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OBJECTIVES The Doppler-based resistive index and semiquantitative evaluation of renal perfusion using color Doppler failed to discriminate renal recovery patterns in a recent study. The influence of operator experience on resistive index and semiquantitative evaluation of renal perfusion performances is however unknown. This study aimed at evaluating the performance of resistive index and semiquantitative evaluation of renal perfusion according to the operator experience to predict short-term renal prognosis in critically ill patients. DESIGN Preplanned ancillary analysis of a prospective multicenter cohort study. SETTING Seven ICUs. PATIENTS Unselected ICU patients. INTERVENTION Renal Doppler was performed at admission to the ICU. The diagnostic performance of resistive index and semiquantitative evaluation of renal perfusion to predict persistent acute kidney injury at day 3 was evaluated. MAIN RESULTS Overall, 371 patients were included, of whom 351 could be assessed for short-term renal recovery. Two thirds of the included patients had acute kidney injury (n = 233; 66.3%), of whom 136 had persistent acute kidney injury (58.4%). Overall performance in discriminating persistent acute kidney injury was however null with an area under the receiver operating characteristic curve less than 0.6 for both resistive index and semiquantitative evaluation of renal perfusion, and no difference across operator experience. A multivariate analysis using logistic regression with the center as a random effect adjusted on the operator experience showed no association between resistive index (odds ratio, 0.02 per international units (95% CI, 0.00-18.60 international units]) or semiquantitative evaluation of renal perfusion (odds ratio, 0.96 per international units [95% CI, 0.43-2.11 international units]) and persistent acute kidney injury. Similar results were obtained within subgroups of expert and nonexpert operators. CONCLUSIONS Doppler-based measurements performed by an expert or a nonexpert operator did not discriminate renal recovery patterns and neither modified the risk stratification of acute kidney injury persistence.

Background Studies describing the clinical features and short-term prognosis of patients admitted to the intensive care unit (ICU) for menstrual toxic shock syndrome (m-TSS) are lacking. Methods This was a multicenter retrospective cohort study of patients with a clinical diagnosis of m-TSS admitted between 1 January 2005 and 31 December 2020 in 43 French pediatric (n = 7) or adult (n = 36) ICUs. The aim of the study was to describe the clinical features and short-term prognosis, as well as to assess the 2011 Centers for Disease and Control (CDC) diagnostic criteria, in critically ill patients with m-TSS. Results In total, 102 patients with m-TSS (median age, 18 years; interquartile range, 16–24 years) were admitted to 1 of the participating ICUs. All blood cultures (n = 102) were sterile. Methicillin-sensitive Staphylococcus aureus grew from 92 of 96 vaginal samples. Screening for superantigenic toxin gene sequences was performed for 76 of the 92 vaginal samples positive for S. aureus (83%), and toxic shock syndrome toxin 1 was isolated from 66 strains (87%). At ICU admission, no patient met the 2011 CDC criteria for confirmed m-TSS, and only 53 (52%) fulfilled the criteria for probable m-TSS. Eighty-one patients (79%) were treated with antitoxin antibiotic therapy, and 8 (8%) received intravenous immunoglobulins. Eighty-six (84%) patients required vasopressors, and 21 (21%) tracheal intubation. No patient required limb amputation or died in the ICU. Conclusions In this large multicenter series of patients included in ICUs for m-TSS, none died or required limb amputation. The CDC criteria should not be used for the clinical diagnosis of m-TSS at ICU admission.

The Doppler-based resistive index (RI) and semi-quantitative evaluation of renal perfusion using color Doppler (SQP) have shown promising results for predicting persistent acute kidney injury (AKI) in preliminary studies. This study aimed at evaluating the performance of RI and SQP to predict short-term renal prognosis in critically ill patients.Prospective multicenter cohort study including unselected critically ill patients. Renal Doppler was performed at admission to the intensive care unit. The diagnostic performance of RI and SQP to predict persistent AKI at day 3 was evaluated.Overall, 371 patients were included, of whom 351 could be assessed for short-term renal recovery. Two thirds of the included patients had AKI (n = 233; 66.3%), of whom 136 had persistent AKI (58.4%). Doppler-based RI was higher and SQP lower in AKI patients and according to AKI recovery. Overall performance in predicting persistent AKI was however poor with area under ROC curve of respectively 0.58 (95% CI 0.52-0.64) and 0.59 (95% CI 0.54-0.65) for RI and SQP. Optimal cutoff was respectively 0.71 and 2 for RI and SQP. At optimal cutoff, sensitivity and specificity were 50% (95% CI 41-58%) and 68% (62-74%) for RI and 39% (32-45%) and 75% (66-82%) for SQP.Although statistically associated with AKI occurrence, RI and SQP perform poorly in predicting persistent AKI at day 3. Further studies are needed to adequately describe factors influencing Doppler-based assessment of renal perfusion and to delineate whether these indicators may be useful at the bedside. CLINICALTRIAL.GOV: NCT02355314.

Objectives Thyroid storm represents a rare but life-threatening endocrine emergency. Only rare data are available on its management and the outcome of the most severe forms requiring ICU admission. We aimed to describe the clinical manifestations, management and in-ICU and 6-month survival rates of patients with those most severe thyroid storm forms requiring ICU admission. Design Retrospective, multicenter, national study over an 18-year period (2000-2017). Setting Thirty-one French ICUs. Patients The local medical records of patients from each participating ICU were screened using the International Classification of Diseases, 10th Revision. Inclusion criteria were "definite thyroid storm," as defined by the Japanese Thyroid Association criteria, and at least one thyroid storm-related organ failure. Measurements and main results Ninety-two patients were included in the study. Amiodarone-associated thyrotoxicosis and Graves' disease represented the main thyroid storm etiologies (30 [33%] and 24 [26%] patients, respectively), while hyperthyroidism was unknown in 29 patients (32%) before ICU admission. Amiodarone use (24 patients [26%]) and antithyroid-drug discontinuation (13 patients [14%]) were the main thyroid storm-triggering factors. No triggering factor was identified for 30 patients (33%). Thirty-five patients (38%) developed cardiogenic shock within the first 48 hours after ICU admission. In-ICU and 6-month postadmission mortality rates were 17% and 22%, respectively. ICU nonsurvivors more frequently required vasopressors, extracorporeal membrane of oxygenation, renal replacement therapy, mechanical ventilation, and/or therapeutic plasmapheresis. Multivariable analyses retained Sequential Organ Failure Assessment score without cardiovascular component (odds ratio, 1.22; 95% CI, 1.03-1.46; p = 0.025) and cardiogenic shock within 48 hours post-ICU admission (odds ratio, 9.43; 1.77-50.12; p = 0.008) as being independently associated with in-ICU mortality. Conclusions Thyroid storm requiring ICU admission causes high in-ICU mortality. Multiple organ failure and early cardiogenic shock seem to markedly impact the prognosis, suggesting a prompt identification and an aggressive management.

Background There are limited treatment options for squamous non-small cell lung cancer (sqNSCLC) and prognosis remains poor. The safety and pharmacokinetics (PK) of nintedanib, a triple angiokinase inhibitor, plus cisplatin/gemcitabine as first-line treatment for advanced sqNSCLC patients, were evaluated. Materials and methods A phase I, dose-escalation study administering drugs in a 21-day cycle: cisplatin (75 mg/m2, Day 1), gemcitabine (1250 mg/m2, Days 1 and 8) and nintedanib (Days 2–7, 9–21) were given for 4–6 cycles, followed by monotherapy until disease progression or adverse events (AEs). Two nintedanib doses were tested, 150 mg twice daily (bid) and 200 mg bid, to determine maximum tolerated dose (MTD) based on occurrence of dose-limiting toxicities (DLTs) during Cycle 1. DLTs were primarily defined as drug-related non-hematologic (Grade ≥3) or hematologic (Grade 4) AEs. Results Sixteen patients were treated with nintedanib; n = 4 for 150 mg bid, n = 12 for 200 mg bid. No DLTs were observed in Cycle 1; therefore, the MTD was 200 mg bid. In subsequent cycles, two patients had DLTs: renal failure and reduced blood magnesium levels. The most common AEs were gastrointestinal. Three patients discontinued last study medication due to AEs and one had a nintedanib dose reduction. No relevant PK interactions were observed. Five patients had partial responses (31.3%) and eight had stable disease (50.0%); disease control rate was 81.3%. There were three long-term survivors (17–35 months). Conclusions The safety profile of nintedanib 200 mg bid plus cisplatin/gemcitabine was manageable, with AEs consistent with previous observations. PK data demonstrated no interaction, and preliminary antitumor activity was observed.

