Systemic tolerance of intravenous milrinone administration for cerebral vasospasm secondary to non-traumatic subarachnoid hemorrhage.

PURPOSE: Delayed cerebral ischemia (DCI) is a severe subarachnoid hemorrhage (SAH) complication, closely related to cerebral vasospasm (CVS). CVS treatment frequently comprises intravenous milrinone, an inotropic and vasodilatory drug. Our objective is to describe milrinone's hemodynamic, respiratory and renal effects when administrated as treatment for CVS. METHODS: Retrospective single-center observational study of patients receiving intravenous milrinone for CVS with systemic hemodynamics, oxygenation, renal disorders monitoring. We described these parameters' evolution before and after milrinone initiation (day - 1, baseline, day 1 and day 2), studied treatment cessation causes and assessed neurological outcome at 3-6 months. RESULTS: Ninety-one patients were included. Milrinone initiation led to cardiac output increase (4.5 L/min [3.4-5.2] at baseline vs 6.6 L/min [5.2-7.7] at day 2, p < 0.001), Mean Arterial Pressure decrease (101 mmHg [94-110] at baseline vs 95 mmHg [85-102] at day 2, p = 0.001) norepinephrine treatment requirement increase (32% of patients before milrinone start vs 58% at day 1, p = 0.002) and slight PaO2/FiO2 ratio deterioration (401 [333-406] at baseline vs 348 [307-357] at day 2, p = 0.016). Milrinone was interrupted in 8% of patients. 55% had a favorable outcome. CONCLUSION: Intravenous milrinone for CVS treatment seems associated with significant impact on systemic hemodynamics leading sometimes to treatment discontinuation.

Trending Ability of End-Tidal Capnography Monitoring During Mechanical Ventilation to Track Changes in Arterial Partial Pressure of Carbon Dioxide in Critically Ill Patients With Acute Brain Injury: A Monocenter Retrospective Study.

BACKGROUND: Changes in arterial partial pressure of carbon dioxide (Pa co2 ) may alter cerebral perfusion in critically ill patients with acute brain injury. Consequently, international guidelines recommend normocapnia in mechanically ventilated patients with acute brain injury. The measurement of end-tidal capnography (Et co2 ) allows its approximation. Our objective was to report the agreement between trends in Et co2 and Pa co2 during mechanical ventilation in patients with acute brain injury. METHODS: Retrospective monocenter study was conducted for 2 years. Critically ill patients with acute brain injury who required mechanical ventilation with continuous Et co2 monitoring and with 2 or more arterial gas were included. The agreement was evaluated according to the Bland and Altman analysis for repeated measurements with calculation of bias, and upper and lower limits of agreement. The directional concordance rate of changes between Et co2 and Pa co2 was evaluated with a 4-quadrant plot. A polar plot analysis was performed using the Critchley methods. RESULTS: We analyzed the data of 255 patients with a total of 3923 paired ΔEt co2 and ΔPa co2 (9 values per patient in median). Mean bias by Bland and Altman analysis was -8.1 (95 CI, -7.9 to -8.3) mm Hg. The directional concordance rate between Et co2 and Pa co2 was 55.8%. The mean radial bias by polar plot analysis was -4.4° (95% CI, -5.5 to -3.3) with radial limit of agreement (LOA) of ±62.8° with radial LOA 95% CI of ±1.9°. CONCLUSIONS: Our results question the performance of trending ability of Et co2 to track changes in Pa co2 in a population of critically ill patients with acute brain injury. Changes in Et co2 largely failed to follow changes in Pa co2 in both direction (ie, low concordance rate) and magnitude (ie, large radial LOA). These results need to be confirmed in prospective studies to minimize the risk of bias.

Radiomic analysis of abdominal organs during sepsis of digestive origin in a French intensive care unit.

