Prophylactic platelet transfusion response in critically ill patients: a prospective multicentre observational study.

BACKGROUND: Response to prophylactic platelet transfusion is suspected to be inconsistent in critically ill patients questioning how to optimize transfusion practices. This study aimed to describe prophylactic platelet transfusion response, to identify factors associated with a suboptimal response, to analyse the correlation between corrected count increment and platelet count increment and to determine the association between poor platelet transfusion response and clinical outcomes. METHODS: This prospective multicentre observational study recruited patients who received at least one prophylactic platelet transfusion in one of the nine participating intensive care units for a period up to 16 months. Poor platelet transfusion response was defined as a corrected count increment (CCI) that adjusts for platelet dose and body surface area, less than 7 at 18-24 h after platelet transfusion. Factors associated with poor platelet transfusion response were assessed in a mixed-effect model. Sensitivity analyses were conducted in patients with and without haematology malignancy and chemotherapy. RESULTS: Poor platelet transfusion response occurred in 349 of the 472 (73.9%) prophylactic platelet transfusions and in 141/181 (77.9%) patients. The mixed-effect model identified haemoglobin at ICU admission (odds ratio (OR): 0.79 [95% confidence interval (CI) 0.7-0.89]) and body mass index (BMI) (OR: 0.93 [0.89-0.98]) being positively and independently associated with platelet transfusion response, while a haematological malignancy (OR 1.93 [1.09-3.43]), sepsis as primary ICU admission diagnosis (OR: 2.81 [1.57-5.03]), SOFA score (OR 1.10 [1.03; 1.17]) and maximum storage duration of platelet (OR: 1.24 [1.02-1.52]) were independently associated with a suboptimal platelet increment. Clinical outcomes did not differ between groups, nor the requirement for red blood cells. Poor platelet transfusion response was found in 93.5% of patients with haematology malignancy and chemotherapy. CONCLUSIONS: In this study of critically ill patients, of whom more than half had bone marrow failure, almost three quarters of prophylactic platelet transfusions led to suboptimal platelet increment measured 18 to 24 h following platelet transfusion. Platelet storage duration was the only factor associated with poor platelet response that may be accessible to intervention. Trial registration in October 2017: ClinicalTrials.gov: NCT03325140.

Anticoagulation strategy and safety in critically ill COVID-19 patients: a French retrospective multicentre study.

BACKGROUND: Patients with critical illness due to COVID-19 exhibit increased coagulability associated with a high risk of venous thrombo-embolism (VTE). Data on prophylactic anticoagulation for these patients are limited and conflicting. The purpose of this study was to evaluate whether intermediate-dose prophylactic anticoagulation in patients with COVID-19 requiring ICU admission was associated with better outcomes compared to standard-dose prophylactic anticoagulation. METHODS: We retrospectively included adults admitted with severe COVID-19 to any of 15 ICUs, in 2020 or 2021. We compared the groups given intermediate-dose vs. standard-dose prophylactic anticoagulation. The primary outcome was all-cause day-90 mortality. Secondary outcomes were VTE (pulmonary embolism or deep vein thrombosis), ICU stay length, and adverse effects of anticoagulation. RESULTS: Of 1174 included patients (mean age, 63 years), 399 received standard-dose and 775 intermediate-dose prophylactic anticoagulation. Of the 211 patients who died within 90 days, 86 (21%) received intermediate and 125 (16%) standard doses. After adjustment on early corticosteroid therapy and critical illness severity, there were no significant between-group differences in day-90 mortality (hazard ratio [HR], 0.73; 95%CI, 0.52-1.04; p = 0.09) or ICU stay length (HR, 0.93; 95%CI, 0.79-1.10; p = 0.38). Intermediate-dose anticoagulation was significantly associated with fewer VTE events (HR, 0.55; 95%CI, 0.38-0.80; p < 0.001). Bleeding events occurred in similar proportions of patients in the two groups (odds ratio, 0.86; 95%CI, 0.50-1.47; p = 0.57). CONCLUSIONS: Mortality on day 90 did not differ between the groups given standard-dose and intermediate-dose prophylactic anticoagulation, despite a higher incidence of VTE in the standard-dose group.

