Protocol for fever control using external cooling in mechanically ventilated patients with septic shock: SEPSISCOOL II randomised controlled trial.

INTRODUCTION: Fever treatment is commonly applied in patients with sepsis but its impact on survival remains undetermined. Patients with respiratory and haemodynamic failure are at the highest risk for not tolerating the metabolic cost of fever. However, fever can help to control infection. Treating fever with paracetamol has been shown to be less effective than cooling. In the SEPSISCOOL pilot study, active fever control by external cooling improved organ failure recovery and early survival. The main objective of this confirmatory trial is to assess whether fever control at normothermia can improve the evolution of organ failure and mortality at day 60 of febrile patients with septic shock. This study will compare two strategies within the first 48 hours of septic shock: treatment of fever with cooling or no treatment of fever. METHODS AND ANALYSIS: SEPSISCOOL II is a pragmatic, investigator-initiated, adaptive, multicentre, open-label, randomised controlled, superiority trial in patients admitted to the intensive care unit with febrile septic shock. After stratification based on the acute respiratory distress syndrome status, patients will be randomised between two arms: (1) cooling and (2) no cooling. The primary endpoint is mortality at day 60 after randomisation. The secondary endpoints include the evolution of organ failure, early mortality and tolerance. The target sample size is 820 patients. ETHICS AND DISSEMINATION: The study is funded by the French health ministry and was approved by the ethics committee CPP Nord Ouest II (Amiens, France). The results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04494074.

Heart involvement: A neglected manifestation of haemophagocytic syndrome associated with high mortality.

Secondary haemophagocytic lymphohistiocytosis (sHLH) proceeds from uncontrolled and inefficient immune activation leading to hyper-inflammation and multi-organ damage. sHLH proceeds from a wide panel of infectious, auto immune and malignant conditions and bears high mortality despite treatment. Literature on sHLH does not mention heart involvement. We sought to describe occurrence of reversible heart dysfunction in the setting of HLH in order to motivate larger prospective studies assessing the causality link between both conditions. We identified 11 cases in our hospital, systematically searched the PubMed database for publications on HLH and heart involvement and reviewed 36 publications with a total of 18 cases. Amongst these 29 cases, 25 presented with myocardial dysfunction and 14 with pericardial effusion. Twenty-six patients required intensive care management, and 14 patients died. This leads us to hypothesize that heart involvement confers worse prognosis to HLH. Formal accountability of HLH in the occurrence of cardiac manifestations is difficult to establish given the numerous differential diagnoses but reversibility of myocardial dysfunction in 14 survivors and results of two necropsies supported it. These data, and the current knowledge on the pathophysiology of both HLH and heart failure lead us to suggest that such a link may exist.

Prospective evaluation of the efficacy, safety, and optimal biomarker enrichment strategy for nangibotide, a TREM-1 inhibitor, in patients with septic shock (ASTONISH): a double-blind, randomised, controlled, phase 2b trial.

BACKGROUND: Activation of the triggering receptor expressed on myeloid cells-1 (TREM-1) pathway is associated with septic shock outcomes. Data suggest that modulation of this pathway in patients with activated TREM-1 might improve survival. Soluble TREM-1 (sTREM-1), a potential mechanism-based biomarker, might facilitate enrichment of patient selection in clinical trials of nangibotide, a TREM-1 modulator. In this phase 2b trial, we aimed to confirm the hypothesis that TREM1 inhibition might improve outcomes in patients with septic shock. METHODS: This double-blind, randomised, placebo-controlled, phase 2b trial assessed the efficacy and safety of two different doses of nangibotide compared with placebo, and aimed to identify the optimum treatment population, in patients across 42 hospitals with medical, surgical, or mixed intensive care units (ICUs) in seven countries. Non-COVID-19 patients (18-85 years) meeting the standard definition of septic shock, with documented or suspected infection (lung, abdominal, or urinary [in patients ≥65 years]), were eligible within 24 h of vasopressor initiation for the treatment of septic shock. Patients were randomly assigned in a 1:1:1 ratio to intravenous nangibotide 0·3 mg/kg per h (low-dose group), nangibotide 1·0 mg/kg per h (high-dose group), or matched placebo, using a computer-generated block randomisation scheme (block size 3). Patients and investigators were masked to treatment allocation. Patients were grouped according to sTREM-1 concentrations at baseline (established from sepsis observational studies and from phase 2a change to data) into high sTREM-1 (≥ 400 pg/mL). The primary outcome was the mean difference in total Sequential Organ Failure Assessment (SOFA) score from baseline to day 5 in the low-dose and high-dose groups compared with placebo, measured in the predefined high sTREM-1 (≥ 400 pg/mL) population and in the overall modified intention-to-treat population. Secondary endpoints included all-cause 28-day mortality, safety, pharmacokinetics, and evaluation of the relationship between TREM-1 activation and treatment response. This study is registered with EudraCT, 2018-004827-36, and Clinicaltrials.gov, NCT04055909. FINDINGS: Between Nov 14, 2019, and April 11, 2022, of 402 patients screened, 355 were included in the main analysis (116 in the placebo group, 118 in the low-dose group, and 121 in the high-dose group). In the preliminary high sTREM-1 population (total 253 [71%] of 355; placebo 75 [65%] of 116; low-dose 90 [76%] of 118; high-dose 88 [73%] of 121), the mean difference in SOFA score from baseline to day 5 was 0·21 (95% CI -1·45 to 1·87, p=0·80) in the low-dose group and 1·39 (-0·28 to 3·06, p=0·104) in the high-dose group versus placebo. In the overall population, the difference in SOFA score from baseline to day 5 between the placebo group and low-dose group was 0·20 (-1·09 to 1·50; p=0·76),and between the placebo group and the high-dose group was 1·06 (-0·23 to 2·35, p=0·108). In the predefined high sTREM-1 cutoff population, 23 (31%) patients in the placebo group, 35 (39%) in the low-dose group, and 25 (28%) in the high-dose group had died by day 28. In the overall population, 29 (25%) patients in the placebo, 38 (32%) in the low-dose, and 30 (25%) in the high-dose group had died by day 28. The number of treatment-emergent adverse events (111 [96%] patients in the placebo group, 113 [96%] in the low-dose group, and 115 [95%] in the high-dose group) and serious treatment-emergent adverse events (28 [24%], 26 [22%], and 31 [26%]) was similar between all three groups. High-dose nangibotide led to a clinically relevant improvement in SOFA score (of two points or more) from baseline to day 5 over placebo in those with higher cutoff concentrations (≥532 pg/mL) of sTREM-1 at baseline. Low dose nangibotide displayed a similar pattern with lower magnitude of effect across all cutoff values. INTERPRETATION: This trial did not achieve the primary outcome of improvement in SOFA score at the predefined sTREM-1 value. Future studies are needed to confirm the benefit of nangibotide at higher concentrations of TREM-1 activation. FUNDING: Inotrem.