Background: This phase Ib study evaluated afatinib plus vinorelbine in patients with advanced solid tumours overexpressing epidermal growth factor receptor (EGFR) and/or human EGFR 2 (HER2). Methods: Maximum tolerated doses (MTDs) were determined for afatinib (20, 40 or 50 mg, once daily) combined with standard intravenous vinorelbine (part A; 25 mg m−2 per week) or oral vinorelbine (part B; 60 mg m−2 per week, increased to 80 mg m−2 per week at week 3). Secondary end points for expanded MTD cohorts included assessments of safety, pharmacokinetics, tumour response and progression-free survival (PFS). Results: The afatinib MTD was 40 mg with intravenous (MTDA) and oral (MTDB) vinorelbine. The most frequent cycle 1 dose-limiting toxicities were febrile neutropenia and diarrhoea, consistent with individual safety profiles of vinorelbine and afatinib. Common treatment-related adverse events included: diarrhoea (92.7%), asthenia (76.4%), nausea (63.6%), neutropenia (56.4%) and vomiting (54.5%). No notable pharmacokinetic interactions were observed. Best overall tumour response was stable disease in part A (16 out of 28 patients), and partial response in part B (3 out of 27 patients). Median PFS was 14.6 and 15.9 weeks for patients treated at the MTDA and MTDB, including dose-escalation and expansion cohorts. Conclusions: Afatinib in combination with intravenous or oral vinorelbine demonstrated a manageable safety profile and antitumour activity at the MTD of 40 mg per day.

IntroductionPre-emptive inhaled antibiotics may be effective to reduce the occurrence of ventilator-associated pneumonia among critically ill patients. Meta-analysis of small sample size trials showed a favourable signal. Inhaled antibiotics are associated with a reduced emergence of antibiotic resistant bacteria. The aim of this trial is to evaluate the benefit of a 3-day course of inhaled antibiotics among patients undergoing invasive mechanical ventilation for more than 3 days on the occurrence of ventilator-associated pneumonia.Methods and analysisAcademic, investigator-initiated, parallel two group arms, double-blind, multicentre superiority randomised controlled trial. Patients invasively ventilated more than 3 days will be randomised to receive 20 mg/kg inhaled amikacin daily for 3 days or inhaled placebo (0.9% Sodium Chloride). Occurrence of ventilator-associated pneumonia will be recorded based on a standardised diagnostic framework from randomisation to day 28 and adjudicated by a centralised blinded committee.Ethics and disseminationThe protocol and amendments have been approved by the regional ethics review board and French competent authorities (Comité de protection des personnes Ouest I, No.2016-R29). All patients will be included after informed consent according to French law. Results will be disseminated in international scientific journals.Trial registration numbersEudraCT 2016-001054-17 and NCT03149640.

Background: Cuff leak test was developed to predict the occurrence of post-extubation stridor (PES). This study evaluated the diagnostic performance of this test in unselected critically ill patients. Methods: Multicenter prospective study including unselected ventilated patients at the time of their first planned extubation. The diagnostic performance of 4 different cuff leak tests was assessed. Results: Post-extubation stridor occurred in 34 (9.4%) of 362 included patients. Compared to patients without PES, patients with PES required more frequently reintubation (6 [17.6%] vs 26 [7.9%], P = .041), prolonged duration of ventilation (6 [3-13] vs 5 [2-9] days, P = .029), and longer intensive care unit (ICU) stay (12 [6-17.5] vs 7.5 [4-13] days, P = .018). However, ICU mortality was similar in both groups (1 [2.9%] vs 23 [7.0%], P = .61). The 4 cuff leak tests display poor diagnostic accuracy: sensitivities ranging from 27% to 46%, specificities from 70% to 88%, positive predictive values from 14% to 19%, and negative predictive values from 92% to 93%. Conclusion: Post-extubation stridor occurs in less than 10% of unselected critically ill patients. The several cuff leak tests display limited diagnostic performance for the detection of PES. Given the high rate of false positives, routine cuff leak test may expose to undue prolonged mechanical ventilation.

Despite the vast amount of literature dedicated to acute kidney injury (AKI) and its clinical consequences, short-term renal recovery has been relatively neglected. Recent studies have suggested that timing of renal recovery is associated with longer-term risk of death, residual renal function, and end-stage renal failure risk. In addition, longer AKI duration is associated with an increased requirement for renal replacement therapy. Comorbidities, especially renal and cardiovascular, severity of AKI, criteria to reach AKI diagnosis, as well as severity of critical illness have been associated with longer AKI duration, and, more specifically, risk of persistent renal dysfunction. Because predicting short-term renal recovery is clinically relevant, several tests, imaging, and biomarkers have been tested in a way to predict the course of AKI and chances for early renal recovery. In this review, the definition of recovery, consequences of persistent AKI, and tools proposed to predict recovery are described. The performance of these tools and their limits are discussed.

Background Overexpression/activation of focal adhesion kinase (FAK) in human malignancies has led to its evaluation as a therapeutic target. We report the first-in-human phase I study of BI 853520, a novel, potent, highly selective FAK inhibitor. Objective Our objectives were to identify the maximum tolerated dose (MTD), and to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), biomarker expression, and preliminary activity. Patients and Methods The study comprised a standard 3 + 3 dose-escalation phase followed by an expansion phase in patients with selected advanced, nonhematologic malignancies. Results Thirty-three patients received BI 853520 in the dose-escalation phase; the MTD was 200 mg once daily (QD). Dose-limiting toxicities included proteinuria and fatigue, both of which were grade 3. Preliminary PK data supported QD dosing. In the expansion cohort, 63 patients received BI 853520 200 mg QD. Drug-related adverse events (AEs) in > 10% of patients included proteinuria (57%), nausea (57%), fatigue (51%), diarrhea (48%), vomiting (40%), decreased appetite (19%), and peripheral edema (16%). Most AEs were grade 1–2; grade 3 proteinuria, reported in 13 patients (21%), was generally reversible upon treatment interruption. Nineteen patients underwent dose reduction due to AEs, and three drug-related serious AEs were reported, none of which were fatal. Preliminary PD analysis indicated target engagement. Of 63 patients, 49 were evaluable; 17 (27%) achieved a best response of stable disease (4 with 150 + days), and 32 (51%) patients had progressive disease. Conclusions BI 853520 has a manageable and acceptable safety profile, favorable PK, and modest antitumor activity at an MTD of 200 mg QD in patients with selected advanced nonhematologic malignancies. ClinicalTrials.gov identifier NCT01335269. Electronic supplementary material The online version of this article (10.1007/s11523-018-00617-1) contains supplementary material, which is available to authorized users.

Background Afatinib, an irreversible ErbB family blocker, has shown synergistic antitumor activity and manageable tolerability in combination with chemotherapy. This phase I study assessed oral afatinib plus intravenous gemcitabine or docetaxel in patients with relapsed/refractory solid tumors. Methods Patients received afatinib (30, 40, or 50 mg) plus gemcitabine (1000 or 1250 mg/m2) or docetaxel (60 or 75 mg/m2). Dose escalation proceeded via a 3 + 3 design until the maximum tolerated dose (MTD) was reached. Adverse events (AEs), pharmacokinetics and antitumor activity were also assessed. Results Dose-limiting toxicities during Cycle 1 were reported in 6/39 patients receiving afatinib/gemcitabine (most commonly diarrhea, thrombocytopenia and vomiting) and 16/54 patients receiving afatinib/docetaxel (most commonly febrile neutropenia and stomatitis). The MTDs were established as afatinib 40 mg/gemcitabine 1000 mg/m2 and afatinib 30 mg/docetaxel 60 mg/m2. The most common drug-related AEs were diarrhea, asthenia and rash with afatinib/gemcitabine, and diarrhea, asthenia and stomatitis with afatinib/docetaxel. No relevant pharmacokinetic interactions were observed for either combination. Both combinations demonstrated clinical activity and durable disease control at the MTDs. Compared with the MTD, higher response rates were achieved with afatinib 30 mg/docetaxel 75 mg/m2 (28% vs 6%); however, this regimen was associated with problematic febrile neutropenia, an expected AE with docetaxel, that is often managed with growth factor support. Conclusions Afatinib/gemcitabine and afatinib/docetaxel demonstrated manageable safety profiles, with evidence of clinical efficacy at the MTDs. For afatinib/docetaxel, a dose level of afatinib 30 mg/docetaxel 75 mg/m2 produced higher response rates. Trial registration: NCT01251653 ( ClinicalTrials.gov ).

Afatinib is an oral irreversible ErbB-Family Blocker indicated for treatment of patients with EGFR mutation positive advanced non-small cell lung cancer. This trial assessed whether renal impairment influences the pharmacokinetics and safety of afatinib. This was an open-label, single-dose study. Pharmacokinetic parameters after afatinib 40 mg were investigated in subjects with moderate (n = 8) or severe (n = 8) renal impairment (estimated glomerular filtration rate 30–59 mL/min/1.73 m2 and 15–29 mL/min/1.73 m2, respectively) and healthy matched controls (n = 14). Plasma and urine samples were collected before and up to 14 days after dosing for pharmacokinetic and plasma protein-binding assessment. Primary endpoints were area under the plasma concentration–time curve from time zero to the last quantifiable concentration (AUClast) and maximum plasma concentration (C max) between subjects with renal impairment and healthy matched controls. Pharmacokinetic profiles and plasma protein binding were similar in all groups. The extent of exposure, as indicated by AUClast and C max, was generally similar between the matched treatment groups, with the exception of the geometric mean ratio of AUClast for subjects with severe renal impairment, which showed a trend towards a higher value compared with matched healthy subjects (150.0 % [90 % CI 105.3–213.7]) Inter-individual variability was moderate (geometric mean coefficient of variation 28–39 % for moderate impairment, 34–42 % for severe impairment). Afatinib was well tolerated and urinary excretion was minimal. Moderate-to-severe renal impairment had a minor influence on the pharmacokinetics of afatinib that was within the observed inter-individual variability, suggesting that afatinib treatment can be considered in this patient population. Registered at ClinicalTrials.gov as NCT02096718.