Continued enteral nutrition until extubation compared with fasting before extubation in patients in the intensive care unit: an open-label, cluster-randomised, parallel-group, non-inferiority trial.

BACKGROUND: Fasting is frequently imposed before extubation in patients in intensive care units, with the aim to reduce risk of aspiration. This unevaluated practice might delay extubation, increase workload, and reduce caloric intake. We aimed to compare continued enteral nutrition until extubation with fasting before extubation in patients in the intensive care unit. METHODS: We conducted an open-label, cluster-randomised, parallel-group, non-inferiority trial in 22 intensive care units in France. Patients aged 18 years or older were eligible for enrolment if they had received invasive mechanical ventilation for at least 48 h in the intensive care unit and received prepyloric enteral nutrition for at least 24 h at the time of extubation decision. Centres were randomly assigned (1:1) to continued enteral nutrition until extubation or 6-h fasting with concomitant gastric suctioning before extubation, to be applied for all patients within the unit. Masking was not possible because of the nature of the trial. The primary outcome was extubation failure (composite criteria of reintubation or death) within 7 days after extubation, assessed in both the intention-to-treat and per-protocol populations. The non-inferiority margin was set at 10%. Pneumonia within 14 days of extubation was a key secondary endpoint. This trial is now complete and is registered with ClinicalTrials.gov, NCT03335345. FINDINGS: Between April 1, 2018, and Oct 31, 2019, 7056 patients receiving enteral nutrition and mechanical ventilation were admitted to the intensive care units and 4198 were assessed for eligibility. 1130 patients were enrolled and included in the intention-to-treat population and 1008 were included in the per-protocol population. In the intention-to-treat population, extubation failure occurred in 106 (17·2%) of 617 patients assigned to receive continued enteral nutrition until extubation versus 90 (17·5%) of 513 assigned to fasting, meeting the a priori defined non-inferiority criterion (absolute difference -0·4%, 95% CI -5·2 to 4·5). In the per-protocol population, extubation failure occurred in 101 (17·0%) of 595 patients assigned to receive continued enteral nutrition versus 74 (17·9%) of 413 assigned to fasting (absolute difference -0·9%, 95% CI -5·6 to 3·7). Pneumonia within 14 days of extubation occurred in ten (1·6%) patients assigned to receive continued enteral nutrition and 13 (2·5%) assigned to fasting (rate ratio 0·77, 95% CI 0·22 to 2·69). INTERPRETATION: Continued enteral nutrition until extubation in critically ill patients in the intensive care unit was non-inferior to a 6-h fasting maximum gastric vacuity strategy comprising continuous gastric tube suctioning, in terms of extubation failure within 7 days (a patient-centred outcome), and thus represents a potential alternative in this population. FUNDING: French Ministry of Health. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Association of early dexamethasone therapy with mortality in critically Ill COVID-19 patients: a French multicenter study.

BACKGROUND: Dexamethasone is recommended for COVID-19 patients who require oxygen therapy. However, its effectiveness in reducing mortality and intubation, and its safety, remain debated. We aimed to investigate whether dexamethasone reduces day-28 mortality in unselected patients with critical COVID-19. METHODS: We performed an observational cohort study in consecutive COVID-19 patients admitted to any of 13 French intensive care units (ICUs) in 2020. The primary objective was to determine whether early dexamethasone therapy was associated with day-28 mortality and the secondary objectives were to assess whether early dexamethasone decreased intubation requirements and to collect adverse events. RESULTS: Of 1058 included patients, 611 (57.75%) received early dexamethasone (early dexamethasone group), 358 (33.83%) did not receive any steroids (no steroids group), and 89 (8.41%) received late dexamethasone or other steroids. Day-28 mortality was similar between the early dexamethasone and the no steroids groups (15.06% and 14.25%, respectively; P = 0.59). Factors associated with day-28 mortality were older age (adjusted hazard ratio [aHR], 1.06; 1.04-1.09; P < 0.001), worse SOFA score (aHR, 1.13; 1.06-1.20; P < 0.001), and immunocompromised status (aHR, 1.59; 1.01-2.50; P = 0.043). Early dexamethasone was associated with fewer intubations (48.55% vs. 61.49%, P < 0.001) and more ventilator-free days by day 28 (22 [2-28] vs. 17 [1-28] days, P = 0.003), compared to no steroids. Ventilator-associated pneumonia (VAP) was more common with early dexamethasone (HR, 1.29 [1.01-1.63], P = 0.04) than with no steroids, whereas no differences were noted for bloodstream infection, fungal infection, or gastrointestinal bleeding. CONCLUSIONS: Early dexamethasone in critically ill COVID-19 patients was not associated with lower day-28 mortality. However, early dexamethasone was associated with lower intubation needs and more ventilator-free days by day 28. In patients treated with invasive mechanical ventilation, early dexamethasone was associated with a higher risk of VAP.

