Bicentric evaluation of stabilizing sampling tubes for assessment of monocyte HLA-DR expression in clinical samples.

BACKGROUND: Diminished expression of human leukocyte antigen DR on circulating monocytes (mHLA-DR), measured by standardized flow cytometry procedure, is a reliable indicator of immunosuppression in severely injured intensive care unit patients. As such, it is used as stratification criteria in clinical trials evaluating novel immunostimulating therapies. Preanalytical constraints relative to the short delay between blood sampling and flow cytometry staining have nevertheless limited its use in multicentric studies. The objective of the present work was to compare mHLA-DR expression between whole blood samples simultaneously drawn in EDTA or Cyto-Chex BCT tubes. METHODS: In two university hospitals, mHLA-DR was assessed in fresh whole blood from septic patients (n = 12) and healthy donors (n = 6) simultaneously sampled on EDTA and Cyto-Chex BCT tubes. Staining was performed immediately after sampling and after blood storage at room temperature. RESULTS: We confirmed that samples collected in Cyto-Chex tube had substantially enhanced stability for mHLA-DR results (48-72 h) over those collected in EDTA. On baseline values, despite good correlation between tubes (r = 0.98, p < 0.001), mHLA-DR expression was systematically lower with Cyto-Chex BCT. CONCLUSION: The present reports confirms the potential of Cyto-Chex BCT tubes to stabilize mHLA-DR expression before staining and extends the work of Quadrini et al. [Cytometry B 2021;100:103-114]. In centers without rapid access to flow cytometry facilities, it enables to tolerate delays in mHLA-DR staining. However, a 30% gap exists between results obtained with EDTA and Cyto-Chex BCT tubes. As current thresholds for clinical decisions were obtained with EDTA samples, further studies are needed to confirm clinical thresholds with Cyto-Chex BCT tubes.

Association between voriconazole exposure and Sequential Organ Failure Assessment (SOFA) score in critically ill patients.

Therapeutic drug monitoring (TDM) is essential for voriconazole to ensure optimal drug exposure, mainly in critically ill patients for whom voriconazole demonstrated a large variability. The study aimed at describing factors associated with trough voriconazole concentrations in critically ill patients and evaluating the impact of voriconazole concentrations on adverse effects. A 2-year retrospective multicenter cohort study (NCT04502771) was conducted in six intensive care units. Adult patients who had at least one voriconazole TDM were included. Univariable and multivariable linear regression analyses were performed to identify predictors of voriconazole concentrations, and univariable logistic regression analysis, to study the relationship between voriconazole concentrations and adverse effects. During the 2-year study period, 70 patients were included. Optimal trough voriconazole concentrations were reported in 37 patients (52.8%), subtherapeutic in 20 (28.6%), and supratherapeutic in 13 (18.6%). Adverse effects were reported in six (8.6%) patients. SOFA score was identified as a factor associated with an increase in voriconazole concentration (p = 0.025), mainly in the group of patients who had SOFA score ≥ 10. Moreover, an increase in voriconazole concentration was shown to be a risk factor for occurrence of adverse effects (p = 0.011). In that respect, critically ill patients who received voriconazole treatment must benefit from a TDM, particularly if they have a SOFA score ≥ 10. Indeed, identifying patients who are overdosed will help to prevent voriconazole related adverse effects. This result is of utmost importance given the recognized COVID-19-associated pulmonary aspergillosis in ICU patients for whom voriconazole is among the recommended first-line treatment.

Assessment of Magnetic Resonance Imaging Changes and Functional Outcomes Among Adults With Severe Herpes Simplex Encephalitis.