Healthcare trajectory of critically ill patients with necrotizing soft tissue infections: a multicenter retrospective cohort study using the clinical data warehouse of Greater Paris University Hospitals.

BACKGROUND: Necrotizing skin and soft tissue infections (NSTIs) are rare but serious and rapidly progressive infections characterized by necrosis of subcutaneous tissue, fascia and even muscle. The care pathway of patients with NSTIs is poorly understood. A better characterization of the care trajectory of these patients and a better identification of patients at risk of a complicated evolution, requiring prolonged hospitalization, multiple surgical re-interventions, or readmission to the intensive care unit (ICU), is an essential prerequisite to improve their care. The main objective of this study is to obtain large-scale data on the care pathway of these patients. We performed a retrospective multicenter observational cohort study in 13 Great Paris area hospitals, including patients hospitalized between January 1, 2015 and December 31, 2019 in the ICU for surgically confirmed NSTIs. RESULTS: 170 patients were included. The median duration of stay in ICU and hospital was 8 (3-17) and 37 (14-71) days, respectively. The median time from admission to first surgical debridement was 1 (0-2) day but 69.9% of patients were re-operated with a median of 1 (0-3) additional debridement. Inter-hospital transfer was necessary in 52.4% of patients. 80.2% of patients developed organ failures during the course of ICU stay with 51.8% of patients requiring invasive mechanical ventilation, 77.2% needing vasopressor support and 27.7% renal replacement therapy. In-ICU and in-hospital mortality rates were 21.8% and 28.8%, respectively. There was no significant difference between patients with abdomino-perineal NSTIs (n = 33) and others (n = 137) in terms of in-hospital or ICU mortality. Yet, immunocompromised patients (n = 43) showed significantly higher ICU and in-hospital mortality rates than non-immunocompromised patients (n = 127) (37.2% vs. 16.5%, p = 0.009, and 53.5% vs. 20.5%, p < 0.001). Factors associated with a complicated course were the presence of a polymicrobial infection (adjusted odds ratio [aOR = 3.18 (1.37-7.35); p = 0.007], of a bacteremia [aOR = 3.29 (1.14-9.52); p = 0.028] and a higher SAPS II score [aOR = 1.05 (1.02-1.07); p < 0.0001]. 62.3% of patients were re-hospitalized within 6 months. CONCLUSION: In this retrospective multicenter study, we showed that patients with NSTI required complex management and are major consumers of care. Two-thirds of them underwent a complicated hospital course, associated with a higher SAPS II score, a polymicrobial NSTI and a bacteremia.

Clinical Added Value of SARS-CoV-2 Antigen Detection in Blood Samples.