Multiple-site decontamination regimen decreases acquired infection incidence in mechanically ventilated COVID-19 patients.

BACKGROUND: Among strategies that aimed to prevent acquired infections (AIs), selective decontamination regimens have been poorly studied in the COVID-19 setting. We assessed the impact of a multiple-site decontamination (MSD) regimen on the incidence of bloodstream infections (BSI) and ventilator-associated pneumonia (VAP) in COVID-19 patients receiving mechanical ventilation. METHODS: We performed an ancillary analysis of a multicenter retrospective observational study in 15 ICUs in western France. In addition to standard-care (SC), 3 ICUs used MSD, a variant of selective digestive decontamination, which consists of the administration of topical antibiotics four times daily in the oropharynx and the gastric tube, chlorhexidine body wash and a 5-day nasal mupirocin course. AIs were compared between the 3 ICUs using MSD (MSD group) and the 12 ICUs using SC. RESULTS: During study period, 614 of 1158 COVID-19 patients admitted in our ICU were intubated for at least 48 h. Due to missing data in 153 patients, 461 patients were finally included of whom 89 received MSD. There were 34 AIs in the MSD group (2117 patient-days), as compared with 274 AIs in the SC group (8957 patient-days) (p < 0.001). MSD was independently associated with a lower risk of AI (IRR = 0.56 [0.38-0.83]; p = 0.004) (Table 2). When the same model was used for each site of infection, MSD remained independently associated with a lower risk of VAP (IRR = 0.52 [0.33-0.89]; p = 0.005) but not of BSI (IRR = 0.58, [0.25-1.34], p = 0.21). Hospital mortality was lower in the MSD group (16.9% vs 30.1%, p = 0.017). CONCLUSIONS: In ventilated COVID-19 patients, MSD was independently associated with lower AI incidence.

Early steroids and ventilator-associated pneumonia in COVID-19-related ARDS.

RATIONALE: Early corticosteroid treatment is used to treat COVID-19-related acute respiratory distress syndrome (ARDS). Infection is a well-documented adverse effect of corticosteroid therapy. OBJECTIVES: To determine whether early corticosteroid therapy to treat COVID-19 ARDS was associated with ventilator-associated pneumonia (VAP). METHODS: We retrospectively included adults with COVID-19-ARDS requiring invasive mechanical ventilation (MV) for ≥ 48 h at any of 15 intensive care units in 2020. We divided the patients into two groups based on whether they did or did not receive corticosteroids within 24 h. The primary outcome was VAP incidence, with death and extubation as competing events. Secondary outcomes were day 90-mortality, MV duration, other organ dysfunctions, and VAP characteristics. MEASUREMENTS AND MAIN RESULTS: Of 670 patients (mean age, 65 years), 369 did and 301 did not receive early corticosteroids. The cumulative VAP incidence was higher with early corticosteroids (adjusted hazard ratio [aHR] 1.29; 95% confidence interval [95% CI] 1.05-1.58; P = 0.016). Antibiotic resistance of VAP bacteria was not different between the two groups (odds ratio 0.94, 95% CI 0.58-1.53; P = 0.81). 90-day mortality was 30.9% with and 24.3% without early corticosteroids, a nonsignificant difference after adjustment on age, SOFA score, and VAP occurrence (aHR 1.15; 95% CI 0.83-1.60; P = 0.411). VAP was associated with higher 90-day mortality (aHR 1.86; 95% CI 1.33-2.61; P = 0.0003). CONCLUSIONS: Early corticosteroid treatment was associated with VAP in patients with COVID-19-ARDS. Although VAP was associated with higher 90-day mortality, early corticosteroid treatment was not. Longitudinal randomized controlled trials of early corticosteroids in COVID-19-ARDS requiring MV are warranted.