BACKGROUND: Sepsis is a severe and common cause of admission to the intensive care unit (ICU). Radiomic analysis (RA) may predict organ failure and patient outcomes. The objective of this study was to assess a model of RA and to evaluate its performance in predicting in-ICU mortality and acute kidney injury (AKI) during abdominal sepsis. METHODS: This single-center, retrospective study included patients admitted to the ICU for abdominal sepsis. To predict in-ICU mortality or AKI, elastic net regularized logistic regression and the random forest algorithm were used in a five-fold cross-validation set repeated 10 times. RESULTS: Fifty-five patients were included. In-ICU mortality was 25.5%, and 76.4% of patients developed AKI. To predict in-ICU mortality, elastic net and random forest models, respectively, achieved areas under the curve (AUCs) of 0.48 (95% confidence interval [CI], 0.43-0.54) and 0.51 (95% CI, 0.46-0.57) and were not improved combined with Simplified Acute Physiology Score (SAPS) II. To predict AKI with RA, the AUC was 0.71 (95% CI, 0.66-0.77) for elastic net and 0.69 (95% CI, 0.64-0.74) for random forest, and these were improved combined with SAPS II, respectively; AUC of 0.94 (95% CI, 0.91-0.96) and 0.75 (95% CI, 0.70-0.80) for elastic net and random forest, respectively. CONCLUSIONS: This study suggests that RA has poor predictive performance for in-ICU mortality but good predictive performance for AKI in patients with abdominal sepsis. A secondary validation cohort is needed to confirm these results and the assessed model.

Continuous and deep sedation until death after a decision to withdraw life-sustaining therapies in intensive care units: A national survey.

BACKGROUND: Continuous and deep sedation until death is a much highly debated end-of-life practice. France is unique in having a regulatory framework for it. However, there are no data on its practice in intensive care units (ICUs). AIM: The aim is to describe continuous and deep sedation in relation to the framework in the specific context of withdrawal of life-sustaining therapies in ICUs, that is, its decision-making process and its practice compared to other end-of-life practices in this setting. DESIGN AND SETTING: French multicenter observational study. Consecutive ICU patients who died after a decision to withdraw life-sustaining therapies. RESULTS: A total of 343 patients in 57 ICUs, 208 (60%) with continuous and deep sedation. A formalized procedure for continuous and deep sedation was available in 32% of the ICUs. Continuous and deep sedation was not the result of a collegial decision-making process in 17% of cases, and did not involve consultation with an external physician in 29% of cases. The most commonly used sedative medicines were midazolam (10 [5-18] mg h-1) and propofol (200 [120-250] mg h -1). The Richmond Agitation Sedation Scale (RASS) was -5 in 60% of cases. Analgesia was associated with sedation in 94% of cases. Compared with other end-of-life sedative practices (n = 98), medicines doses were higher with no difference in the depth of sedation. CONCLUSIONS: This study shows a poor compliance with the framework for continuous and deep sedation. It highlights the need to formalize it to improve the decision-making process and the match between the intent, the practice and the actual effect.

Relationship between positive end-expiratory pressure levels, central venous pressure, systemic inflammation and acute renal failure in critically ill ventilated COVID-19 patients: a monocenter retrospective study in France.

BACKGROUND: The role of positive pressure ventilation, central venous pressure (CVP) and inflammation on the occurrence of acute kidney injury (AKI) have been poorly described in mechanically ventilated patient secondary to coronavirus disease 2019 (COVID-19). METHODS: This was a monocenter retrospective cohort study of consecutive ventilated COVID-19 patients admitted in a French surgical intensive care unit between March 2020 and July 2020. Worsening renal function (WRF) was defined as development of a new AKI or a persistent AKI during the 5 days after mechanical ventilation initiation. We studied the association between WRF and ventilatory parameters including positive end-expiratory pressure (PEEP), CVP, and leukocytes count. RESULTS: Fifty-seven patients were included, 12 (21%) presented WRF. Daily PEEP, 5 days mean PEEP and daily CVP values were not associated with occurrence of WRF. 5 days mean CVP was higher in the WRF group compared to patients without WRF (median [IQR], 12 mm Hg [11-13] vs. 10 mm Hg [9-12]; P=0.03). Multivariate models with adjustment on leukocytes and Simplified Acute Physiology Score (SAPS) II confirmed the association between CVP value and risk of WRF (odd ratio, 1.97; 95% confidence interval, 1.12-4.33). Leukocytes count was also associated with occurrence of WRF in the WRF group (14 G/L [11-18]) and the no-WRF group (9 G/L [8-11]) (P=0.002). CONCLUSIONS: In mechanically ventilated COVID-19 patients, PEEP levels did not appear to influence occurrence of WRF. High CVP levels and leukocytes count are associated with risk of WRF.