This study evaluated the performances of immunoassays (LFIA and ELISA) designed for SARS-CoV-2 Antigen (Ag)-detection in nasopharyngeal (NP) and serum samples in comparison to RT-PCR. NP samples from patients with respiratory symptoms (183 RT-PCR-positive and 74 RT-PCR-negative samples) were collected from March to April and November to December 2020. Seroconversion and antigen dynamics were assessed by symptom onset and day of RT-PCR diagnosis. Serum samples from 87 COVID-19 patients were used to investigate the added value of Ag quantification, at diagnosis and during follow-up. The sensitivity of COVID-VIRO-LFIA on samples with Ct ≤ 33, considered as the contagious threshold, was 86% on NPs (CI 95%: 79-90.5) and 76% on serum samples (CI 95%: 59.4-88), with a specificity of 100%. Serum N-Ag was detected during active infection as early as day two from symptom onset, with a diagnostic sensitivity of 81.5%. Within one week of symptom onset, diagnostic sensitivity and specificity reached 90.9% (95% CI, 85.1%-94.6%) and 98.3% (95% CI, 91.1%-99.9%), respectively. Serum N-Ag concentration closely correlated with disease severity. Longitudinal analysis revealed the simultaneous increase of antibodies and decrease of N-Ag. Sensitivities of COVID-VIRO-LFIA and COV-QUANTO-ELISA tests on NP and serum samples were close to 80%. They are suitable COVID-19-laboratory diagnostic tests, particularly when blood samples are available, thus reducing the requirement for NP sampling, and subsequent PCR analysis. ELISA titers may help to identify patients at risk of poor outcomes.

Effects of mean arterial pressure target on mottling and arterial lactate normalization in patients with septic shock: a post hoc analysis of the SEPSISPAM randomized trial.

BACKGROUND: In patients with septic shock, the impact of the mean arterial pressure (MAP) target on the course of mottling remains uncertain. In this post hoc analysis of the SEPSISPAM trial, we investigated whether a low-MAP (65 to 70 mmHg) or a high-MAP target (80 to 85 mmHg) would affect the course of mottling and arterial lactate in patients with septic shock. METHODS: The presence of mottling was assessed every 2 h from 2 h after inclusion to catecholamine weaning. We compared mottling and lactate time course between the two MAP target groups. We evaluated the patient's outcome according to the presence or absence of mottling. RESULTS: We included 747 patients, 374 were assigned to the low-MAP group and 373 to the high-MAP group. There was no difference in mottling and lactate evolution during the first 24 h between the two MAP groups. After adjustment for MAP and confounding factors, the presence of mottling ≥ 6 h during the first 24 h was associated with a significantly higher risk of death at day 28 and 90. Patients without mottling or with mottling < 6 h and lactate ≥ 2 mmol/L have a higher probability of survival than those with mottling ≥ 6 h and lactate < 2 mmol/L. CONCLUSION: Compared with low MAP target, higher MAP target did not alter mottling and lactate course. Mottling lasting for more than 6 h was associated with higher mortality. Compared to arterial lactate, mottling duration appears to be a better marker of mortality.

Factors associated with acute mesenteric ischemia among critically ill ventilated patients with shock: a post hoc analysis of the NUTRIREA2 trial.

PURPOSE: Acute mesenteric ischemia (AMI) is a rare, but life-threatening condition occurring among critically ill patients. Several factors have been associated with AMI, but the causal link is debated, most studies being retrospective. Among these factors, enteral nutrition (EN) could be associated with AMI, in particular among patients with shock. We aimed to study the factors independently associated with AMI in a post hoc analysis of the NUTRIREA-2 trial including 2410 critically ill ventilated patients with shock, randomly assigned to receive EN or parenteral nutrition (PN). METHODS: Post hoc analysis of the NUTRIREA-2 trial was conducted. Ventilated adults with shock were randomly assigned to receive EN or PN. AMI was assessed by computed tomography, endoscopy, or laparotomy. Factors associated with AMI were studied by univariate and multivariate analysis. RESULTS: 2410 patients from 44 French intensive care units (ICUs) were included in the study: 1202 patients in the enteral group and 1208 patients in the parenteral group. The median age was 67 [58-76] years, with 67% men, a SAPS II score of 59 [46-74], and a medical cause for ICU admission in 92.7%. AMI was diagnosed among 24 (1%) patients, mainly by computed tomography (79%) or endoscopy (38%). The mechanism of AMI was non-occlusive mesenteric ischemia (n = 12), occlusive (n = 4), and indeterminate (n = 8). The median duration between inclusion in the trial and AMI diagnosis was 4 [1-11] days. Patients with AMI were older, had a higher SAPS II score at ICU admission, had higher plasma lactate, creatinine, and ASAT concentrations and lower hemoglobin concentration, had more frequently EN, dobutamine, and CVVHDF at inclusion, developed more frequently bacteremia during ICU stay, and had higher 28-day and 90-day mortality rates compared with patients without AMI. By multivariate analysis, AMI was independently associated with EN, dobutamine use, SAPS II score ≥ 62 and hemoglobin concentration ≤ 10.9 g/dL. CONCLUSION: Among critically ill ventilated patients with shock, EN, dobutamine use, SAPS II score ≥ 62 and hemoglobin ≤ 10.9 g/dL were independently associated with AMI. Among critically ill ventilated patients requiring vasopressors, EN should be delayed or introduced cautiously in case of low cardiac output requiring dobutamine and/or in case of multiple organ failure with high SAPS II score.