Importance: Current guidelines recommend brain magnetic resonance imaging (MRI) for clinical management of patients with severe herpes simplex encephalitis (HSE). However, the prognostic value of brain imaging has not been demonstrated in this setting. Objective: To investigate the association between early brain MRI data and functional outcomes of patients with HSE at 90 days after intensive care unit (ICU) admission. Design, Setting, and Participants: This multicenter cohort study was conducted in 34 ICUs in France from 2007 to 2019 and recruited all patients who received a clinical diagnosis of encephalitis and exhibited cerebrospinal fluid positivity for herpes simplex virus DNA in the polymerase chain reaction analysis. Data analysis was performed from January to April 2020. Exposures: All patients underwent a standard brain MRI during the first 30 days after ICU admission. Main Outcomes and Measures: MRI acquisitions were analyzed by radiologists blinded to patients' outcomes, using a predefined score. Multivariable logistic regression and supervised hierarchical classifiers methods were used to identify factors associated with poor outcome at 90 days, defined by a score of 3 to 6 (indicating moderate-to-severe disability or death) on the Modified Rankin Scale. Results: Overall, 138 patients (median [interquartile range {IQR}] age, 62.6 [54.0-72.0] years; 75 men [54.3%]) with an admission median (IQR) Glasgow Coma Scale score of 9 (6-12) were studied. The median (IQR) delay between ICU admission and MRI was 1 (1-7) days. At 90 days, 95 patients (68.8%) had a poor outcome, including 16 deaths (11.6%). The presence of fluid-attenuated inversion recovery MRI signal abnormalities in more than 3 brain lobes (odds ratio [OR], 25.71; 95% CI, 1.21-554.42), age older than 60 years (OR, 7.62; 95% CI, 2.02-28.91), and the presence of diffusion-weighted MRI signal abnormalities in the left thalamus (OR, 6.90; 95% CI, 1.12-43.00) were independently associated with poor outcome. Machine learning models identified bilateral diffusion abnormalities as an additional factor associated with poor outcome (34 of 39 patients [87.2%] with bilateral abnormalities had poor outcomes) and confirmed the functional burden of left thalamic lesions, particularly in older patients (all 11 patients aged >60 years had left thalamic lesions). Conclusions and Relevance: These findings suggest that in adult patients with HSE requiring ICU admission, extensive MRI changes in the brain are independently associated with poor functional outcome at 90 days. Thalamic diffusion signal changes were frequently observed and were associated with poor prognosis, mainly in older patients.

Longitudinal assessment of IFN-I activity and immune profile in critically ill COVID-19 patients with acute respiratory distress syndrome.

BACKGROUND: Since the onset of the pandemic, only few studies focused on longitudinal immune monitoring in critically ill COVID-19 patients with acute respiratory distress syndrome (ARDS) whereas their hospital stay may last for several weeks. Consequently, the question of whether immune parameters may drive or associate with delayed unfavorable outcome in these critically ill patients remains unsolved. METHODS: We present a dynamic description of immuno-inflammatory derangements in 64 critically ill COVID-19 patients including plasma IFNα2 levels and IFN-stimulated genes (ISG) score measurements. RESULTS: ARDS patients presented with persistently decreased lymphocyte count and mHLA-DR expression and increased cytokine levels. Type-I IFN response was initially induced with elevation of IFNα2 levels and ISG score followed by a rapid decrease over time. Survivors and non-survivors presented with apparent common immune responses over the first 3 weeks after ICU admission mixing gradual return to normal values of cellular markers and progressive decrease of cytokines levels including IFNα2. Only plasma TNF-α presented with a slow increase over time and higher values in non-survivors compared with survivors. This paralleled with an extremely high occurrence of secondary infections in COVID-19 patients with ARDS. CONCLUSIONS: Occurrence of ARDS in response to SARS-CoV2 infection appears to be strongly associated with the intensity of immune alterations upon ICU admission of COVID-19 patients. In these critically ill patients, immune profile presents with similarities with the delayed step of immunosuppression described in bacterial sepsis.

Bench Assessment of Expiratory Valve Resistance of Current ICU Ventilators in Dynamic Conditions.