Impact of Early Out-of-Bed Mobilization on Functional Outcome in Patients with Aneurysmal Subarachnoid Hemorrhage: A Retrospective Cohort Study.

BACKGROUND: Effects of early mobilization are not well documented in patients with aneurysmal subarachnoid hemorrhage (aSAH). Only a few studies have investigated it through progressive mobilization protocols and suggested that it is safe and feasible. This study aimed to determine the impact of early out-of-bed mobilization (EOM) on 3-month functional outcome and cerebral vasospasm (CVS) occurrence in patients with aSAH. METHODS: A retrospective review of consecutive patients admitted to the intensive care unit with a diagnosis of aSAH was performed. EOM was defined as out-of-bed (OOB) mobilization performed before or on day 4 after aSAH onset. The primary outcome was 3-month functional independence (i.e., a modified Rankin Scale below 3) and the occurrence of CVS. RESULTS: A total of 179 patients with aSAH met the inclusion criteria. Thirty-one patients constituted the EOM group, and 148 patients were in the delayed out-of-bed mobilization group. Functional independence was more frequent in the EOM group than in the delayed out-of-bed mobilization group (n = 26 [84%] vs. n = 83 [56%], P = 0.004). In a multivariable analysis, EOM was an independent predictor of functional independence (adjusted odds ratio = 3.11; 95% confidence interval, 1.11-10.36; P < 0.05). The delay between bleeding and first OOB mobilization was also identified as an independent risk factor for the occurrence of CVS (adjusted odds ratio = 1.12; 95% confidence interval = 1.06-1.18, P < 0.001). CONCLUSIONS: EOM was independently associated with favorable functional outcome after aSAH. The delay between bleeding and OOB mobilization was an independent risk factor for reduced functional independence and CVS occurrence. Prospective randomized trials are necessary to confirm these results and improve clinical practice.

Efficacy of almitrine as a rescue therapy for refractory hypoxemia in COVID and non-COVID acute respiratory distress syndrome. A retrospective monocenter study.

BACKGROUND: Almitrine, a drug enhancing hypoxic pulmonary vasoconstriction, has been proposed as a rescue therapy for refractory hypoxemia in COVID related acute respiratory distress syndrome (C-ARDS). We aimed at investigating the response to almitrine depending on the cause of ARDS (COVID vs. non-COVID). METHODS: Monocenter retrospective study from 2014 to 2021. All patients diagnosed with moderate to severe ARDS and treated with almitrine as rescue therapy for refractory hypoxemia were studied. Factor independently associated with oxygenation response to almitrine infusion were determined. RESULTS: Sixty patients with ARDS and treated with almitrine were analyzed, 36 (60%) due to SARS-CoV-2 infection and 24 (40%) due to other causes. Baseline PaO2/FiO2 was 78 [61-101] mmHg, 76% had at least one prone positioning before the start of almitrine infusion. Median PaO2/FiO2 increased by +38 [7-142] mmHg (+61% [10-151]) after almitrine infusion. PaO2/FiO2 increased by +134 [12-186] mmHg in non-COVID ARDS (NC-ARDS) and by +19 [8-87] mmHg in C-ARDS. The increase in PaO2/FiO2 was lower in C-ARDS than in NC-ARDS (P=0.013). In multivariable analysis, C-ARDS, non-invasive ventilation and concomitant use of norepinephrine were independently associated with a decreased oxygenation response to almitrine infusion. CONCLUSIONS: Our study reports a highly variable response to almitrine infusion in ARDS patients with refractory hypoxemia. Independent factors associated with a reduced oxygenation response to almitrine infusion were: COVID ARDS, concomitant use of norepinephrine, and non-invasive ventilatory strategy.

Immunotherapy to treat sepsis induced-immunosuppression: Immune eligibility or outcome criteria, a systematic review.