Prior Exposure to Angiotensin II Receptor Blockers in Patients With Septic Shock to Individualize Mean Arterial Pressure Target? A Post Hoc Analysis of the Sepsis and Mean Arterial Pressure (SEPSISPAM) Trial.

OBJECTIVES: Individualizing a target mean arterial pressure is challenging during the initial resuscitation of patients with septic shock. The Sepsis and Mean Arterial Pressure (SEPSISPAM) trial suggested that targeting high mean arterial pressure might reduce the occurrence of acute kidney injury among those included patients with a past history of chronic hypertension. We investigated whether the class of antihypertensive medications used before the ICU stay in chronic hypertensive patients was associated with the severity of acute kidney injury occurring after inclusion, according to mean arterial pressure target. DESIGN: Post hoc analysis of the SEPSISPAM trial. SETTING: The primary outcome was the occurrence of severe acute kidney injury during the ICU stay defined as kidney disease improving global outcome stage 2 or higher. Secondary outcomes were mortality at day 28 and mortality at day 90. PATIENTS: All patients with chronic hypertension included in SEPSISPAM with available antihypertensive medications data in the hospitalization report were included. MEASUREMENTS AND MAIN RESULTS: We analyzed 297 patients. Severe acute kidney injury occurred in 184 patients, without difference according to pre-ICU exposure to antihypertensive medications. Patients with pre-ICU exposure to angiotensin II receptor blockers had significantly less severe acute kidney injury in the high mean arterial pressure target group (adjusted odd ratio 0.24 with 95% CI [0.09-0.66]; p = 0.006). No statistically significant association was found after adjustment for pre-ICU exposure to antihypertensive medications and survival. CONCLUSIONS: Our results suggest that patients with septic shock and chronic hypertension treated with angiotensin II receptor blocker may benefit from a high mean arterial pressure target to reduce the risk of acute kidney injury occurrence.

ADAMTS13 and von Willebrand factor assessment in steady state and acute vaso-occlusive crisis of sickle cell disease.

BACKGROUND: Sickle cell disease (SCD) is characterized by vaso-occlusive crisis (VOC), acute chest syndrome (ACS) and multiorgan failure (MOF) complicated by thrombosis. Von Willebrand factor (VWF) is a strong marker of SCD-related endothelial injury. OBJECTIVES: To decipher the role of VWF and its specific-cleaving metalloprotease, ADAMTS13, in the vaso-occlusive and thrombotic process of SCD. PATIENTS/METHODS: We investigated the VWF antigen (Ag), ADAMTS13 activity, ADAMTS13 Ag and ADAMTS13 IgGs in a cohort of 65 patients with SCD prospectively enrolled in a 20-month period from three centers. Patients were divided into two groups: an asymptomatic group (n = 30) with treated or untreated SCD at steady state, and a VOC/ACS group (n = 35) with SCD with VOC/ACS requiring either medical management or intensive care management for MOF. RESULTS AND CONCLUSIONS: VWF:Ag levels were increased (median, 167 IU/dL; interquartile range [IQR], 124 - 279), especially in patients with VOC SCD (227 IU/dL; IQR, 134-305; P = .04), and positively correlated with inflammatory markers (P < .02). Median ADAMTS13 activity was normal (70 IU/dL; IQR, 60-80), but 7 patients exhibited a partial deficiency between 25 and 45 IU/dL. ADAMTS13 activity/VWF:Ag ratio, however, did not change during VOC. Median ADAMTS13:Ag was slightly decreased (611 ng/mL; IQR, 504-703) with no significant difference between groups. Surprisingly, ADAMTS13 IgGs were detected in 33 (51%) of our patients. We conclude that, in SCD, VWF:Ag and nonrelevant ADAMTS13 IgGs may reflect the severity of the inflammatory vasculopathy enhancing vaso-occlusive and thrombotic complications.

How to detect a positive response to a fluid bolus when cardiac output is not measured?

BACKGROUND: Volume expansion is aimed at increasing cardiac output (CO), but this variable is not always directly measured. We assessed the ability of changes in arterial pressure, pulse pressure variation (PPV) and heart rate (HR) or of a combination of them to detect a positive response of cardiac output (CO) to fluid administration. METHODS: We retrospectively included 491 patients with circulatory failure. Before and after a 500-mL normal saline infusion, we measured CO (PiCCO device), HR, systolic (SAP), diastolic (DAP), mean (MAP) and pulse (PP) arterial pressure, PPV, shock index (HR/SAP) and the PP/HR ratio. RESULTS: The fluid-induced changes in HR were not correlated with the fluid-induced changes in CO. The area under the receiver operating characteristic curve (AUROC) for changes in HR as detectors of a positive fluid response (CO increase ≥ 15%) was not different from 0.5. The fluid-induced changes in SAP, MAP, PP, PPV, shock index (HR/SAP) and the PP/HR ratio were correlated with the fluid-induced changes in CO, but with r < 0.4. The best detection was provided by increases in PP, but it was rough (AUROC = 0.719 ± 0.023, best threshold: increase ≥ 10%, sensitivity = 72 [66-77]%, specificity = 64 [57-70]%). Neither the decrease in shock index nor the changes in other indices combining changes in HR, shock index, PPV and PP provided a better detection of a positive fluid response than changes in PP. CONCLUSION: A positive response to fluid was roughly detected by changes in PP and not detected by changes in HR. Changes in combined indices including the shock index and the PP/HR ratio did not provide a better diagnostic accuracy.