Background: \ud This multicentre, open-label, phase-I/randomised phase-II trial evaluated safety, pharmacokinetics, maximum-tolerated-dose (MTD) per dose-limiting toxicities (DLTs), and efficacy of nintedanib vs. sorafenib in European patients with unresectable advanced hepatocellular carcinoma (aHCC).\ud \ud Methods: \ud Phase I: Patients were stratified into two groups per baseline aminotransferase/alanine aminotransferase and Child-Pugh score; MTD was determined. Phase II: Patients were randomised 2:1 to nintedanib (MTD) or sorafenib (400-mg bid) in 28-day cycles until intolerance or disease progression. Time-to-progression (TTP, primary endpoint), overall survival (OS) and progression-free survival (PFS) were determined.\ud \ud Results: \ud Phase-I: no DLTs observed; nintedanib MTD in both groups was 200 mg bid. Phase-II: patients (N = 93) were randomised to nintedanib (n = 62) or sorafenib (n = 31); TTP was 5.5 vs. 4.6 months (HR = 1.44 [95% CI, 0.81–2.57]), OS was 11.9 vs. 11.4 months (HR = 0.88 [95% CI, 0.52–1.47]), PFS was 5.3 vs. 3.9 months (HR = 1.35 [95% CI, 0.78–2.34]), respectively (all medians). Dose intensity and tolerability favoured nintedanib. Fewer patients on nintedanib (87.1%) vs. sorafenib (96.8%) had drug-related adverse events (AEs) or grade ≥ 3 AEs (67.7% vs. 90.3%), but more patients on nintedanib (28 [45.2%]) had AEs leading to drug discontinuation than did those on sorafenib (7 [22.6%]).\ud \ud Conclusions: \ud Nintedanib may have similar efficacy to sorafenib in aHCC.

PURPOSE: Over the last two decades, noninvasive ventilation (NIV) has been proposed in various causes of acute respiratory failure (ARF) but some indications are debated. Current trends in NIV use are unknown. METHODS: Comparison of three multicenter prospective audits including all patients receiving mechanical ventilation and conducted in 1997, 2002, and 2011 in francophone countries. RESULTS: Among the 4132 patients enrolled, 2094 (51%) required ventilatory support for ARF and 2038 (49 %) for non-respiratory conditions. Overall NIV use was markedly increased in 2010/11 compared to 1997 and 2002 (37% of mechanically ventilated patients vs. 16% and 28%, P < 0.05). In 2010/11, the use of first-line NIV for ARF had reached a plateau (24% vs. 16% and 23%, P < 0.05) whereas pre-ICU and post-extubation NIV had substantially increased (11% vs. 4% and 11% vs. 7%, respectively, P < 0.05). First-line NIV remained stable in acute-on-chronic RF, continued to increase in cardiogenic pulmonary edema, but decreased in de novo ARF (16% in 2010/11 vs. 23% in 2002, P < 0.05). The NIV success rate increased from 56% in 2002 to 70% in 2010/11 and remained the lowest in de novo ARF. NIV failure in de novo ARF was associated with increased mortality in 2002 but not in 2010/11. Mortality decreased over time, and overall, NIV use was associated with a lower mortality. CONCLUSION: Increases in NIV use and success rate, an overall decrease in mortality, and a decrease of the adverse impact NIV failure has in de novo ARF suggest better patient selection and greater proficiency of staff in administering NIV. TRIAL REGISTRATION: Clinicaltrials.gov Identifier NCT01449331.

Purpose: The HER2 mAb, trastuzumab, is a standard therapy for patients with HER2-positive breast cancer before acquired resistance. Afatinib, an irreversible, oral, small-molecule ErbB family blocker, shows clinical activity in trastuzumab-refractory HER2-positive breast cancer. Experimental Design: This phase I study used a 3+3 dose escalation to determine the MTD of oral once-daily afatinib in combination with the recommended dose of intravenous trastuzumab (4 mg/kg week 1; 2 mg/kg/wk thereafter). Adult women with confirmed advanced/metastatic HER2-positive breast cancer were eligible. Results: Of 18 patients treated, 16 received daily afatinib 20 mg and two 30 mg. Overall, 4 of 13 and 2 of 2 patients receiving afatinib 20 mg and 30 mg, respectively, experienced dose-limiting toxicity (DLT; all CTCAE grade 3 diarrhea). Most frequent treatment-related adverse events were diarrhea (94%), rash (56%), and fatigue (56%). Overall, pharmacokinetic profiles of afatinib and trastuzumab in combination were consistent with the known characteristics of each alone. Overall, objective response and disease control rates were 11% and 39%, respectively, with median progression-free survival 111.0 days (95% confidence interval, 56.0–274.0). Conclusions: The MTD of afatinib was 20 mg daily combined with the recommended weekly dose of trastuzumab, with 1 of 6 patients showing DLTs in the dose escalation. However, additional DLTs occurred in the dose-expansion phase meaning that this MTD cannot be recommended for phase II development without strict diarrhea management. There was no evidence suggesting relevant pharmacokinetic drug–drug interactions. Signs of clinical activity were seen in trastuzumab-resistant HER2-positive breast cancer, suggesting further investigation with optimal diarrhea management is warranted. Clin Cancer Res; 21(12); 2737–44. ©2014 AACR. See related commentary by Sledge and Pegram, p. 2663

La dyspnee laryngee post-extubation (DLP) est une complication iatrogene de l’intubation. Elle est secondaire a un obstacle sur les voies aeriennes superieures (VAS) qui se manifeste au decours de l’extubation. Elle entraine des manifestations respiratoires de gravite variable allant du stridor isole a un tableau d’insuffisance respiratoire aigue necessitant la reintubation en urgence dans des conditions techniques parfois difficiles. La DLP represente une des premieres causes d’insuffisance respiratoire aigue post-extubation. Pour des raisons evidentes, predire sa survenue avant l’extubation est rendu difficile du fait de la presence de la sonde d’intubation. Le test de fuite a ete developpe pour s’affranchir de ces contraintes et represente a ce jour le gold standard pour predire la survenue d’une DLP. Pourtant, sa faible valeur predictive positive le fait apparaitre plutot comme un indicateur de risque accru de DLP que comme un test diagnostique suffisamment performant pour permettre une modification de prise en charge ou retarder l’extubation. Chez des patients non selectionnes de reanimation, sa realisation systematique est donc discutable et pourrait exposer un nombre excessif de patients a une prolongation injustifiee de la ventilation mecanique invasive. Chez les patients a haut risque de DLP, la place exacte du test de fuite reste a evaluer.

Background: Nintedanib is an oral, triple angiokinase inhibitor of vascular endothelial growth factor/platelet-derived growth factor/fibroblast growth factor receptors. This randomized, multicenter, open-label, phase I/II study evaluated the safety, pharmacokinetics, maximum tolerated dose (MTD) in terms of dose-limiting toxicities (DLTs), and efficacy of nintedanib versus sorafenib in Asian patients with unresectable advanced hepatocellular carcinoma (HCC). Patients and Methods: For the phase I portion, patients were stratified into two groups according to their alanine aminotransferase/aspartate aminotransferase (ALT/AST) and Child-Pugh score at baseline. For phase I, the primary endpoint was determination of the MTD in terms of DLTs. For phase II, patients with a Child-Pugh score of 5–6, an Eastern Cooperative Oncology Group performance score ≤2, and an ALT/AST ≤2× the upper limit of normal were enrolled and randomized 2: 1 to nintedanib 200 mg twice daily (b.i.d.) (the MTD determined in phase I) or sorafenib 400 mg b.i.d. continuously in 28-day cycles until intolerable adverse events (AEs) or disease progression (PD); treatment beyond PD was allowed if clinical benefit was perceived. The primary endpoint for phase II was time to progression (TTP) by central independent review (CIR; by Response Evaluation Criteria in Solid Tumors v1.0); the secondary endpoints included overall survival (OS). All analyses were exploratory. Results: The MTD was 200 mg in both groups. For phase II, 95 patients were randomized to nintedanib (n = 63) or sorafenib (n = 32). For nintedanib and sorafenib, respectively, the median CIR TTP was 2.8 vs. 3.7 months (hazard ratio [HR] = 1.21, 95% confidence interval [CI] 0.73–2.01) and the median OS 10.2 vs. 10.7 months (HR = 0.94, 95% CI 0.59–1.49). Nintedanib-treated patients had fewer grade 3 or higher AEs (56 vs. 84%), serious AEs (46 vs. 56%), and AEs leading to dose reduction (19 vs. 59%) and drug discontinuation (24 vs. 34%). AEs associated more frequently with nintedanib were vomiting and nausea, whereas those associated more frequently with sorafenib were ALT/AST increases, diarrhea, rash, and palmar-plantar erythrodysesthesia syndrome. Conclusions: Nintedanib showed numerically similar efficacy to sorafenib for CIR TTP and OS in Asian patients with advanced HCC and adequate liver function. AEs were generally manageable.

