow-up as the experimental group and a 500 mL crystalloid fluid bolus as the control group for oliguria in critically ill oliguric patients. METHODS: Our trial is an investigator-initiated, randomized, controlled, pilot trial conducted in three ICUs in two centers. We aim to randomize 1:1 altogether 130 hemodynamically stable oliguric patients either to a 2-hour follow-up without interventions or to receive a crystalloid bolus of 500 mL over 30 minutes. The primary outcome is the change in individual urine output during the 2-hour period compared to 2 hours preceding randomization. Doubling of the urine output is considered clinically significant. Additionally, we record the duration of oliguria, physiological and biochemical variables, adverse events, and the incidences of acute kidney injury and renal replacement therapy. CONCLUSIONS: Oliguria is a frequent trigger for potentially harmful fluid loading. Therefore, the RESPONSE trial will give information of the potential effect of fluid bolus on oliguria in critically ill patients. TRIAL REGISTRATION: clinical.trials.gov, NCT02860572.

Clinical and microbiological factors associated with mortality in candidemia in adult patients 2007-2016.

Background: Candidemia is a life-threatening infection with high mortality. Our aim was to evaluate the Candida species distribution, antifungal susceptibilities and risk factors associated with 30-day mortality in candidemia in Southern Finland. Methods: We present a retrospective analysis of candidemia cases from the hospital district of Helsinki and Uusimaa during 2007-2016. Patients younger than 18 years old were excluded. A total of 386 candida isolates from 374 episodes of candidemia were identified in 350 adult patients. Results:Candida albicans was the leading cause of candidemia (60.4%), followed by C. glabrata (21.5%), C. parapsilosis (5.2%) and C. dubliniensis (5.2%). There was no statistically significant change in the distribution of C. albicans vs non-albicans species during the study period. Thirty-day overall mortality was 30.7%. When patients who received no antifungal treatment were excluded from the mortality analysis, 30-day mortality was 23.0%. Severity of underlying illnesses (OR 20.55, 95% CI 5.98-70.60), ICU stay at the onset of candidemia (OR 5.06, 95% CI 1.75-14.68) and age >65 years (OR 3.98, 95% CI 1.97-8.02) were independent risk factors of 30-day mortality in multivariable analysis. However, there was no statistically significant association between 30-day mortality and an early start of an effective antifungal. Conclusion: There was not a significant shift to non-albicans species as the cause of candidemia in Southern Finland during the 10-year study period. Furthermore, we did not find an association between 30-day mortality and the early start of an antifungal treatment. Comorbidity considerably increased the risk of fatal outcome.

Influenza and associated co-infections in critically ill immunosuppressed patients.

BACKGROUND: It is unclear whether influenza infection and associated co-infection are associated with patient-important outcomes in critically ill immunocompromised patients with acute respiratory failure. METHODS: Preplanned secondary analysis of EFRAIM, a prospective cohort study of 68 hospitals in 16 countries. We included 1611 patients aged 18 years or older with non-AIDS-related immunocompromise, who were admitted to the ICU with acute hypoxemic respiratory failure. The main exposure of interest was influenza infection status. The primary outcome of interest was all-cause hospital mortality, and secondary outcomes ICU length of stay (LOS) and 90-day mortality. RESULTS: Influenza infection status was categorized into four groups: patients with influenza alone (n = 95, 5.8%), patients with influenza plus pulmonary co-infection (n = 58, 3.6%), patients with non-influenza pulmonary infection (n = 820, 50.9%), and patients without pulmonary infection (n = 638, 39.6%). Influenza infection status was associated with a requirement for intubation and with LOS in ICU (P < 0.001). Patients with influenza plus co-infection had the highest rates of intubation and longest ICU LOS. On crude analysis, influenza infection status was associated with ICU mortality (P < 0.001) but not hospital mortality (P = 0.09). Patients with influenza plus co-infection and patients with non-influenza infection alone had similar ICU mortality (41% and 37% respectively) that was higher than patients with influenza alone or those without infection (33% and 26% respectively). A propensity score-matched analysis did not show a difference in hospital mortality attributable to influenza infection (OR = 1.01, 95%CI 0.90-1.13, P = 0.85). Age, severity scores, ARDS, and performance status were all associated with ICU, hospital, and 90-day mortality. CONCLUSIONS: Category of infectious etiology of respiratory failure (influenza, non-influenza, influenza plus co-infection, and non-infectious) was associated with ICU but not hospital mortality. In a propensity score-matched analysis, influenza infection was not associated with the primary outcome of hospital mortality. Overall, influenza infection alone may not be an independent risk factor for hospital mortality in immunosuppressed patients.