Impact of targeted hypothermia in expanded-criteria organ donors on recipient kidney-graft function: study protocol for a multicentre randomised controlled trial (HYPOREME).

INTRODUCTION: Expanded-criteria donors (ECDs) are used to reduce the shortage of kidneys for transplantation. However, kidneys from ECDs are associated with an increased risk of delayed graft function (DGF), a risk factor for allograft loss and mortality. HYPOREME will be a multicentre randomised controlled trial (RCT) comparing targeted hypothermia to normothermia in ECDs, in a country where the use of machine perfusion for organ storage is the standard of care. We hypothesise that hypothermia will decrease the incidence of DGF. METHODS AND ANALYSIS: HYPOREME is a multicentre RCT comparing the effect on kidney function in recipients of targeted hypothermia (34°C-35°C) and normothermia (36.5°C-37.5°C) in the ECDs. The temperature intervention starts from randomisation and is maintained until aortic clamping in the operating room. We aim to enrol 289 ECDs in order to analyse the kidney function of 516 recipients in the 53 participating centres. The primary outcome is the occurrence of DGF in kidney recipients, defined as a requirement for renal replacement therapy within 7 days after transplantation (not counting a single session for hyperkalemia during the first 24 hours). Secondary outcomes include the proportion of patients with individual organs transplanted in each group; the number of organs transplanted from each ECD and the vital status and kidney function of the recipients 7 days, 28 days, 3 months and 1 year after transplantation. An interim analysis is planned after the enrolment of 258 kidney recipients. ETHICS AND DISSEMINATION: The trial was approved by the ethics committee of the French Intensive Care Society (CE-SRLF-16-07) on 26 April 2016 and by the competent French authorities on 20 April 2016 (Comité de Protection des Personnes-TOURS-Région Centre-Ouest 1, registration #2016-S3). Findings will be published in peer-reviewed journals and presented during national and international scientific meetings. TRIAL REGISTRATION NUMBER: NCT03098706.

Inased (inhaled sedation in ICU) trial protocol: a multicentre randomised open-label trial.

INTRODUCTION: The use of sedation in intensive care units (ICUs) is necessary and ubiquitous. The impact of sedation strategy on outcome, particularly when delivered early after initiation of mechanical ventilation, is unknown. Evidence is increasing that volatile anaesthetic agents could be associated with better outcome. Their use in delirium prevention is unknown. METHODS AND ANALYSIS: This study is an investigator-initiated, prospective, multicentre, two-arm, randomised, control, open-trial comparing inhaled sedation strategy versus intravenous sedation strategy in mechanically ventilated patients in ICU. Two hundred and fifty patients will be randomly assigned to the intravenous sedation group or inhaled sedation group, with a 1:1 ratio in two groups according to the sedation strategy. The primary outcome is the occurrence of delirium assessed using two times a day confusion assessment method for the ICU (CAM-ICU). Secondary outcomes include cognitive and functional outcomes at 3 and 12 months. ETHICS AND DISSEMINATION: The study has been approved by the Regional Ethics Committee (CPP Ouest) and national authorities (ANSM). The results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04341350.

Does Chloride Intake at the Early Phase of Septic Shock Resuscitation Impact on Renal Outcome?

INTRODUCTION: Fluid administration is one of the first lines of treatment for hemodynamic management of sepsis and septic shock. Studies investigating the effects of chloride-rich fluids including normal saline on renal function report controversial findings. METHODS: This is a prospective, observational, multicenter study. Patients with septic shock, defined according to Sepsis-2 definition, were eligible. A "high-dose" of chloride was defined as a chloride intake greater than 18 g administrated within the first 48 h of septic shock management. The purpose of this study was to investigate the impact of cumulative chloride infusion within the first 48 h of septic shock resuscitation on acute kidney injury (AKI). RESULTS: Two hundred thirty-nine patients with septic shock were included. Patients who received a "high-dose" of chloride had significantly higher Sequential Organ Failure Assessment score at the time of enrolment (P < 0.001). Cumulative chloride load was higher in patients requiring renal replacement therapy (RRT) (31.1 vs. 25.2 g/48 h; P < 0.005). Propensity score-weighted regression did not find any association between "high-dose" of chloride and AKI requiring RRT (OR: 0.97 [0.88-1.1]; P = 0.69). There was no association between "high-dose" of chloride and worsening kidney function at H48 (OR: 0.94 [0.83-1.1]; P = 0.42). There was also no association between "high-dose" of chloride and ICU length of stay (P = 0.61), 28-day mortality (P = 0.83), or hospital mortality (P = 0.89). CONCLUSION: At the early stage of resuscitation of critically ill patients with septic shock, administration of "high-dose" of chloride (> 18 g/48 h) was not associated with renal prognosis.