Nintedanib is an intracellular inhibitor of tyrosine kinases used in the treatment of non–small cell lung cancer and idiopathic pulmonary fibrosis (IPF). This phase 1 open‐label study investigated the influence of mild and moderate hepatic impairment on the pharmacokinetics (PK), safety, and tolerability of nintedanib following oral administration of a single 100‐mg dose. Subjects with hepatic impairment classified as Child‐Pugh A (mild hepatic impairment) or Child‐Pugh B (moderate hepatic impairment) were eligible. The control group comprised healthy matched subjects. Primary end points were Cmax and AUC0–∞ of nintedanib. Thirty‐three subjects received nintedanib (8 in each of the Child‐Pugh A and Child‐Pugh B groups and 17 controls). The shape of the plasma concentration–time curve for nintedanib was similar between Child‐Pugh A or B and healthy subjects. Nintedanib exposure was ∼2‐fold higher in Child‐Pugh A subjects and ∼8‐fold higher in Child‐Pugh B subjects than in healthy subjects. Adverse events were reported in 3 Child‐Pugh B subjects (37.5%), no Child‐Pugh A subjects, and 3 healthy subjects (17.6%). In conclusion, exposure to nintedanib was higher in Child‐Pugh A and B subjects than in matched healthy subjects. A single dose of nintedanib 100 mg had an acceptable safety and tolerability profile in subjects with hepatic impairment. Results of this dedicated phase 1 study are in line with exploratory investigations into the PK of nintedanib in patients with advanced solid tumors or IPF and hepatic impairment.

Purpose To describe gastrointestinal emergencies in cancer patients. Methods All cancer patients admitted to the medical ICU of Saint-Louis Hospital for an acute abdominal syndrome during the study period (1997–2011) were included. Results A total of 164 patients were included. The most common diagnoses were: neutropenic enterocolitis (NE) (n = 54, 33%), infectious colitis and peritonitis (n = 51, 31%), bowel infiltration by malignancy (n = 14, 9%), and mucosal toxicity of chemotherapy (n = 12, 7%). Microbiologically documented infections were reported in 82 patients (50%), including 12 fungal infections. Twenty-seven patients (16%) underwent urgent surgery. The hospital mortality rate was 35%. Five factors were independently associated with hospital mortality: the Simplified Acute Physiology Score II (SAPS II) score on day 1 (OR 1.03/SAPS II point, 95% CI 1.01 to 1.05), microbiological documentation (OR 0.27, 95% CI 0.11 to 0.64), neutropenia (OR 0.42, 95% CI 0.19 to 0.95), allogenic hematopoietic stem-cell transplantation (HSCT) (OR 5.13, 95% CI 1.71 to 15.4), and mechanical ventilation (OR 3.42, 95% CI 1.37 to 8.51). Conclusions Gastrointestinal emergencies in cancer patients are associated with significant mortality. Mortality correlated both with the severity of organ failure upon ICU admission and the underlying diagnosis. Interestingly, patients admitted to the ICU with neutropenia had better survival.

Purpose The combination of afatinib, an irreversible ErbB family blocker, with paclitaxel and bevacizumab was assessed in patients with advanced solid tumors. Methods This phase I study used a 3 + 3 design to determine the maximum tolerated dose (MTD) of afatinib combined with paclitaxel and bevacizumab. Safety, pharmacokinetics, and anti-tumor activity were also assessed. The starting dose was oral afatinib 40 mg once daily plus intravenous paclitaxel (fixed dose 80 mg/m2, Days 1, 8, and 15 of a 4-week cycle) and intravenous bevacizumab 5 mg/kg every 2 weeks. Results Twenty-nine patients were enroled. The afatinib dose was de-escalated to 30 mg and then 20 mg after 2/6 and 2/5 evaluable patients developed dose-limiting toxicities at 40 and 30 mg, respectively, when combined with paclitaxel and bevacizumab 5 mg/kg. The bevacizumab dose was subsequently escalated to 10 mg/kg, and MTD was defined as afatinib 20 mg plus paclitaxel 80 mg/m2 and bevacizumab 10 mg/kg. Frequent (any grade) treatment-related adverse events (AEs) included diarrhea (83%), rash/acne (83%), fatigue (79%), mucosal inflammation (59%), and nausea (59%). Based on overall safety, bevacizumab was amended to 7.5 mg/kg for the recommended phase II dose. Pharmacokinetic analyses suggested no relevant drug–drug interactions. Three (10%) confirmed partial responses were observed; 15 (52%) patients had stable disease. Conclusions The recommended phase II dose schedule was afatinib 20 mg/day with paclitaxel 80 mg/m2 (Days 1, 8, and 15 every 4 weeks) and bevacizumab 7.5 mg/kg every 2 weeks. At this dose schedule, AEs were manageable, and anti-tumor activity was observed. Electronic supplementary material The online version of this article (doi:10.1007/s00280-016-3189-1) contains supplementary material, which is available to authorized users.

Objectives Dysregulation of the downstream PI3K/AKT/mTOR signaling pathway is a proposed mechanism of resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). We investigated safety and antitumor activity of afatinib plus sirolimus as a potential combination to reverse acquired resistance to EGFR-TKIs in a phase IB trial in patients with EGFR mutation-positive non-small-cell lung cancer ( EGFR mut NSCLC) and/or disease progression following prior erlotinib/gefitinib. Materials and methods Patients with EGFR mut NSCLC and/or disease progression following at least prior erlotinib/gefitinib were included in the trial. The primary endpoint was incidence of dose-limiting toxicities (DLT) to determine the maximum tolerated dose (MTD). Four initial dose cohorts were proposed to evaluate DLTs. Other endpoints included tumor response, safety, progression-free survival (PFS) and pharmacokinetics. Results Thirty-nine patients received afatinib and sirolimus. Additional dose cohorts were added since the second cohort (afatinib 40 mg/day and sirolimus 5 mg/day) was considered to have excessive toxicity. All patients experienced adverse events (AE) [grade 3: 66.7%; serious AE: 56.4%]. The most frequent AEs were diarrhea (94.9%), mucosal inflammation (64.1%), asthenia (53.8%) and rash (53.8%). Discontinuations and dose reduction due to AEs occurred in 23.1% and 25.6% of patients. MTD was determined as afatinib 30 mg and sirolimus 1 mg. Responses were observed in 5 patients (12.8%) [2 (5.1%) with confirmed partial response (PR); 3 (7.7%) with unconfirmed PR], and stable disease in 18 patients (46.2%). Four of the 5 responses were at doses above MTD. PFS at 6 months was estimated in 33.3% (median PFS 3.4 months). Pharmacokinetic parameters of afatinib and sirolimus were similar after single administration or in combination. Conclusion The combination of afatinib and sirolimus showed lower responses than expected. Together with increased AEs and poor tolerability, this precludes clinical use and further clinical development of this combination. No pharmacokinetic interactions were observed. ClinicalTrials.gov Identifier NCT00993499.

Respiratory viruses (RVs) are ubiquitous pathogens that represent a major cause of community-acquired pneumonia and chronic pulmonary diseases exacerbations. However, their contribution to acute respiratory failure events requiring intensive care unit admission in the era of rapid multiplex molecular assay deserves further evaluation. This study investigated the burden of viral infections in non immunocompromised patients admitted to the intensive care unit for acute respiratory failure using a multiplex molecular assay. Patients were investigated for RVs using immunofluoresence testing and a commercial multiplex molecular assay, and for bacteria using conventional culture. Half the patients (34/70, 49%) had a documented RVs infection. No other pathogen was found in 24 (71%) patients. Viral infection was detected more frequently in patients with obstructive respiratory diseases (64% vs. 29%; P = 0.0075). Multiplex molecular assay should be considered as an usefull diagnostic tool in patients admitted to the intensive care unit with acute respiratory failure, especially those with acute exacerbations of chronic obstructive pulmonary disease and asthma. J. Med. Virol. 86:1198–1202, 2014. © 2013 Wiley Periodicals, Inc.