Intra-Abdominal Hypertension Is Responsible for False Negatives to the Passive Leg Raising Test.

OBJECTIVES: To compare the passive leg raising test ability to predict fluid responsiveness in patients with and without intra-abdominal hypertension. DESIGN: Observational study. SETTING: Medical ICU. PATIENTS: Mechanically ventilated patients monitored with a PiCCO2 device (Pulsion Medical Systems, Feldkirchen, Germany) in whom fluid expansion was planned, with (intra-abdominal hypertension+) and without (intra-abdominal hypertension-) intra-abdominal hypertension, defined by an intra-abdominal pressure greater than or equal to 12 mm Hg (bladder pressure). INTERVENTIONS: We measured the changes in cardiac index during passive leg raising and after volume expansion. The passive leg raising test was defined as positive if it increased cardiac index greater than or equal to 10%. Fluid responsiveness was defined by a fluid-induced increase in cardiac index greater than or equal to 15%. MEASUREMENTS AND MAIN RESULTS: We included 60 patients, 30 without intra-abdominal hypertension (15 fluid responders and 15 fluid nonresponders) and 30 with intra-abdominal hypertension (21 fluid responders and nine fluid nonresponders). The intra-abdominal pressure at baseline was 4 ± 3 mm Hg in intra-abdominal hypertension- and 20 ± 6 mm Hg in intra-abdominal hypertension+ patients (p < 0.01). In intra-abdominal hypertension- patients with fluid responsiveness, cardiac index increased by 25% ± 19% during passive leg raising and by 35% ± 14% after volume expansion. The passive leg raising test was positive in 14 patients. The passive leg raising test was negative in all intra-abdominal hypertension- patients without fluid responsiveness. In intra-abdominal hypertension+ patients with fluid responsiveness, cardiac index increased by 10% ± 14% during passive leg raising (p = 0.01 vs intra-abdominal hypertension- patients) and by 32% ± 18% during volume expansion (p = 0.72 vs intra-abdominal hypertension- patients). Among these patients, the passive leg raising test was negative in 15 patients (false negatives) and positive in six patients (true positives). Among the nine intra-abdominal hypertension+ patients without fluid responsiveness, the passive leg raising test was negative in all but one patient. The area under the receiver operating characteristic curve of the passive leg raising test for detecting fluid responsiveness was 0.98 ± 0.02 (p < 0.001 vs 0.5) in intra-abdominal hypertension- patients and 0.60 ± 0.11 in intra-abdominal hypertension+ patients (p = 0.37 vs 0.5). CONCLUSIONS: Intra-abdominal hypertension is responsible for some false negatives to the passive leg raising test.

Effects of mean arterial pressure on arousal in sedated ventilated patients with septic shock: a SEPSISPAM post hoc exploratory study.

BACKGROUND: It is unknown whether the recommended mean arterial pressure (MAP) target of 65 mmHg during initial resuscitation of septic shock is sufficient to maintain cerebral perfusion. Thus, we tested the hypothesis that a higher MAP target in patients with septic shock may improve level of arousal. METHODS: We performed a post hoc exploratory analysis of the SEPSISPAM trial, which assessed the effect of a "high-target" level of MAP (80-85 mmHg) versus the recommended "low-target" MAP (65-70 mm Hg) on mortality in patients with septic shock. Among the 776 patients originally recruited in SEPSISPAM trial, we selected those who were mechanically ventilated and sedated and with available evaluation of arousal level assessed by the Richmond Agitation and Sedation Scale (RASS). RESULTS: We restricted our analysis to the period in which patients were treated with vasoactive drugs. Cumulative sedative drugs were assessed daily. A total of 532 patients were included in this study: 253 (47.6%) in the low-target group and 279 (52.4%) in the high-target group. Daily cumulative sedative drugs were similar in both groups. Compared to the low-target group, minimal and maximal RASS were significantly higher in the high-target group at day 2, 4 and 5. Furthermore, in order to consider the fact that multiple measures were done for each patient and to consider the global effect of time on these measures, we used a mixed linear regression and multivariate models: we confirmed that maximal RASS values were significantly higher in the high-target group. CONCLUSION: In patients with septic shock who were mechanically ventilated and sedated, resuscitation with MAP target between 80 and 85 mmHg was associated with higher arousal level as compared to a MAP target between 65 and 70 mmHg.

The effects of passive leg raising may be detected by the plethysmographic oxygen saturation signal in critically ill patients.