BACKGROUND: We hypothesized that the lack of benefit of setting a low versus a high PEEP in patients with ARDS may be due in part to differences in the dynamic behavior of the expiratory valve in ventilators. We tested this hypothesis by conducting a bench comparison of the dynamic behavior of expiratory valves on ICU ventilators currently in use. METHODS: We attached 7 ICU ventilators (C5, C6, Carescape, PB980, ServoU, V500, and V680) to the ASL 5000 lung model (passive condition with compliance 20 mL/cm H2O and resistance 5 cm H2O/L/s) and set in volume controlled mode (tidal volume 0.8 L, breathing frequency 10 breaths/min). Flow and pressure were measured just before the exhalation valve. At PEEP of 5, 10, and 15 cm H2O, the median instantaneous expiratory resistance, the time to valve opening, and the pressure time products above or below the values of PEEP (expressed in cm H2O × s) were determined. RESULTS: Median instantaneous expiratory resistance values differed between the ventilators and PEEP settings with a significant interaction: at PEEP 5 cm H2O, the median (interquartile range) expiratory resistance values were 3.9 (3.5-4.7), 3.0 (3.0-3.1), 20.9 (15.8-24.9), 27.4 (26.5-43.2), 13.8 (13.6-13.9), 4.4 (4.0-4.6), and 34.3 (33.7-33.8) cm H2O/L/s, for the C5, C6, Carescape, PB980, ServoU, V500, and V680, respectively. For all the PEEP settings, the corresponding times to valve opening were 0.080 (0.077-0.082), 0.082 (0.080-0.085), 0.110 (0.105-0.110), 0.100 (0.085-1.05), 0.072 (0.062-0.072), 0.145 (0.115-0.150), and 0.075 (0.070-0.080) s, respectively, and pressure-time products were 2.8 (2.1-7.4), 6.8 (6.7-7.3), 2.4 (2.1-2.4), 3.5 (2.7-3.6), 1.8 (1.8-2.1), 2.8 (2.7-2.9), and 5.7 (5.4-5.9) cm H2O × s, respectively. CONCLUSIONS: The resistance of active expiratory valves differed significantly between the 7 ICU ventilators tested.

A Comprehensive Bench Assessment of Automatic Tube Compensation in ICU Ventilators for Better Clinical Management.

BACKGROUND: Automatic tube compensation (ATC) unloads endotracheal tube (ETT) resistance. We conducted a bench assessment of ATC functionality in ICU ventilators to improve clinical management. METHODS: This study had 2 phases. First, we performed an international survey on the use of ATC in clinical practice, hypothesizing a rate of ATC use of 25%. Second, we tested 7 modern ICU ventilators in a lung model mimicking a normal subject (Normal), a subject with ARDS, and a subject with COPD. Inspiratory effort consisted of esophageal pressure over 30 consecutive breaths obtained in a real patient under weaning. A brand new 8-mm inner diameter ETT was attached to the lung model, and ATC was set at 100% compensation for the ETT. The 30 breaths were first run with ATC off and no ETT (ie, reference period), and then with ATC on and ETT (ie, active period). The primary end point was the difference in tidal volume (VT) between reference and active periods. We hypothesized that the VT difference should be equal to 0 in an ideally functioning ATC. VT difference was compared across ventilators and respiratory mechanics conditions using a linear mixed-effects model. RESULTS: The clinical use of ATC was 64% according to 644 individuals who responded to the international survey. The VT difference varied significantly across ventilators in all respiratory mechanics configurations. The divergence between VT difference and 0 was small but significant: the extreme median (interquartile range) values were -0.013 L (-0.019 to -0.002) in the COPD model and 0.056 L (0.051-0.06) in the Normal model. VT difference for all ventilators was 0.015 L (95% CI 0.013-0.018) in the ARDS model, which was significantly different from 0.021 L (95% CI 0.018-0.024) in the Normal model (P < .001) and 0.010 L (0.007-0.012) in the COPD model (P = .003). CONCLUSIONS: ATC is used more frequently in clinical practice than expected. In addition, VT delivery by ATC differed slightly though significantly between ventilators.

The ICU-Diary study: prospective, multicenter comparative study of the impact of an ICU diary on the wellbeing of patients and families in French ICUs.