BACKGROUND Characteristics and outcomes of adult patients with disseminated toxoplasmosis admitted to the intensive care unit (ICU) have rarely been described. METHODS We performed a retrospective study on consecutive adult patients with disseminated toxoplasmosis who were admitted from January 2002 through December 2012 to the ICUs of 14 university-affiliated hospitals in France. Disseminated toxoplasmosis was defined as microbiological or histological evidence of disease affecting >1 organ in immunosuppressed patients. Isolated cases of cerebral toxoplasmosis were excluded. Clinical data on admission and risk factors for 60-day mortality were collected. RESULTS Thirty-eight patients were identified during the study period. Twenty-two (58%) had received an allogeneic hematopoietic stem cell transplant (median, 61 [interquartile range {IQR}, 43-175] days before ICU admission), 4 (10%) were solid organ transplant recipients, and 10 (27%) were infected with human immunodeficiency virus (median CD4 cell count, 14 [IQR, 6-33] cells/µL). The main indications for ICU admission were acute respiratory failure (89%) and shock (53%). The 60-day mortality rate was 82%. Allogeneic hematopoietic stem cell transplant (hazard ratio [HR] = 2.28; 95% confidence interval [CI], 1.05-5.35; P = .04) and systolic cardiac dysfunction (HR = 3.54; 95% CI, 1.60-8.10; P < .01) within 48 hours of ICU admission were associated with mortality. CONCLUSIONS Severe disseminated toxoplasmosis leading to ICU admission has a poor prognosis. Recipients of allogeneic hematopoietic stem cell transplant appear to have the highest risk of mortality. We identified systolic cardiac dysfunction as a major determinant of outcome. Strategies aimed at preventing this fatal opportunistic infection may improve outcomes.

To assess renal resistive index variations in response to fluid challenge.Prospective cohort study.Three ICUs in French teaching hospitals.Consecutive patients receiving mechanical ventilation and requiring a fluid challenge.Resistive index measurement before and after fluid challenge.Renal Doppler was used to measure resistive index and esophageal Doppler to monitor aortic blood flow. Of the 35 included patients, 17 (49%) met our definition for fluid challenge responsiveness, that is, had at least a 10% increase in aortic blood flow. After fluid challenge, mean arterial pressure increased from 73 mm Hg (interquartile range 68-79) to 80 mm Hg (75-86; p0.0001) and stroke volume from 50 mL (30-77) to 55 mL (39-84; p0.0001). Stroke volume changes after fluid challenge were +28.6% (+18.8% to +38.8%) in fluid challenge responders and +3.1% (-1.6% to 7.4%) in fluid challenge nonresponders. Renal resistive index was unchanged after fluid challenge in both nonresponders (0.72 [0.67-0.75] before and 0.71 [0.67-0.75] after fluid challenge; p = 0.62) and responders (0.70 [0.65-0.75] before and 0.72 [0.68-0.74] after fluid challenge; p = 0.11). Stroke volume showed no correlations with resistive index changes after fluid challenge in the overall population (r² = 0.04, p = 0.25), in fluid challenge responders (r² = -0.02, p = 0.61), or in fluid challenge nonresponders (r² = 0.08, p = 0.27). Stroke volume did not correlate with resistive index changes after fluid challenge in the subgroups without acute kidney injury (AKIN definition), with transient acute kidney injury, or with persistent acute kidney injury.Systemic hemodynamic changes induced by fluid challenge do not translate into resistive index variations in patients without acute kidney injury, with transient acute kidney injury, or with persistent acute kidney injury.

Evaluating the clinical significance of blood cultures positive for coagulase-negative staphylococci (CoNS) is of critical importance since these microorganisms represent both the first contaminants of blood cultures and one of the leading causes of bloodstream infection (BSI). This prospective 2-centre study aimed to compare a previously reported algorithm to a clinical algorithm based on our experience. We identified 84 patients with CoNS-positive blood cultures. Twenty-seven (32%) were considered to have BSI according to our study algorithm. Thirty-seven (44%) patients were considered to have CoNS BSI according to the previously reported algorithm. The 2 algorithms isolated patients with similar rates of recurrences and hospital mortality. Our algorithm seemed to result in less diagnoses of CoNS BSI without harmful consequences compared to the previously reported algorithm. The impact on patient outcome and the inappropriate use of antibiotics deserves further investigation.

The objective of this study was to compare the dose and the duration of vasopressor during septic shock in recently treated cancer patients, untreated cancer patients, and patients without malignancy. This was a retrospective single-center study. This study was performed on a 12-bed medical intensive care unit at a teaching hospital. There were 147 patients admitted to the intensive care unit with septic shock: 82 cancer patients recently treated (TCPs), 20 untreated cancer patients (UCPs), and 45 without malignancy (NPs). The primary outcomes were the maximal dose and the duration of vasopressor support. Treated cancer patients were younger (P < 0.0001) and compared with NPs had less comorbidity (P = 0.003), had more frequently an intra-abdominal source of sepsis (P = 0.011), less frequently a gram-positive bacteria (P = 0.036), and a shorter delay for antibiotics (P = 0.029). All patients received norepinephrine with similar maximal doses (0.66 [0.29-1.5] µg · kg(-1) · min(-1) in TCPs vs. 0.82 [0.41-1.4] µg · kg(-1) · min(-1) in NPs and 0.79 [0.48-1.7] µg · kg(-1) · min(-1) in UCPs; P = 0.61) and duration in the three groups (2 [2-4] days in TCPs vs. 3 [2-4] days in NPs and 3 [2-5] days in UCPs; P = 0.13). Mechanical ventilation (P = 0.11), renal replacement therapy (P = 0.19), and 28-day mortality (43% in TCPs vs. 49% in NPs, and 50% in UCPs; P = 0.77) were similar between the three groups. Cancer patients recently treated with chemotherapy had similar needs in vasopressor support during septic shock compared with untreated cancer patients and patients without malignancy. Mortality was not different in cancer and noncancer patients with septic shock.

Acute respiratory failure (ARF) is the leading reason for intensive care unit (ICU) admission in patients with cancer. The aim of this study was to identify early predictors of death in patients with cancer admitted to the ICU for ARF who were not intubated at admission. We conducted analysis of a prospective randomized controlled trial including 219 patients with cancer with ARF in which day-28 mortality was a secondary endpoint. Mortality at day 28 was 31.1%. By multivariate analysis, independent predictors of day-28 mortality were: age (odds ratio [OR] 1.30/10 years, 95% confidence interval [CI] [1.01-1.68], p = 0.04), more than one line of chemotherapy (OR 2.14, 95% CI [1.08-4.21], p = 0.03), time between respiratory symptoms onset and ICU admission > 2 days (OR 2.50, 95% CI [1.25-5.02], p = 0.01), oxygen flow at admission (OR 1.07/L, 95% CI [1.00-1.14], p = 0.04) and extra-respiratory symptoms (OR 2.84, 95%CI [1.30-6.21], p = 0.01). After adjustment for the logistic organ dysfunction (LOD) score at admission, only time between respiratory symptoms onset and ICU admission > 2 days and LOD score were independently associated with day-28 mortality. Determinants of death include both factors non-amenable to change, and delay in ARF management. These results suggest that early intensive care management of patients with cancer with ARF may translate to better survival.

Noninvasive ventilation (NIV) is a treatment option in patients with acute respiratory failure who are good candidates for intensive care but have declined tracheal intubation. The aim of our study was to report outcomes after NIV in patients with a do-not-intubate (DNI) order.Prospective observational cohort study in all patients who received NIV for acute respiratory failure in 54 ICUs in France and Belgium, in 2010/2011.Goals of care, comfort, and vital status were assessed daily. On day 90, a telephone interview with patients and relatives recorded health-related quality of life (HRQOL), posttraumatic stress disorder-related symptoms, and symptoms of anxiety and depression. Post-ICU burden was compared between DNI patients and patients receiving NIV with no treatment-limitation decisions (TLD). Of 780 NIV patients, 574 received NIV with no TLD, and 134 had DNI orders. Hospital mortality was 44 % in DNI patients and 12 % in the no-TLD group. Mortality in the DNI group was lowest in COPD patients compared to other patients in the DNI group (34 vs. 51 %, P = 0.01). In the DNI group, HRQOL showed no significant decline on day 90 compared to baseline; day-90 data of patients and relatives did not differ from those in the no-TLD group.Do-not-intubate status was present among one-fifth of ICU patients who received NIV. DNI patients who were alive on day 90 experienced no decrease in HRQOL compared to baseline. The prevalences of anxiety, depression, and PTSD-related symptoms in these patients and their relatives were similar to those seen after NIV was used as part of full-code management (clinicaltrial.govNCT01449331).