Sepsis-induced immunosuppression (SIS) is the target of multiple clinical studies testing immunotherapies. To date, most trials are performed on a heterogeneous and unselected population. Without any consensual definition of immunosuppression and therapeutic goals, results from these trials remain poorly transposable. In this perspective, we conducted a systematic review aiming at 1/registering the inclusion criteria, 2/ report the outcomes evaluated in this literature. We searched Pubmed, Embase, and ClinicalTrials.gov for studies using an immunotherapy to reverse SIS. This review collected for each study: design, intervention, immune inclusion criteria, outcome, definition of sepsis, and source of infection. From the 80 studies assessed for eligibility, 29 were included: 17 RCT, 6 observational prospective studies, 6 ongoing RCT. Sepsis was defined based upon current recommendations at the time, with most patients presenting at least one organ failure. We found important heterogeneity regarding the use of immune parameters, both as inclusion and as outcome criteria. Only 13 studies selected patients suffering from immunosuppression based on immune biomarkers. Two immune criterias were commonly used: lymphocyte count and monocytic HLA-DR expression. This heterogeneity criteria in studies targeting SIS justify the conduct of a consensus process to define criteria to diagnose SIS and identify relevant outcomes markers.

Early echocardiography by treating physicians and outcome in the critically ill: An ancillary study from the prospective multicenter trial FROG-ICU.

PURPOSE: This study aimed to investigate the association between the use of early echocardiography performed by the treating physician certified in critical care ultrasound and mortality in ICU patients. MATERIALS AND METHODS: FROG-ICU was a multi-center cohort designed to investigate the outcome of critically ill patients. Of the 1359 patients admitted to centers where echocardiography was available, 372 patients underwent echocardiography during the initial 3 days. RESULTS: Of the ICU patients admitted for cardiac disease, 47.4% underwent echocardiography, and those patients had the lowest left ventricular ejection fraction 40 [31-58] % and the lowest cardiac output 4.2 [3.2-5.7] L/min compared to patients admitted for other causes (p < 0.001 for both). One-year mortality was 36.8% and 39.9% in patients with and without echocardiography, respectively [HR 0.92 (95% CI 0.75-1.11)]. This result was confirmed after multivariable Cox regression analysis [HR 0.88 (95% CI 0.71-1.08)]. Subgroup analyses suggest that among patients admitted to ICU for cardiac disease, those managed with echocardiography had a lower risk of one-year mortality [HR 0.65 (95% CI 0.43-0.98)]. CONCLUSIONS: Early echocardiography by treating physicians was not associated with short- or long-term survival in ICU patients. In subgroups, early echocardiography improved survival in ICU patients admitted for cardiac disease. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01367093.

Accuracy of cumulative volumes of fluid challenge to assess fluid responsiveness in critically ill patients with acute circulatory failure: a pharmacodynamic approach.

BACKGROUND: The relationship between the dose (volume of fluid) and the effect (increase of stroke volume [SV]) has been poorly described. We hypothesised that the analysis of the dynamic response of SV during fluid challenge (FC) helps to determine the optimal volume of FC, along with its diagnostic accuracy parameters for fluid responsiveness. METHODS: A prospective observational study was conducted in critically ill patients with circulatory failure. Patients monitored with oesophageal Doppler and assigned to an FC of 500 ml of crystalloid were included. The areas under the curve (AUC) and 95% confidence intervals (CI95) of the receiver operating characteristic curves for cumulative volumes from 50 to 450 ml were determined for fluid responsiveness (SV increase ≥15% from baseline) along with other parameters of diagnostic accuracy. In the pharmacodynamic analysis, dose-effect and dose-response models were constructed, with determination of median and 90% effective dose (ED50 and ED90). RESULTS: Forty-five patients were included. The AUC increased with cumulative volumes of FC up to 250 ml (AUC250 0.93 [CI95: 0.85-1.00]), followed by a plateau above 0.95 of AUC. The optimal volume was 250 ml, associated with a specificity of 0.89 [CI95: 0.78-1.00], a sensitivity of 0.92 [CI95: 0.69-1.00], and a threshold of 9.6% increase in SV. The ED50 was 156 [CI95: 136-177] ml and the ED90 was 312 [CI95: 269-352] ml. CONCLUSIONS: A volume of FC of 250 ml with a threshold of 9.6% increase in SV showed the highest accuracy in detecting fluid responsiveness in critically ill patients with shock. CLINICAL TRIAL REGISTRATION: .

Comparison of Circulating Immune Cells Profiles and Kinetics Between Coronavirus Disease 2019 and Bacterial Sepsis.