Low Temperature and Low UV Indexes Correlated with Peaks of Influenza Virus Activity in Northern Europe during 2010⁻2018.

With the increasing pace of global warming, it is important to understand the role of meteorological factors in influenza virus (IV) epidemics. In this study, we investigated the impact of temperature, UV index, humidity, wind speed, atmospheric pressure, and precipitation on IV activity in Norway, Sweden, Finland, Estonia, Latvia and Lithuania during 2010⁻2018. Both correlation and machine learning analyses revealed that low temperature and UV indexes were the most predictive meteorological factors for IV epidemics in Northern Europe. Our in vitro experiments confirmed that low temperature and UV radiation preserved IV infectivity. Associations between these meteorological factors and IV activity could improve surveillance and promote development of accurate predictive models for future influenza outbreaks in the region.

Plasma bradykinin concentrations during septic shock determined by a novel LC-MS/MS assay.

BACKGROUND: Bradykinin is an important mediator of inflammation and vascular permeability and could have an important role in the development of septic shock. Measurement of bradykinin by immunological methods may suffer from interference and lack of specificity. We developed and validated a liquid chromatography mass spectrometry assay (LC-MS/MS) for plasma bradykinin. METHODS: We used plasma samples from healthy volunteers (n = 19) and patients with septic shock (n = 47). Stable isotope bradykinin internal standard was added to samples before solid-phase extraction and quantification by LC-MS/MS. Stability of bradykinin was studied for 12 months. RESULTS: Our assay has good sensitivity (0.1 nmol/l) and a wide linear range (0.1-1000 nmol/l). Bradykinin added to plasma was stable for 12 months at -20 °C when a mixture of protease inhibitors was added at sampling but degraded during repeated freezing and thawing. Bradykinin concentration in plasma from septic shock patients (<0.1-0.6 nmol/l) did not change significantly during shock and recovery but differed slightly from that in healthy individuals (0.5-1.1 nmol/l). CONCLUSIONS: Our bradykinin assay was successfully used to determine bradykinin concentrations in plasma samples. Intensive care unit patients with septic shock had low concentrations of plasma bradykinin during both shock and recovery phases.

Targeting low-normal or high-normal mean arterial pressure after cardiac arrest and resuscitation: a randomised pilot trial.

PURPOSE: We aimed to determine the feasibility of targeting low-normal or high-normal mean arterial pressure (MAP) after out-of-hospital cardiac arrest (OHCA) and its effect on markers of neurological injury. METHODS: In the Carbon dioxide, Oxygen and Mean arterial pressure After Cardiac Arrest and REsuscitation (COMACARE) trial, we used a 23 factorial design to randomly assign patients after OHCA and resuscitation to low-normal or high-normal levels of arterial carbon dioxide tension, to normoxia or moderate hyperoxia, and to low-normal or high-normal MAP. In this paper we report the results of the low-normal (65-75 mmHg) vs. high-normal (80-100 mmHg) MAP comparison. The primary outcome was the serum concentration of neuron-specific enolase (NSE) at 48 h after cardiac arrest. The feasibility outcome was the difference in MAP between the groups. Secondary outcomes included S100B protein and cardiac troponin (TnT) concentrations, electroencephalography (EEG) findings, cerebral oxygenation and neurological outcome at 6 months after cardiac arrest. RESULTS: We recruited 123 patients and included 120 in the final analysis. We found a clear separation in MAP between the groups (p < 0.001). The median (interquartile range) NSE concentration at 48 h was 20.6 µg/L (15.2-34.9 µg/L) in the low-normal MAP group and 22.0 µg/L (13.6-30.9 µg/L) in the high-normal MAP group, p = 0.522. We found no differences in the secondary outcomes. CONCLUSIONS: Targeting a specific range of MAP was feasible during post-resuscitation intensive care. However, the blood pressure level did not affect the NSE concentration at 48 h after cardiac arrest, nor any secondary outcomes.