BACKGROUND: A passive leg raising (PLR) test is positive if the cardiac index (CI) increased by > 10%, but it requires a direct measurement of CI. On the oxygen saturation plethysmographic signal, the perfusion index (PI) is the ratio between the pulsatile and the non-pulsatile portions. We hypothesised that the changes in PI could predict a positive PLR test and thus preload responsiveness in a totally non-invasive way. METHODS: In patients with acute circulatory failure, we measured PI (Radical-7) and CI (PiCCO2) before and during a PLR test and, if decided, before and after volume expansion (500-mL saline). RESULTS: Three patients were excluded because the plethysmography signal was absent and 3 other ones because it was unstable. Eventually, 72 patients were analysed. In 34 patients with a positive PLR test (increase in CI ≥ 10%), CI and PI increased during PLR by 21 ± 10% and 54 ± 53%, respectively. In the 38 patients with a negative PLR test, PI did not significantly change during PLR. In 26 patients in whom volume expansion was performed, CI and PI increased by 28 ± 14% and 53 ± 63%, respectively. The correlation between the PI and CI changes for all interventions was significant (r = 0.64, p < 0.001). During the PLR test, if PI increased by > 9%, a positive response of CI (≥ 10%) was diagnosed with a sensitivity of 91 (76-98%) and a specificity of 79 (63-90%) (area under the receiver operating characteristics curve 0.89 (0.80-0.95), p < 0.0001). CONCLUSION: An increase in PI during PLR by 9% accurately detects a positive response of the PLR test. TRIAL REGISTRATION: ID RCB 2016-A00959-42. Registered 27 June 2016.

Enteral versus parenteral early nutrition in ventilated adults with shock: a randomised, controlled, multicentre, open-label, parallel-group study (NUTRIREA-2).

BACKGROUND: Whether the route of early feeding affects outcomes of patients with severe critical illnesses is controversial. We hypothesised that outcomes were better with early first-line enteral nutrition than with early first-line parenteral nutrition. METHODS: In this randomised, controlled, multicentre, open-label, parallel-group study (NUTRIREA-2 trial) done at 44 French intensive-care units (ICUs), adults (18 years or older) receiving invasive mechanical ventilation and vasopressor support for shock were randomly assigned (1:1) to either parenteral nutrition or enteral nutrition, both targeting normocaloric goals (20-25 kcal/kg per day), within 24 h after intubation. Randomisation was stratified by centre using permutation blocks of variable sizes. Given that route of nutrition cannot be masked, blinding of the physicians and nurses was not feasible. Patients receiving parenteral nutrition could be switched to enteral nutrition after at least 72 h in the event of shock resolution (no vasopressor support for 24 consecutive hours and arterial lactate <2 mmol/L). The primary endpoint was mortality on day 28 after randomisation in the intention-to-treat-population. This study is registered with ClinicalTrials.gov, number NCT01802099. FINDINGS: After the second interim analysis, the independent Data Safety and Monitoring Board deemed that completing patient enrolment was unlikely to significantly change the results of the trial and recommended stopping patient recruitment. Between March 22, 2013, and June 30, 2015, 2410 patients were enrolled and randomly assigned; 1202 to the enteral group and 1208 to the parenteral group. By day 28, 443 (37%) of 1202 patients in the enteral group and 422 (35%) of 1208 patients in the parenteral group had died (absolute difference estimate 2·0%; [95% CI -1·9 to 5·8]; p=0·33). Cumulative incidence of patients with ICU-acquired infections did not differ between the enteral group (173 [14%]) and the parenteral group (194 [16%]; hazard ratio [HR] 0·89 [95% CI 0·72-1·09]; p=0·25). Compared with the parenteral group, the enteral group had higher cumulative incidences of patients with vomiting (406 [34%] vs 246 [20%]; HR 1·89 [1·62-2·20]; p<0·0001), diarrhoea (432 [36%] vs 393 [33%]; 1·20 [1·05-1·37]; p=0·009), bowel ischaemia (19 [2%] vs five [<1%]; 3·84 [1·43-10·3]; p=0·007), and acute colonic pseudo-obstruction (11 [1%] vs three [<1%]; 3·7 [1·03-13·2; p=0·04). INTERPRETATION: In critically ill adults with shock, early isocaloric enteral nutrition did not reduce mortality or the risk of secondary infections but was associated with a greater risk of digestive complications compared with early isocaloric parenteral nutrition. FUNDING: La Roche-sur-Yon Departmental Hospital and French Ministry of Health.

Haemodynamic response to crystalloids or colloids in shock: an exploratory subgroup analysis of a randomised controlled trial.