OBJECTIVES: Although clinical presentation of coronavirus disease 2019 has been extensively described, immune response to severe acute respiratory syndrome coronavirus 2 remains yet not fully understood. Similarities with bacterial sepsis were observed; however, few studies specifically addressed differences of immune response between both conditions. Here, we report a longitudinal analysis of the immune response in coronavirus disease 2019 patients, its correlation with outcome, and comparison between severe coronavirus disease 2019 patients and septic patients. DESIGN: Longitudinal, retrospective observational study. SETTING: Tertiary-care hospital during the first 2020 coronavirus disease 2019 outbreak in France. PATIENTS: All successive patients with confirmed severe acute respiratory syndrome coronavirus 2 infection admitted to the emergency department, medical ward, and ICU with at least one available immunophenotyping performed during hospital stay. MEASUREMENTS AND MAIN RESULTS: Between March and April 2020, 247 patients with coronavirus disease 2019 were included and compared with a historical cohort of 108 severe septic patients. Nonsevere coronavirus disease 2019 patients (n = 153) presented normal or slightly altered immune profiles. Severe coronavirus disease 2019 (n = 94) immune profile differed from sepsis. Coronavirus disease 2019 exhibited profound and prolonged lymphopenia (mostly on CD3, CD4, CD8, and NK cells), neutrophilia, and human leukocyte antigen D receptor expression on CD14+ monocytes down-regulation. Surprisingly, coronavirus disease 2019 patients presented a unique profile of B cells expansion, basophilia, and eosinophilia. Lymphopenia, human leukocyte antigen D receptor expression on CD14+ monocytes down-regulation, and neutrophilia were associated with a worsened outcome, whereas basophilia and eosinophilia were associated with survival. Circulating immune cell kinetics differed between severe coronavirus disease 2019 and sepsis, lack of correction of immune alterations in coronavirus disease 2019 patients during the first 2 weeks of ICU admission was associated with death and nosocomial infections. CONCLUSIONS: Circulating immune cells profile differs between mild and severe coronavirus disease 2019 patients. Severe coronavirus disease 2019 is associated with a unique immune profile as compared with sepsis. Several immune features are associated with outcome. Thus, immune monitoring of coronavirus disease 2019 might be of help for patient management.

Evaluation of glomerular filtration rate using iohexol plasma clearance in critically ill patients with augmented renal creatinine clearance: A single-centre retrospective study.

BACKGROUND: Augmented renal creatinine clearance (ARC) (≥130 ml min-1 1.73 m-2) is frequent in intensive care unit (ICU) patients and may impact patient outcome. OBJECTIVES: To compare glomerular filtration rate (GFR) measured with iohexol plasma clearance and creatinine clearance in critically ill patients with augmented renal clearance. DESIGN: Single-centre, retrospective study. SETTING: French University Hospital ICU from November 2016 to May 2019. PATIENTS: Adult patients with augmented renal clearance who had a measurement of iohexol plasma clearance. MAIN OUTCOME MEASURE: Agreement between 6 h creatinine clearance (6 h CrCl) and iohexol plasma clearance (GFRio). RESULTS: Twenty-nine patients were included. The median 6 h creatinine clearance was 195 [interquartile range (IQR) 162 to 251] ml min-1 1.73 m-2 and iohexol clearance was 133 [117 to 153] ml min-1 1.73 m-2. Sixteen patients (55%) had hyperfiltration (clearance >130 ml min-1 1.73 m-2) measured with iohexol clearance. Mean bias between iohexol and creatinine clearance was -80 [limits of agreement (LoA) -216 to 56 ml min-1 1.73 m-2]. For Cockcroft and Gault Modification of Diet in Renal Disease equation (MDRD), Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) formulae, mean biases were, respectively -27 (LoA -99 to 45), -14 (LoA -86 to 59) and 15 (LoA -33 to 64) ml min-1 1.73 m-2. CONCLUSION: In the present study, we found that in patients with augmented renal creatinine clearance, half of the patients do not have hyperfiltration using iohexol clearance measurements. We observed an important bias between 6 h CrCl and GFRio with large LoA. In critically patients with ARC, 6 h CrCl does not reliably estimate GFR and 6 h CrCl nearly systematically overestimates renal function. Comparison of creatinine-based GFR estimations and GFRio show acceptable bias but wide LoA.