In cancer patients with acute respiratory failure (ARF), early adequate therapy is associated with better outcomes. We investigated the performance of the DIRECT approach, which uses criteria available at the bedside at admission to the intensive care unit (ICU), to identify causes of ARF in cancer patients. This cohort study included cancer patients with ARF of determined aetiology. Associations of aetiological groups with the selected criteria were evaluated using correspondence analysis. 424 cancer patients were included: 201 (47%) with bacterial pneumonia, 131 (31%) with opportunistic infections and 92 (22%) with noninfectious disorders. Mechanical ventilation (both invasive and noninvasive) was needed in 328 (77%) patients, treatment for shock in 217 (51%) patients and dialysis in 82 (19%) patients. 142 (34%) patients died in the ICU. Correspondence plots showed that bacterial pneumonia was associated with neutropenia, solid tumour, multiple myeloma

Invasive pulmonary aspergillosis (IPA) is a life-threatening infection documented in up to 15% of hematology patients who require intensive care for acute respiratory failure. We report outcomes in hematology patients given mechanical ventilation (MV) with IPA. Retrospective study of all hematology patients given MV with IPA between January 1998 and March 2011 at a single center. Predictors of 6-month survival or mortality were identified using multivariable analysis. We studied 67 patients including 49 (73%) with neutropenia, 23 (34%) with long-term steroid therapy, and 14 (21%) with allogeneic bone marrow transplantation. Incidence of IPA in the ICU decreased between 1998 and 2011, and mortality in patients receiving mechanical ventilation did not change. IPA was confirmed in 6 patients by autopsy and was probable in 61 patients based on host factors, clinical and radiographic features, and either Aspergillus isolation (50 patients) or Aspergillus antigen detection alone (11 patients). Concomitant bacterial infections were documented in 24 (36%) patients. ICU and 6-month mortality rates were 67 and 82%, respectively. Mortality was stable throughout the study period. Concomitant bacterial infection was independently associated with higher mortality [HR, 2.1 (1.2–3.8)]. Mortality was lower in patients given voriconazole [OR, 0.5 (0.3–0.9)]. Hospital mortality remains high in hematology patients requiring MV with IPA, particularly when concommittant infection occurred. The use of voriconazole improved survival.

This study determined the safety, maximum tolerated dose (MTD), pharmacokinetics, and preliminary efficacy of BI 847325, an oral dual MEK and Aurora kinase inhibitor, in patients with refractory solid tumors. This trial recruited patients with an advanced non-resectable and/or metastatic solid tumor following failure of conventional treatment (NCT01324830; 1287.1). BI 847325 was administered orally, once daily (starting at 6 mg in the first cohort) using two dosing schedules: Schedule A (2 weeks on, 1 week off) and Schedule B (three periods of 5 days on, 2 days off). The primary objective was to identify the MTD of BI 847325 for both dosing schedules. Sixty-nine patients (Schedule A, n = 47; Schedule B, n = 22) were treated. The MTD was 120 mg per day for Schedule A (cumulative dose of 1680 mg per 3-week cycle) and 150 mg per day for Schedule B (cumulative dose of 2250 mg per 3-week cycle). Reversible hematologic and gastrointestinal toxicities were the most common dose-limiting toxicities. One patient with esophageal cancer (receiving 160 mg BI 847325, Schedule A) experienced a partial response for 67 days, and 21 patients (n = 11 [23.4 %], Schedule A; n = 10 [45.5 %], Schedule B) had stable disease. Pharmacokinetic analyses showed at least bi-exponential disposition, with high inter-subject variability. There was no obvious relationship between markers of MEK or Aurora kinase inhibition and exposure to BI 847325 (exploratory analysis). This first-in-human trial suggests that BI 847325 has an acceptable safety profile. However, due to insufficient drug exposure at the MTD to achieve relevant MEK inhibition, a decision was taken to halt the development of BI 847325.

BACKGROUND: This phase I study evaluated afatinib, an irreversible ErbB family blocker, plus paclitaxel in patients with advanced solid tumours likely to express human epidermal growth factor receptor (HER1/EGFR) or HER2.METHODS: Oral afatinib was combined with intravenous paclitaxel (80mg/m(2); days 1, 8 and 15 every four weeks) starting at 20mg once daily and escalated to 40 and 50mg in successive cohorts of ⩾3 patients. The primary objective was to determine the maximum tolerated dose (MTD) of afatinib combined with paclitaxel. Secondary objectives included safety, pharmacokinetics and antitumour activity.RESULTS: Sixteen patients were treated. Dose-limiting toxicities with afatinib 50mg were fatigue and mucositis. The MTD was determined as afatinib 40mg with paclitaxel 80mg/m(2), which proved tolerable with repeated dosing. Frequent adverse events (AEs) included diarrhoea (94%), fatigue (81%), rash/acne (81%), decreased appetite (69%) and inflammation of mucosal membranes (69%); no grade 4 treatment-related AEs were observed. Five (31%) confirmed partial responses were observed in patients with non-small cell lung cancer (n=3), oesophageal cancer and cholangiocarcinoma; eight (50%) patients remained on study for ⩾6months. Pharmacokinetic parameters of afatinib and paclitaxel were similar for single administration or in combination.CONCLUSIONS: The MTD and recommended phase II dose of once-daily afatinib combined with paclitaxel 80mg/m(2) (days 1, 8 and 15 every four weeks) was 40mg. AEs at or below this dose were generally manageable with repeated dosing. No pharmacokinetic interactions were observed. This combination demonstrated promising antitumour activity.TRIAL REGISTRATION: ClinicalTrials.gov, NCT00809133.

Three Doppler-derived techniques have been proposed to assess renal perfusion at bedside: Doppler-based renal resistive index (RI) which has been extensively but imperfectly studied in assessing renal allograft status and changes in renal perfusion in critically ill patients and for predicting the reversibility of an acute kidney injury (AKI), semi-quantitative evaluation of renal perfusion using colour-Doppler which may be easier to perform and may give similar information than RI and contrast-enhanced sonography that may allow more precise renal and cortical perfusion assessment. These promising tools have several obvious advantages including their feasibility, non-invasiveness, repeatability and potential interest in assessing renal function or perfusion. However, several limits need to be taken into account with these techniques, and promising results remain associated with large areas of uncertainty. This editorial will describe more carefully advantages and limits of these techniques and will discuss their potential interest in assessing renal perfusion. Electronic supplementary material The online version of this article (doi:10.1186/s13089-015-0024-6) contains supplementary material, which is available to authorized users.

An increasing body of evidences suggests that renal Doppler may help to assess perfusion of native or transplanted kidneys. Renal Doppler has been proven to be a valuable tool for assessing large arterial or venous abnormalities. The resistive index (RI) is a Doppler-derived parameter that is calculated as follows: RI = [peak systolic shift − minimum diastolic shift]/peak systolic shift. Renal RI has been shown to be correlated with renal arteriosclerosis and may help to assess prognosis, and even to tailor treatment, in hypertensive patients or those with diabetes mellitus. This parameter has also been evaluated in various renal diseases but seems to be an integrative parameter rather than a predictor of a specific event. Also, RI has been suggested for the early detection of acute kidney injury (AKI). However, numerous factors have been shown to influence RI, and this integrative parameter neither constitutes an alternative to renal biopsy nor provides valuable information on renal blood flow. Moreover, experience with RI in all these fields is scant, and our understanding of factors influencing RI is limited. Before implementing this technique in clinical practice, large, adequately powered studies conducted in unselected patients are warranted to better evaluate RI determinants and clinical significance.

Doppler-based renal resistive index (RI) might help in distinguishing transient from persistent acute kidney injury (AKI). The main objective of these systematic review and meta-analysis was to investigate the diagnostic performance of RI in predicting short-term reversibility of AKI.A systematic review of the literature was performed. Relevant studies were identified in Pubmed and Cochrane databases covering the years 1985 to 2013 and reviewed independently by 3 authors. Renal transplant recipients were excluded from this analysis. The summary estimates were computed using a random-effects model based on the DerSimonian and Lair meta-analytic method.Among the 154 unique articles identified, 9 studies were included. Of the 176 patients in these studies with elevated RI or pulsatility index, 146 (83%) had a persistent AKI vs 44 (16%) of the 273 patients with normal values. Elevated RI or pulsatility index was associated with an increased risk of persistent AKI (odds ratio, 29.85; 95% confidence interval [CI], 8.73-102.16; P.00001) with significant heterogeneity (I(2) = 75.0%, P.0001). The pooled sensitivity and specificity were 0.83 (95% CI, 0.77-0.88) and 0.84 (95% CI, 0.79-0.88). The summary positive and negative likelihood ratios were 4.9 (95% CI, 2.44-9.87) and 0.21 (95% CI, 0.11-0.41).These results suggest that an elevated RI may be a predictor of persistent AKI in critically ill patients. Further studies are warranted, however, to clarify the exact test performance given the marked heterogeneity among the included studies.