OBJECTIVE: To compare the haemodynamic effect of crystalloids and colloids during acute severe hypovolaemic shock. DESIGN: Exploratory subgroup analysis of a multicentre randomised controlled trial (Colloids Versus Crystalloids for the Resuscitation of the Critically Ill, CRISTAL, ClinicalTrials.gov NCT00318942). SETTING: CRISTAL was conducted in intensive care units in Europe, North Africa and Canada. PARTICIPANTS: Current analysis included all patients who had a pulmonary artery catheter in place at randomisation. 220 patients (117 received crystalloids vs 103 colloids) underwent pulmonary artery catheterisation. INTERVENTION: Crystalloids versus colloids for fluid resuscitation in hypovolaemic shock. OUTCOME MEASURES: Haemodynamic data were collected at the time of randomisation and subsequently on days 1, 2, 3, 4, 5, 6 and 7. RESULTS: Median cumulative volume of fluid administered during the first 7 days was higher in the crystalloids group than in the colloids group (3500 (2000-6000) vs 2500 (1000-4000) mL, p=0.01). Patients in the colloids arm exhibited a lower heart rate over time compared with those allocated to the crystalloids arm (p=0.014). There was no significant difference in Cardiac Index (p=0.053), mean blood pressure (p=0.4), arterial lactates (p=0.9) or global Sequential Organ Failure Assessment score (p=0.3) over time between arms. CONCLUSIONS: During acute severe hypovolaemic shock, patients monitored by a pulmonary artery catheter achieved broadly similar haemodynamic outcomes, using lower volumes of colloids than crystalloids. The heart rate was lower in the colloids arm.

Hyperoxia and hypertonic saline in patients with septic shock (HYPERS2S): a two-by-two factorial, multicentre, randomised, clinical trial.

BACKGROUND: There is insufficient research into the use of mechanical ventilation with increased inspiratory oxygen concentration (FiO2) and fluid resuscitation with hypertonic saline solution in patients with septic shock. We tested whether these interventions are associated with reduced mortality. METHODS: This two-by-two factorial, multicentre, randomised, clinical trial (HYPERS2S) recruited patients aged 18 years and older with septic shock who were on mechanical ventilation from 22 centres in France. Patients were randomly assigned 1:1:1:1 to four groups by a computer generated randomisation list stratified by site and presence or absence of acute respiratory distress syndrome by use of permuted blocks of random sizes. Patients received, in an open-labelled manner, mechanical ventilation either with FiO2 at 1·0 (hyperoxia) or FiO2 set to target an arterial haemoglobin oxygen saturation of 88-95% (normoxia) during the first 24 h; patients also received, in a double-blind manner, either 280 mL boluses of 3·0% (hypertonic) saline or 0·9% (isotonic) saline for fluid resuscitation during the first 72 h. The primary endpoint was mortality at day 28 after randomisation in the intention-to-treat population. This study was registered with ClinicalTrials.gov, number NCT01722422. FINDINGS: Between Nov 3, 2012, and June 13, 2014, 442 patients were recruited and assigned to a treatment group (normoxia [n=223] or hyperoxia [n=219]; isotonic [n=224] or hypertonic [n=218]). The trial was stopped prematurely for safety reasons. 28 day mortality was recorded for 434 patients; 93 (43%) of 217 patients had died in the hyperoxia group versus 77 (35%) of 217 patients in the normoxia group (hazard ratio [HR] 1·27, 95% CI 0·94-1·72; p=0·12). 89 (42%) of 214 patients had died in the hypertonic group versus 81 (37%) of 220 patients in the isotonic group (HR 1·19, 0·88-1·61; p=0·25). We found a significant difference in the overall incidence of serious adverse events between the hyperoxia (185 [85%]) and normoxia groups (165 [76%]; p=0·02), with a clinically relevant doubling in the hyperoxia group of the number of patients with intensive care unit-acquired weakness (24 [11%] vs 13 [6%]; p=0·06) and atelectasis (26 [12%] vs 13 [6%]; p=0·04) compared with the normoxia group. We found no statistical difference for serious adverse events between the two saline groups (p=0·23). INTERPRETATION: In patients with septic shock, setting FiO2 to 1·0 to induce arterial hyperoxia might increase the risk of mortality. Hypertonic (3%) saline did not improve survival. FUNDING: The French Ministry of Health.

Cardiac dysfunction induced by weaning from mechanical ventilation: incidence, risk factors, and effects of fluid removal.

BACKGROUND: Weaning-induced pulmonary oedema (WiPO) is a well-recognised cause of failure of weaning from mechanical ventilation, but its incidence and risk factors have not been reliably described. We wanted to determine the incidence and risk factors in a population of critically ill patients. In addition, we wanted to describe the effects of diuretics when they are administered in this context. METHODS: We monitored 283 consecutive spontaneous breathing trials (SBT; T-piece trial) performed in 81 patients. In cases with cardiac output monitoring (n = 85, 29 patients), a passive leg raising (PLR) test was performed before SBT. Three experts established the diagnosis of WiPO based on various patient characteristics. RESULTS: SBT failed in 128 cases (45 % of all SBT). WiPO occurred in 59 % of these failing cases. Compared to patients without WiPO (n = 52), patients with at least one WiPO (n = 29) had a higher prevalence of chronic obstructive pulmonary disease (COPD) (38 % vs. 12 %, respectively; p < 0.01), previous "structural" cardiopathy (dilated and/or hypertrophic and/or hypokinetic cardiopathy and/or significant valvular disease, 9 % vs. 25 %, respectively; p < 0.01), obesity (45 % vs. 17 %, respectively; p < 0.01), and low left ventricular ejection fraction (55 % vs. 21 %, respectively; p = 0.01). At logistic regression, COPD (odds ratio (OR) 8.7, 95 % confidence interval (CI) 2.0-37.3), previous structural cardiopathy (OR 4.5, 95 % CI 1.4-14.1), and obesity (OR 3.6, 95 % CI 1.2-12.6) were independent risk factors for experiencing at least one episode of WiPO. In 16 cases with WiPO and a negative PLR at baseline, treatment including diuretics was started. In 9 of these cases, the PLR remained negative before the following SBT. A new episode of WiPO occurred in 7 of these instances, while the two other were extubated. In 7 other cases, the PLR became positive before the following SBT. WiPO did not occur anymore in 6 of these 7 patients who were extubated, while the remaining one was not. CONCLUSIONS: In our population of critically ill patients, WiPO was responsible for 59 % of weaning failures. COPD, previous "structural" cardiopathy, and, to a lesser extent, obesity were the main risk factors. When a treatment including fluid removal had changed preload-independence to preload-dependence, the following SBT was very likely to succeed.