Effect of Human Recombinant Alkaline Phosphatase on 7-Day Creatinine Clearance in Patients With Sepsis-Associated Acute Kidney Injury: A Randomized Clinical Trial.

Importance: Sepsis-associated acute kidney injury (AKI) adversely affects long-term kidney outcomes and survival. Administration of the detoxifying enzyme alkaline phosphatase may improve kidney function and survival. Objective: To determine the optimal therapeutic dose, effect on kidney function, and adverse effects of a human recombinant alkaline phosphatase in patients who are critically ill with sepsis-associated AKI. Design, Setting, and Participants: The STOP-AKI trial was an international (53 recruiting sites), randomized, double-blind, placebo-controlled, dose-finding, adaptive phase 2a/2b study in 301 adult patients admitted to the intensive care unit with a diagnosis of sepsis and AKI. Patients were enrolled between December 2014 and May 2017, and follow-up was conducted for 90 days. The final date of follow-up was August 14, 2017. Interventions: In the intention-to-treat analysis, in part 1 of the trial, patients were randomized to receive recombinant alkaline phosphatase in a dosage of 0.4 mg/kg (n = 31), 0.8 mg/kg (n = 32), or 1.6 mg/kg (n = 29) or placebo (n = 30), once daily for 3 days, to establish the optimal dose. The optimal dose was identified as 1.6 mg/kg based on modeling approaches and adverse events. In part 2, 1.6 mg/kg (n = 82) was compared with placebo (n = 86). Main Outcomes and Measures: The primary end point was the time-corrected area under the curve of the endogenous creatinine clearance for days 1 through 7, divided by 7 to provide a mean daily creatinine clearance (AUC1-7 ECC). Incidence of fatal and nonfatal (serious) adverse events ([S]AEs) was also determined. Results: Overall, 301 patients were enrolled (men, 70.7%; median age, 67 years [interquartile range {IQR}, 59-73]). From day 1 to day 7, median ECC increased from 26.0 mL/min (IQR, 8.8 to 59.5) to 65.4 mL/min (IQR, 26.7 to 115.4) in the recombinant alkaline phosphatase 1.6-mg/kg group vs from 35.9 mL/min (IQR, 12.2 to 82.9) to 61.9 mL/min (IQR, 22.7 to 115.2) in the placebo group (absolute difference, 9.5 mL/min [95% CI, -23.9 to 25.5]; P = .47). Fatal adverse events occurred in 26.3% of patients in the 0.4-mg/kg recombinant alkaline phosphatase group; 17.1% in the 0.8-mg/kg group, 17.4% in the 1.6-mg/kg group, and 29.5% in the placebo group. Rates of nonfatal SAEs were 21.0% for the 0.4-mg/kg recombinant alkaline phosphatase group, 14.3% for the 0.8-mg/kg group, 25.7% for the 1.6-mg/kg group, and 20.5% for the placebo group. Conclusions and Relevance: Among patients who were critically ill with sepsis-associated acute kidney injury, human recombinant alkaline phosphatase compared with placebo did not significantly improve short-term kidney function. Further research is necessary to assess other clinical outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT02182440.

Novel activities of safe-in-human broad-spectrum antiviral agents.

According to the WHO, there is an urgent need for better control of viral diseases. Re-positioning existing safe-in-human antiviral agents from one viral disease to another could play a pivotal role in this process. Here, we reviewed all approved, investigational and experimental antiviral agents, which are safe in man, and identified 59 compounds that target at least three viral diseases. We tested 55 of these compounds against eight different RNA and DNA viruses. We found novel activities for dalbavancin against echovirus 1, ezetimibe against human immunodeficiency virus 1 and Zika virus, as well as azacitidine, cyclosporine, minocycline, oritavancin and ritonavir against Rift valley fever virus. Thus, the spectrum of antiviral activities of existing antiviral agents could be expanded towards other viral diseases.

Acute hypoxemic respiratory failure in immunocompromised patients: the Efraim multinational prospective cohort study.