The Extent of Aspergillosis in Critically Ill Patients With Severe Influenza Pneumonia: A Multicenter Cohort Study.

OBJECTIVES: To determine the frequency and prognosis of invasive pulmonary aspergillosis in critically ill patients with severe influenza pneumonia. DESIGN: Retrospective multicenter cohort study. SETTING: Five French ICUs. PATIENTS: Patients with influenza admitted to ICU between 2009 and 2018. MEASUREMENTS AND MAIN RESULTS: Of the 524 patients admitted for severe influenza diagnosed with a positive airway reverse-transcriptase polymerase chain reaction test, 450 (86%) required mechanical ventilation. A lower respiratory tract sample yielded with Aspergillus (Asp+) in 28 patients (5.3%). Ten patients (1.9%) were diagnosed with putative or proven invasive pulmonary aspergillosis, based on the validated AspICU algorithm. A multivariate model was built to identify independent risk factors for Aspergillus-positive pulmonary culture. Factors independently associated with Aspergillus-positive culture were liver cirrhosis (odds ratio = 6.7 [2.1-19.4]; p < 0.01), hematologic malignancy (odds ratio = 3.3 [1.2-8.5]; p = 0.02), Influenza A(H1N1)pdm09 subtype (odds ratio = 3.9 [1.6-9.1]; p < 0.01), and vasopressor requirement (odds ratio = 4.1 [1.6-12.7]; p < 0.01). In-hospital mortality of Asp+ patients was 36% versus 21% in patients without Aspergillus-positive pulmonary culture (p = 0.09). CONCLUSIONS: In this large retrospective multicenter cohort of critically ill patients, putative invasive pulmonary aspergillosis according to AspICU algorithm was a relatively rare complication of influenza. Patients at higher risk of Aspergillus pulmonary colonization included those with liver cirrhosis, hematologic malignancy, H1N1pdm09 influenza A virus, and requiring vasopressors. Our results provide additional data on the controversial association between severe influenza and invasive pulmonary aspergillosis. Reaching a consensual definition of invasive pulmonary aspergillosis becomes mandatory and confers further prospective research.

Association between fluid overload and SOFA score kinetics in septic shock patients: a retrospective multicenter study.

BACKGROUND: Fluid infusion represents one of the cornerstones of resuscitation therapies in order to increase oxygen delivery during septic shock. Fluid overload as a consequence of excessive fluid administration seems to be linked to worse long-term outcome. However, its immediate effect on patient's clinical state is poorly described. The goal of this study was to assess the impact of FO on SOFA score kinetics as a surrogate marker of organ dysfunction from day 0 to day 5. MATERIAL AND METHODS: Retrospective, multicenter, investigator-initiated study. All adult patients (> 18 years old) admitted from January 2012 to April 2017 in one of the three ICUs for septic shock, secondary to peritonitis or pulmonary infection and mechanically ventilated, were included. Univariate analysis was performed with Student's t and chi-square test, for continuous and categorical variables, respectively. A multivariate linear regression model evaluated the impact of FO on delta SOFA score from day 0 to day 5. Secondly, a multivariate mixed-model accounting for repeated measures analyzed the impact of FO on SOFA score kinetics. RESULTS: One hundred twenty-nine patients met the inclusion criteria and were assigned into FO and no FO groups. FO occurred in 39% of the patients. The difference between SOFA score at day 0 and day 5 was more than twofold higher in the no FO group than in the FO group with a difference of 2.37 between the two groups (4.52 vs. 2.15; p = 0.001). Cumulative fluid intake at day 5 was higher in the FO group (2738 vs. 8715 ml, p < 0.001). In multivariate analysis, FO was associated with delta SOFA score: aRR = 0.15 (95% CI 0.03-0.63; p = 0.009). In mixed model, the regression coefficient for fluid overload status (r 2 = 1.16; p = 0.014) indicated that the slope for SOFA score kinetic was less pronounced for patients with FO than for patients without FO. CONCLUSIONS: FO patients had a more prolonged multi-organ failure according to SOFA score kinetics during septic shock from resuscitation phase to day 5.