Noninvasive ventilation (NIV) had proven benefits in clinical trials that included selected patients admitted to highly skilled centers. Whether these benefits apply to every patient and in everyday practice deserves appraisal. The aim of the study was to assess the use and outcomes of NIV over the last 15 years. Multicenter database study of critically ill patients who required ventilatory support for acute respiratory failure between 1997 and 2011. The impact of first-line NIV on 60-day mortality was evaluated using a marginal structural model. Follow-up was censored on day 60. Of 3,163 patients, 1,232 (39 %) received NIV. Over the study period, first-line NIV increased from 29 to 42 %, and NIV success rates increased from 69 to 84 %. NIV decreased 60-day mortality [adjusted hazard ratio (aHR), 0.75; 95 % confidence interval (95 % CI), 0.68–0.83; P

Background: Few outcome data are available about intraoperative cardiac arrest (IOCA). The authors studied 90-day functional outcomes and their determinants in patients admitted to the intensive care unit after IOCA. Methods: Patients admitted to 11 intensive care units in a period of 2000–2013 were studied retrospectively. The main outcome measure was a day-90 Cerebral Performance Category score of 1 or 2. Results: Of the 140 patients (61 women and 79 men; median age, 60 yr [interquartile range, 46 to 70]), 131 patients (93.6%) had general anesthesia, 80 patients (57.1%) had emergent surgery, and 73 patients (52.1%) had IOCA during surgery. First recorded rhythms were asystole in 73 patients (52.1%), pulseless electrical activity in 44 patients (31.4%), and ventricular fibrillation/ventricular tachycardia in 23 patients (16.4%). Median times from collapse to cardiopulmonary resuscitation and return of spontaneous circulation were 0 min (0 to 0) and 10 min (5 to 20), respectively. Postcardiac arrest shock was identified in 114 patients (81.4%). Main causes of IOCA were preoperative complications (n = 46, 32.9%), complications of anesthesia (n = 39, 27.9%), and complications of surgical procedures (n = 36, 25.7%). On day 90, 63 patients (45.3%) were alive with Cerebral Performance Category score 1/2. Independent predictors of day-90 Cerebral Performance Category score 1/2 were day-1 Logistic Organ Dysfunction score (odds ratio, 0.78 per point; 95% CI, 0.71 to 0.87; P = 0.0001), ventricular fibrillation/tachycardia as first recorded rhythm (odds ratio, 4.78; 95% CI, 1.38 to 16.53; P = 0.013), and no epinephrine therapy during postcardiac arrest syndrome (odds ratio, 3.14; 95% CI, 1.29 to 7.65; P = 0.012). Conclusions: By day 90, 45% of IOCA survivors had good functional outcomes. The main outcome predictors were directly related to IOCA occurrence and postcardiac arrest syndrome; they suggest that the intensive care unit management of postcardiac arrest syndrome may be amenable to improvement.

Acute kidney injury (AKI) is associated with high morbidity and mortality in tumor lysis syndrome (TLS). The goal of this study was to assess a practical approach involving a simple risk-prediction model for AKI in patients at high risk for clinical TLS treated according to standardized guidelines. We collected data on 62 patients at high risk for clinical TLS. We evaluated whether the magnitude of the plasma uric acid decrease in response to rasburicase predicted AKI. According to RIFLE criteria (Risk, Injury, Failure, sustained Loss, End-stage kidney disease), 41 (66.1%) patients had AKI. AKI was associated with higher hospital (26.8% vs. 0%, p = 0.01) and 6-month (41.4% vs. 9.5%, p = 0.04) mortality. The plasma uric acid decrease after rasburicase was significantly larger in patients who did not develop AKI than in those who did (95% vs. 84%; p < 0.01). By multivariate analysis, independent determinants of AKI were hypertension and a plasma uric acid decrease smaller than 92.9% 6 h after rasburicase.

International audience; BACKGROUND:Although recent studies have demonstrated an improvement in the prognosis of critically ill cancer patients, little is known regarding the prognosis of patients with non-aggressive underlying malignancies. The aims of this study were to assess the prognosis of critically ill patients with chronic lymphocytic leukemia (CLL) and to evaluate risk factors for hospital mortality.METHODS:In retrospective mono-center cohort study, consecutive adult patients with CLL requiring ICU admission from 1997 to 2008 were included.RESULTS:Sixty-two patients of 67 years (62-75) were included. Median time interval between CLL diagnosis and ICU admission was 6.7 years (2.6-10.8). Nine patients (15 %) had stage C disease at the time of ICU admission, and seven patients (11 %) had Richter syndrome. Most ICU admissions were related to bacterial or fungal pulmonary infections (n = 47; 76 %). ICU, in-hospital, and 90-day mortality were 35 % (n = 22), 42 % (n = 26), and 58 % (n = 36), respectively. Only three factors were independently associated with in-hospital mortality: oxygen saturation lower than 95 % when breathing room air (odds ratio (OR) 5.80; 95 % confidence interval (CI) 1.23-27.33), need for vasopressors (OR 27.94; 95 % CI 5.37-145.4), and past history of infection (OR 6.62; 95 % CI 1.34-32.68). The final model did not change when disease-related variables (Binet classification, Richter syndrome, long-term steroids) or treatment-related variables (fludarabine, rituximab, or alemtuzumab) were included.CONCLUSION:Acute pulmonary infections remain the leading cause of ICU admission in patients with CLL. The severity at ICU admission and past history of infection were the only factors associated with hospital mortality. Neither disease characteristics nor previous cancer treatments were associated with outcome.

The objective of this study was to determine the predictive value of the renal resistive index (RI) and cystatin C values in serum (SCys) and urine (UCys) in the development of acute kidney injury (AKI) in critically ill patients with severe sepsis or polytrauma. This was a prospective, double-center, descriptive study. There were 58 patients with severe sepsis (n= 28) or polytrauma (n = 30). Renal resistive index, SCys, and UCys were measured within 12 h following admission (day 1 [D1]) to the intensive care unit. Renal function was assessed using the AKI network classification: On day 3 (D3), 40 patients were at stage 0 or 1, and 18 were at stage 2 or 3. Patients with AKI stage 2 or 3 had significantly higher RI (0.80 vs. 0.66, P0.0001), SCys (1.23 vs. 0.68 mg/L, P = 0.0002), and UCys (3.32 vs. 0.09 mg/L, P = 0.0008). They also had higher Simplified Acute Physiology Score II, arterial lactate level, and intensive care unit mortality. In multivariate analysis, an RI of greater than 0.707 on D1 was the only parameter predictive of the development of AKI stage 2 or 3 on D3 (P = 0.0004). In the subgroup of patients with AKI stage 2 or 3 on D1, RI remained the only parameter associated with persistent AKI on D3 (P = 0.016). In multivariate analysis comparing the predictive value of RI, SCys, and UCys, RI was the only parameter predictive of AKI stage 2 or 3 on D3. Renal resistive index seems to be a promising tool to assess the risk of AKI.

To describe the method and significance of Doppler-based resistive index (RI) and to provide an updated description of its interest with a special focus on the critically ill. Review of selected studies on RI found in the PubMed, Ovid and Cochrane databases. Additional references were retrieved from the selected studies. An increasing body of evidence suggests that renal Doppler may help to assess perfusion of native or transplanted kidneys. In addition, recent studies suggest that it may be useful in critically ill patients. The RI is a parameter derived from Doppler examination that is calculated as follows: $$ {\text{RI}} = \left[ {\text{peak systolic shift}}\,-\,{\text{minimum diastolic shift}} \right]/{\text{peak systolic shift}} $$ . Renal Doppler has proven to be valuable for assessing large arterial or venous abnormalities and has been suggested to assess renal perfusion and to predict acute kidney injury (AKI) in critically ill patients. However, numerous factors have been shown to influence renal Doppler and may constitute potential confounding factors. Moreover, experience with critically ill patients is scant and our understanding of factors influencing RI in this setting is limited. Doppler-based RI seems to be a promising tool in the critically ill to assess the risk of AKI, help in differentiating persistent from transient AKI, or assess changes in renal perfusion as consequences of therapeutic intervention. However, we still lack large, adequately powered studies in non-selected populations of patients before implementing this technique in clinical practice. In addition, the impact of several factors that may influence this parameter remains to be evaluated.

OBJECTIVE: Few outcome data are available about posterior reversible encephalopathy syndrome (PRES). We studied 90-day functional outcomes and their determinants in patients with severe PRES. DESIGN: 70 patients with severe PRES admitted to 24 ICUs in 2001-2010 were included in a retrospective cohort study. The main outcome measure was a Glasgow Outcome Scale (GOS) of 5 (good recovery) on day 90. MAIN RESULTS: Consciousness impairment was the most common clinical sign, occurring in 66 (94%) patients. Clinical seizures occurred in 57 (81%) patients. Median mean arterial pressure was 122 (105-143) mmHg on scene. Cerebral imaging abnormalities were bilateral (93%) and predominated in the parietal (93%) and occipital (86%) white matter. Median number of brain areas involved was 4 (3-5). Imaging abnormalities resolved in 43 (88%) patients. Ischaemic and/or haemorrhagic complications occurred in 7 (14%) patients. The most common causes were drug toxicity (44%) and hypertensive encephalopathy (41%). On day 90, 11 (16%) patients had died, 26 (37%) had marked functional impairments (GOS, 2 to 4), and 33 (56%) had a good recovery (GOS, 5). Factors independently associated with GOS

Acute respiratory failure (ARF) is the main reason for ICU admission in patients with haematological malignancies. High mortality rates of up to 50% are reported in this situation, and mortality is highest when mechanical ventilation is needed. Rapid and accurate diagnostic methods are needed in these vulnerable patients to ensure the prompt initiation of effective treatment. However, the broad array of possible cause of ARF raises diagnostic challenges. In this review, we discuss the DIRECT strategy, which identifies the most plausible diagnosis in each patient based on the type of immune deficiency and clinical presentation. We will focus on non-invasive laboratory tests developed in recent years, discussing their sensitivity and specificity. We also discuss the usefulness in cancer patients with specific organ dysfunctions of biomarkers introduced over the past few years.