The passive leg raising test to guide fluid removal in critically ill patients.

BACKGROUND: To investigate whether haemodynamic intolerance to fluid removal during intermittent renal replacement therapy (RRT) in critically ill patients can be predicted by a passive leg raising (PLR) test performed before RRT. METHODS: We included 39 patients where intermittent RRT with weight loss was decided. Intradialytic hypotension was defined as hypotension requiring a therapeutic intervention, as decided by the physicians in charge. Before RRT, the maximal increase in cardiac index (CI, pulse contour analysis) induced by a PLR test was recorded. RRT was then started. RESULTS: Ultrafiltration rate was similar in patients with and without intradialytic hypotension. Thirteen patients presented intradialytic hypotension, while 26 did not. In patients with intradialytic hypotension, it occurred 120 min [interquartile range 60-180 min] after onset of RRT. In the 26 patients without intradialytic hypotension, the PLR test induced no significant change in CI. Conversely, in patients with intradialytic hypotension, PLR significantly increased CI by 15 % [interquartile range 11-36 %]. The PLR-induced increase in CI predicted intradialytic hypotension with an area under the ROC curve of 0.89 (95 % interval confidence 0.75-0.97) (p < 0.05 from 0.50). The best diagnostic threshold was 9 %. The sensitivity was 77 % (95 % confidence interval 46-95 %), the specificity was 96 % (80-100 %), the positive predictive value was 91 % (57-100 %), and the negative predictive value was 89 % (72-98 %). Compared to patients without intolerance to RRT, CI decreased significantly faster in patients with intradialytic hypotension, with a slope difference of -0.17 L/min/m(2)/h. CONCLUSION: The presence of preload dependence, as assessed by a positive PLR test before starting RRT with fluid removal, predicts that RRT will induce haemodynamic intolerance.

Outcomes of patients admitted to intensive care units for acute manifestation of small-vessel vasculitis: a multicenter, retrospective study.

BACKGROUND: The outcomes of patients admitted to the intensive care unit (ICU) for acute manifestation of small-vessel vasculitis are poorly reported. The aim of the present study was to determine the mortality rate and prognostic factors of patients admitted to the ICU for acute small-vessel vasculitis. METHODS: This retrospective, multicenter study was conducted from January 2001 to December 2014 in 20 ICUs in France. Patients were identified from computerized registers of each hospital using the International Classification of Diseases, Ninth Revision (ICD-9). Inclusion criteria were (1) known or highly suspected granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, microscopic polyangiitis (respectively, ICD-9 codes M31.3, M30.1, and M31.7), or anti-glomerular basement membrane antibody disease (ICD-9 codes N08.5X-005 or M31.0+); (2) admission to the ICU for the management of an acute manifestation of vasculitis; and (3) administration of a cyclophosphamide pulse in the ICU or within 48 h before admission to the ICU. The primary endpoint was assessment of mortality rate 90 days after admission to the ICU. RESULTS: Eighty-two patients at 20 centers were included, 94% of whom had a recent (<6 months) diagnosis of small-vessel vasculitis. Forty-four patients (54%) had granulomatosis with polyangiitis. The main reasons for admission were respiratory failure (34%) and pulmonary-renal syndrome (33%). Mechanical ventilation was required in 51% of patients, catecholamines in 31%, and renal replacement therapy in 71%. Overall mortality at 90 days was 18% and the mortality in ICU was 16 %. The main causes of death in the ICU were disease flare in 69% and infection in 31%. In univariable analysis, relevant factors associated with death in nonsurvivors compared with survivors were Simplified Acute Physiology Score II (median [interquartile range] 51 [38-82] vs. 36 [27-42], p = 0.005), age (67 years [62-74] vs. 58 years [40-68], p < 0.003), Sequential Organ Failure Assessment score on the day of cyclophosphamide administration (11 [6-12] vs. 6 [3-7], p = 0.0004), and delayed administration of cyclophosphamide (5 days [3-14] vs. 2 days [1-5], p = 0.0053). CONCLUSIONS: Patients admitted to the ICU for management of acute small-vessel vasculitis benefit from early, aggressive intensive care treatment, associated with an 18% death rate at 90 days.