BACKGROUND: Post-intensive care syndrome includes the multiple consequences of an intensive care unit (ICU) stay for patients and families. It has become a new challenge for intensivists. Prevention programs have been disappointing, except for ICU diaries, which report the patient's story in the ICU. However, the effectiveness of ICU diaries for patients and families is still controversial, as the interpretation of the results of previous studies was open to criticism hampering an expanded use of the diary. The primary objective of the study is to evaluate the post-traumatic stress syndrome in patients. The secondary objectives are to evaluate the post-traumatic stress syndrome in families, anxiety and depression symptoms in patients and families, and the recollected memories of patients. Endpoints will be evaluated 3 months after ICU discharge or death. METHODS: A prospective, multicenter, randomized, assessor-blind comparative study of the effect of an ICU diary on patients and families. We will compare two groups: one group with an ICU diary written by staff and family and given to the patient at ICU discharge or to the family in case of death, and a control group without any ICU diary. Each of the 35 participating centers will include 20 patients having at least one family member who will likely visit the patient during their ICU stay. Patients must be ventilated within 48 h after ICU admission and not have any previous chronic neurologic or acute condition responsible for cognitive impairments that would hamper their participation in a phone interview. Three months after ICU discharge or death of the patient, a psychologist will contact the patient and family by phone. Post-traumatic stress syndrome will be evaluated using the Impact of Events Scale-Revised questionnaire, anxiety and depression symptoms using the Hospital Anxiety and Depression Scale questionnaire, both in patients and families, and memory recollection using the ICU Memory Tool Questionnaire in patients. The content of a randomized sample of diaries of each center will be analyzed using a grid. An interview of the patients in the intervention arm will be conducted 6 months after ICU discharge to analyze in depth how they use the diary. DISCUSSION: This study will provide new insights on the impact of ICU diaries on post-traumatic stress disorders in patients and families after an ICU stay. TRIAL REGISTRATION: ClinicalTrial.gov, ID: NCT02519725 . Registered on 13 July 2015.

Cost awareness of physicians in intensive care units: a multicentric national study.

PURPOSE: Physicians play an important role in strategies to control health care spending. Being aware of the cost of prescriptions is surely the first step to incorporating cost-consciousness into medical practice. The aim of this study was to evaluate current intensivists' knowledge of the costs of common prescriptions and to identify factors influencing the accuracy of cost estimations. METHODS: Junior and senior physicians in 99 French intensive care units were asked, by questionnaire, to estimate the true hospital costs of 46 selected prescriptions commonly used in critical care practice. RESULTS: With an 83% response rate, 1092 questionnaires were examined, completed by 575 (53%) and 517 (47%) junior and senior intensivists, respectively. Only 315 (29%) of the overall estimates were within 50% of the true cost. Response errors included a 14,756 ± 301 € underestimation, i.e., -58 ± 1% of the total sum (25,595 €). High-cost drugs (>1000 €) were significantly (p < 0.001) the most underestimated prescriptions (-67 ± 1%). Junior grade physicians underestimated more costs than senior physicians (p < 0.001). Using multivariate analysis, junior physicians [odds ratio (OR), 2.1; 95% confidence interval (95% CI), 1.43-3.08; p = 0.0002] and female gender (OR, 1.4; 95% CI, 1.04-1.89; p = 0.02) were both independently associated with incorrect cost estimations. CONCLUSIONS: ICU physicians have a poor awareness of prescriptions costs, especially with regards to high-cost drugs. Considerable emphasis and effort are still required to integrate the cost-containment problem into the daily prescriptions in ICUs.

[Cost awareness at emergencies: multicentric survey among prescribers]. / Connaissance du coût des prescriptions aux urgences : enquête multicentrique auprès des prescripteurs.

AIM: Regular increasing of health-care expense brought about the development of medical implication in prescription control and the will to give more responsibility to prescribers. Emergency departments account for a large part of hospital expenses. This study was carried out to evaluate cost awareness among French emergency physicians. METHODS: A questionnaire was sent to 160 physicians (junior and senior grade) working at the emergency department of 12 hospitals in the Lyon region (France). Every participant had to estimate the true hospital costs of a selection of drugs, blood products, laboratory tests and imaging modalities. RESULTS: One hundred and seven questionnaires (68%) were returned and analysed: 48 filled in by juniors (45%), 59 by seniors (55%). Only 26 physicians accurately estimated costs within 50% of the true cost. Response errors were underestimations averaging 4695±226euros, i.e. -59±3% of the total sum (7899euros). Drug prescriptions were significantly (P<0.001) the most underestimated (-74±3%), when compared to both imaging modalities (-23±5%) or blood products prescriptions (-37±6%). High-cost drugs (>1000euros) were the most overestimated pharmaceuticals (-82±2%). Laboratory tests were rather overestimated (+12±8%). Junior grade physicians underestimated more costs than senior physicians (P=0.04). DISCUSSION: Physicians had a poor understanding of prescription costs at the emergencies, especially regarding high-cost drugs. Much progress is required to integrate the cost-containment problem in daily prescriptions at the emergency department.