BACKGROUND: In immunocompromised patients with acute hypoxemic respiratory failure (ARF), initial management aims primarily to avoid invasive mechanical ventilation (IMV). METHODS: To assess the impact of initial management on IMV and mortality rates, we performed a multinational observational prospective cohort study in 16 countries (68 centers). RESULTS: A total of 1611 patients were enrolled (hematological malignancies 51.9%, solid tumors 35.2%, systemic diseases 17.3%, and solid organ transplantation 8.8%). The main ARF etiologies were bacterial (29.5%), viral (15.4%), and fungal infections (14.7%), or undetermined (13.2%). On admission, 915 (56.8%) patients were not intubated. They received standard oxygen (N = 496, 53.9%), high-flow oxygen (HFNC, N = 187, 20.3%), noninvasive ventilation (NIV, N = 153, 17.2%), and NIV + HFNC (N = 79, 8.6%). Factors associated with IMV included age (hazard ratio = 0.92/year, 95% CI 0.86-0.99), day-1 SOFA (1.09/point, 1.06-1.13), day-1 PaO2/FiO2 (1.47, 1.05-2.07), ARF etiology (Pneumocystis jirovecii pneumonia (2.11, 1.42-3.14), invasive pulmonary aspergillosis (1.85, 1.21-2.85), and undetermined cause (1.46, 1.09-1.98). After propensity score matching, HFNC, but not NIV, had an effect on IMV rate (HR = 0.77, 95% CI 0.59-1.00, p = 0.05). ICU, hospital, and day-90 mortality rates were 32.4, 44.1, and 56.4%, respectively. Factors independently associated with hospital mortality included age (odds ratio = 1.18/year, 1.09-1.27), direct admission to the ICU (0.69, 0.54-0.87), day-1 SOFA excluding respiratory score (1.12/point, 1.08-1.16), PaO2/FiO2 < 100 (1.60, 1.03-2.48), and undetermined ARF etiology (1.43, 1.04-1.97). Initial oxygenation strategy did not affect mortality; however, IMV was associated with mortality, the odds ratio depending on IMV conditions: NIV + HFNC failure (2.31, 1.09-4.91), first-line IMV (2.55, 1.94-3.29), NIV failure (3.65, 2.05-6.53), standard oxygen failure (4.16, 2.91-5.93), and HFNC failure (5.54, 3.27-9.38). CONCLUSION: HFNC has an effect on intubation but not on mortality rates. Failure to identify ARF etiology is associated with higher rates of both intubation and mortality. This suggests that in addition to selecting the appropriate oxygenation device, clinicians should strive to identify the etiology of ARF.

Plasma anti-FXa concentration after continuous intravenous infusion and subcutaneous dosing of enoxaparin for thromboprophylaxis in critically ill patients. A randomized clinical trial.

INTRODUCTION: In intensive care unit (ICU) patients, subcutaneous low-molecular weight heparin thromboprophylaxis results in lower plasma anti-factor Xa (anti-FXa) levels compared to general ward patients. The aim of this study was to examine whether enoxaparin thromboprophylaxis given as a continuous intravenous infusion (CII) results in more constant and predictable anti-FXa concentration than standard subcutaneous bolus (SCB) administration. MATERIALS AND METHODS: This was a prospective, single-blind, multicenter, randomized controlled trial where ICU patients requiring thromboprophylaxis received enoxaparin either 40mg as a SCB once daily or 40mg as a CII over 24h for three consecutive days. The primary outcome was maximum serum anti-FXa concentration (Cmax24h) within the first 24h; the secondary outcome was anti-FXa area under the curve (AUC)(0-24h). Trough level was measured at 72h. RESULTS: Thirty-nine patients were included in the intention to treat analysis. The median anti-FXa Cmax24h was 0.05 (interquartile range, IQR, 0.05-0.18) IU/ml in the CII group and 0.18 (IQR, 0.12-0.33) IU/ml in the SCB group (p=0.05). Median anti-FXa AUC(0-24h) was 1.20 (IQR, 0.98-2.88) in the CII and 1.54 (IQR, 1.22-4.12) in the SCB group (p=0.095). After 72h, 66.7% of patients in the CII group had a detectable anti-FXa concentration of >0.1IU/ml, compared with 16.7% in the SCB group (p=0.019). CONCLUSIONS: Continuous infusion of enoxaparin led to lower anti-FXa Cmax24h than standard SCB administration. No difference in anti-FXa AUC0-24h was detected.