High-flow nasal cannula oxygen during endotracheal intubation in hypoxemic patients: a randomized controlled clinical trial.

PURPOSE: Intubation of hypoxemic patients is associated with life-threatening adverse events. High-flow therapy by nasal cannula (HFNC) for preoxygenation before intubation has never been assessed by randomized study. Our objective was to evaluate the efficiency of HFNC for preoxygenation, compared to high fraction-inspired oxygen facial mask (HFFM). METHODS: Multicenter, randomized, open-labelled, controlled PREOXYFLOW trial (NCT 01747109) in six French intensive care units. Acute hypoxemic adults requiring intubation were randomly allocated to HFNC or HFFM. Patients were eligible if PaO2/FiO2 ratio was below 300 mmHg, respiratory rate at least 30/min and if they required FiO2 50% or more to obtain at least 90% oxygen saturation. HFNC was maintained throughout the procedure, whereas HFFM was removed at the end of general anaesthesia induction. Primary outcome was the lowest saturation throughout intubation procedure. Secondary outcomes included adverse events related to intubation, duration of mechanical ventilation and death. RESULTS: A total of 124 patients were randomized. In the intent-to-treat analysis, including 119 patients (HFNC n = 62; HFFM n = 57), the median (interquartile range) lowest saturation was 91.5% (80-96) for HFNC and 89.5% (81-95) for the HFFM group (p = 0.44). There was no difference for difficult intubation (p = 0.18), intubation difficulty scale, ventilation-free days (p = 0.09), intubation-related adverse events including desaturation <80% or mortality (p = 0.46). CONCLUSIONS: Compared to HFFM, HFNC as a preoxygenation device did not reduce the lowest level of desaturation.

Oxygen blood transport during experimental sepsis: effect of hypothermia*.

OBJECTIVES: The aim of this study was to highlight the link between induced hypothermia and increased survival duration as observed in the septic model developed by the laboratory. To reach this objective, survival duration and blood oxygen transport capacity were measured at two temperatures-38 °C (induced normothermia) and 34 °C (induced hypothermia)-in septic rats. DESIGN: A prospective, randomized, experimental animal study. SETTING: University laboratory. SUBJECTS: Forty-four male Sprague-Dawley rats (median weight, 232 g; range, 200-303 g). INTERVENTIONS: After anesthesia and obtention of the temperature goal, sepsis was induced by cecal ligation and perforation. MEASUREMENTS AND MAIN RESULTS: Sepsis induction led to death 5 hrs 11 mins ± 0 hr 36 mins after cecal ligation and perforation at 38 °C. At this temperature, significant changes in blood oxygen transport capacity were observed in septic rats; Hill number decreased from 2.36 ± 0.10 (baseline group) to 1.99 ± 0.17 (septic group) (p = .008) and oxygen-hemoglobin affinity decreased and P50 increased from 41.40 ± 2.4 Torr (baseline group) to 51.17 ± 14.07 Torr (septic group). Furthermore, in normothermia, a significant increase of creatinine and albumin plasmatic concentrations was observed 4 hrs after sepsis induction. Survival duration was significantly higher in induced hypothermia (7 hrs 22 mins ± 0 hr 12 mins at 34 °C) compared with induced normothermia. At 34 °C, no significant change in blood oxygen transport capacity was observed. In the same way, exposure to 34 °C induced no change in measured plasmatic parameters except an increase in albumin concentration in septic rats compared with the baseline group. CONCLUSIONS: Sepsis led to a decrease of both oxygen hemoglobin cooperativity and affinity at 38 °C. By contrast, no change in these parameters was observed when sepsis was induced during hypothermia. Taken together, these results could be interpreted in normothermia septic rats as an adaptive mechanism that could enhance the release of oxygen at the tissue level. Hypothermia by slowing down sepsis evolution could increase survival duration.