Human herpesvirus 6 (HHV6) is an emerging cause of interstitial pneumonia in immunocompromised hosts. However, the clinical significance of a positive PCR test for HHV6 in respiratory samples from patients with hematological malignancies remains unclear.We retrospectively studied the features and outcomes of 29 critically ill hematology patients with acute respiratory failure and lung pulmonary infiltrates visible on a chest radiograph, who tested positive for a qualitative PCR for HHV6 in bronchoalveolar lavage fluid.Of the 29 patients, 18 (62%) were stem cell transplant recipients and 11 (38%) had received chemotherapy. All patients had a fever. Clinical manifestations consistent with extra-pulmonary HHV6 disease were noted in 17 (59%) patients. One or more co-pathogens were found in 25 (86%) patients. The four remaining patients diagnosed with HHV6 pneumonia and subsequently recovered with foscarnet therapy. Antiviral therapy was also given to seven patients with co-infections, of whom two ultimately died.In most cases, HHV6 recovered from BAL fluid is a co-pathogen whose clinical relevance remains undetermined. However, in some cases, HHV6 is the only pathogen, along with disseminated systemic viral disease, and the patient is likely to benefit from foscarnet therapy.

SummaryBackgroundImmunocompromised patients with influenza are at higher risk of pneumonia and death. However, risk factors for progression to pneumonia still need evaluation.MethodsRetrospective study in immunocompromised patients with influenza-related respiratory infections. Risk factors for pneumonia were identified by multivariable logistic regression.ResultsWe identified 100 immunocompromised patients infected with influenza (68 hematological malignancies, 11 HIV, 21 iatrogenic immunosuppression). Immunofluorescence was positive in 95% of patients, mainly on nasopharyngeal aspirates (84%). Influenza A virus was involved in 80% of patients. Associated infection was documented in 34 patients. All patients presented with upper respiratory tract infection and 53 progressed to pneumonia. Thirty-two patients were critically ill, 11 received mechanical ventilation, and 10 died. All the patients who died had pneumonia. Patients with pneumonia were older (46y (36–63) vs. 33y (13–51), P=0.003) and more often had influenza A (89% vs. 70%, P=0.04) and associated infection (56% vs. 9%, P

2541 Background: BI 853520 is a potent and highly selective inhibitor of FAK. In the dose-finding part of this study in patients (pts) with advanced or metastatic solid tumors, the maximum tolerate...

Background. Little attention has been given to patients with neutropenic enterocolitis (NEC or typhlitis). However, as significant advances have been made in both hematology, oncology and critical care management, updating outcome data on these patients is timely. Patients and methods. We conducted here a retrospective hospital-based cohort from patients admitted to the intensive care unit (ICU) from a cancer center that includes 10 wards of oncology and hematology (a 650-bed public hospital with 330 beds for treatment of malignancies). Patients with NEC were compared to patients with other digestive complications. We used the NEC definition suggested by Gorschlüter based on presence of neutropenia and at least one major criteria (bowel thickening and fever) with one or several minor criteria (abdominal aches, diarrhea, abdominal distension, abdominal cramps and low digestive bleedings), after exclusion of other intestinal affections listed above. Results. Among the 171 patients admitted for acute digestive complications over a 15-y study period (1997-2011), 54 (33%) presented with NEC. Median age was 48 years (IQR: 38-60y) and there were 34 men and 20 women. Hematological malignancies were more common (87% versus 13% solid tumors), mainly non hodgkin lymphoma (41%) and among them 5 undergoing autologous SCT. Abdominal pains were present in 74% of the patients. Vomiting, diarrhea and mucositis were present in 91%, 76% and 39%, respectively. All patients were treated with fasting, naso-gastric aspiration, hydroelectrolytic equilibration, large spectrum antibiotics and parenteral nutrition. Eight (15%) patients were operated. Vasopressive drugs were used for 31 patients (57%), mechanical ventilation for 22 (41%) and renal replacement for 14 (26%). Microbiological infection was documented for 32 patients: 1 fungal infection (Candida), 16 Escherichia coli, 7 Clostridium difficile (2 toxinogen), 6 Pseudomonas aeruginosae, 2 other enterobacteria. Twelve (22%) patients died. Compared to non-NEC patients, patients with NEC were sickest (median Simplified Acute Physiology II score was 54.5 (IQR 42.5-62.5) vs. 48 (IQR 35.5-61.5). Also, NEC was associated with more exposure to cytosine arabinoside (46% vs 20%, p=0.0008), anthracyclines (37% vs 13%, p=0.0008), vinca-alkaloids (28% vs 8%, p=0.002) and VP16 (24% vs 12%, p=0.0067). Steroids were not associated with incidence of NEC (19% vs 21%, p=0.84). Clinical symptoms that were significantly different in patients with NEC were vomiting (91% vs 70%, p=0.003), diarrhea (76% vs 53%, p=0.006) and mucositis (39% vs 17%, p=0.004). However, digestive bleedings were less common (11% vs 30%, p=0.01). CT findings helped to differentiate NEC and non-NEC patients with, colic (57% vs 33%, p=0.033) and small intestine (35% vs 14%, p=0.023) thickening, occlusive findings (51% vs 19%, p=0.002). Pneumatosis and pneumoperitoneum were not significantly different in the two groups (8% vs 4%, and 8% vs 12%, respectively). Need for surgery was non significantly higher in non-NEC patients (25% vs. 15%, p=0.22). However, mortality was significantly lower in NEC patients (22% vs 41%, p=0.023). Median time hospitalization in ICU was 7 days (IQR: 6.5-23.5d) vs 4d (IQR: 3-10d) for non-NEC patients. Conclusion: Neutropenic enterocolitis is a clinical entity that has its own clinical, radiological and management peculiarities that translate into different outcomes. Early recognition of the syndrome may help in setting prompt appropriate treatment and monitoring. Disclosures No relevant conflicts of interest to declare.

Aim: Preclinical data show that A, an irreversible ErbB family blocker, combined with an mTOR inhibitor such as S, may restore sensitivity in EGFR M+ NSCLC pts who progress after E/G. This trial was conducted to identify the maximum tolerated dose (MTD) of A + S. Methods: Pts with stage IIIB/IV NSCLC who failed ≥1 prior treatment, and whose tumour was EGFR M + , or negative/unknown, but had progressive disease after response or stable disease (SD) for ≥6 months on prior E/G were eligible. Pts received run-in treatment with sirolimus for 8 days before starting the combination therapy. Definition of MTD was initially based on dose-limiting toxicities (DLTs) in cycle (C) 1 (28 days) but with an amendment this was extended to C1 and 2. EGFR mutation was assessed (from blood and archival tumour) and PK sampling was performed. Tumour assessment was performed at week 4, 8, 12, then every 8 weeks. Results: 39 pts were treated: median age 61y (range: 32-81); male: 15; ECOG 0/1/2: 16/21/1; adeno/squamous/large cell carcinoma: 33/3/3. All had prior E/G; 32 had ≥1 prior chemotherapy. Median treatment duration: 103 days (range: 10-367). Pts were treated at 6 dose levels (A, mg/S, mg): 30/1 (n = 12), 40/1 (n = 3), 30/3 (n = 9), 30/5 (n = 9), 30/10 (n = 3), 40/5 (n = 3), with 30/1 defined as MTD. DLTs (C1 and 2) were seen in 12 pts (Table). The most frequent (≥20%, all grades) drug-related adverse events were: diarrhoea, mucositis, rash, asthenia, decreased appetite and nausea. The best response was partial response (PR) in 4 pts (2 at 30/5, 2 at 40/5); 23 had stable disease (SD) (median duration [days]: 105, range: 51-337). PK, tumour and blood mutation results will be presented. DLTs (grade [n]) by dose level 30/1 40/1 30/3 30/5 30/10 40/5 Diarrhoea – G3 (1) G3 (1) – G3 (2)* G3 (1) Mucositis – – G3 (1) G3 (2) G3 (1) G3 (2) Raised CPK – G4 (1) – – – – *1 pt had G3 diarrhoea, asthenia, anorexia and iliac fossa pain. Conclusions: A + S combination had limited tolerability in pts with EGFR M+ NSCLC progressing on E/G mainly due to overlapping DLTs of diarrhoea and mucositis. A 30 mg + S 1 mg was defined as MTD. PRs were observed at doses exceeding MTD; SD was observed at all doses. Disclosure: M. Majem: Membership on an advisory board for Roche, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb and Pfizer; N. Reguart: Membership on an advisory board for Roche, Lilly, Boehringer Ingelheim and Pfizer; C.P. Lee: Employee of Boehringer Ingelheim; S. Kraemer: Employee of Boehringer Ingelheim; D. Schnell: Employee of Boehringer Ingelheim. All other authors have declared no conflicts of interest.