Decreased risk of underdosing with continuous infusion versus intermittent administration of cefotaxime in patients with sickle cell disease and acute chest syndrome.

OBJECTIVE: Underdosing of antibiotics is common in patients with sickle cell disease (SCD). We hypothesized that in critically-ill patients with SCD receiving cefotaxime during acute chest syndrome, the continuous infusion may outperform the intermittent administration in achieving pharmacokinetic/pharmacodynamic targets. DESIGN: Prospective before-after study. SETTINGS: Intensive-care unit of a French teaching hospital and sickle cell disease referral center. PATIENTS: Sixty consecutive episodes of severe acute chest syndrome in 58 adult patients with sickle cell disease. INTERVENTIONS: Patients were treated with intermittent administration during the first period (April 2016 -April 2018) and with continuous infusion during the second period (May 2018 -August 2019). MEASUREMENTS AND MAIN RESULTS: We included 60 episodes of acute chest syndrome in 58 patients (29 [25-34] years, 37/58 (64%) males). Daily dose of cefotaxime was similar between groups (59 [48-88] vs. 61 [57-64] mg/kg/day, p = 0.84). Most patients (>75%) presented a glomerular hyperfiltration with no difference between groups (p = 0.25). More patients had a cefotaxime trough level ≥2 mg/L with continuous infusion than intermittent administration: 28 (93%) vs. 5 (16%), p<0.001. The median residual concentration was higher in the continuous infusion than intermittent administration group: 10.5 [7.4-13.3] vs. 0 [0-0] mg/L, p<0.001. No infection relapse was observed in the entire cohort. Hospital length of stay was similar between groups. CONCLUSION: As compared to intermittent administration, continuous infusion of cefotaxime maximizes the pharmacokinetic/pharmacodynamic parameters in patients with SCD. The clinical outcome did not differ between the two administration methods; however, the study was underpowered to detect such a difference.

Effect of volume infusion on left atrial strain in acute circulatory failure.

BACKGROUND: Left atrial strain (LAS) is a measure of atrial wall deformation during cardiac cycle and reflects atrial contribution to cardiovascular performance. Pathophysiological significance of LAS in critically ill patients with hemodynamic instability has never been explored. This study aimed at describing LAS and its variation during volume expansion and to assess the relationship between LAS components and fluid responsiveness. METHODS: This prospective observational study was performed in a French ICU and included patients with acute circulatory failure, for whom the treating physician decided to proceed to volume expansion (rapid infusion of 500 mL of crystalloid solution). Trans-thoracic echocardiography was performed before and after the fluid infusion. LAS analysis was performed offline. Fluid responsiveness was defined as an increase in velocity-time integral (VTI) of left ventricular outflow tract ≥ 10%. RESULTS: Thirty-eight patients were included in the final analysis. Seventeen (45%) patients were fluid responders. LAS analysis had a good feasibility and reproducibility. Overall, LAS was markedly reduced in all its components, with values of 19 [15 - 32], -9 [-19 - -7] and - 9 [-13 - -5] % for LAS reservoir (LASr), conduit (LAScd) and contraction (LASct), respectively. LASr, LAScd and LASct significantly increased during volume expansion in the entire population. Baseline value of LAS did not predict fluid responsiveness and the changes in LAS and VTI during volume expansion were not significantly correlated. CONCLUSIONS: LAS is severely altered during acute circulatory failure. LAS components significantly increase during fluid administration, but cannot be used to predict or assess fluid responsiveness.

Bleeding complications, coagulation disorders, and their management in acute myocardial infarction-related cardiogenic shock rescued by veno-arterial ECMO: A retrospective cohort study.

PURPOSE: Management of dual antiplatelet therapy (DAPT) in patients on venoarterial-extracorporeal membrane (VA-ECMO) after acute myocardial infarction (AMI) is challenging. Our objective was to describe the frequency, management and outcomes of severe bleeding complications and determine their occurrence risk factors. MATERIAL AND METHODS: We conducted a retrospective observational cohort study including post-AMI cardiogenic shock patients requiring VA-ECMO. Severe bleeding was defined based on the Bleeding Academic Research Consortium classification. We calculated multivariable Fine-Gray models to assess factors associated with risk of severe bleeding. RESULTS: From January 2015 to July 2019, 176 patients received VA-ECMO after AMI and 132 patients were included. Sixty-five (49%) patients died. Severe bleeding occurred in 39% of cases. Severe thrombocytopenia (< 50 G/L) and hypofibrinogenemia (<1,5 g/L) occurred in respectively 31% and 19% of patients. DAPT was stopped in 32% of patients with a 6% rate of stent thrombosis. Anticoagulation was stopped in 39% of patients. Using a multivariate competing risk model, female sex, time on ECMO, troponin at admission and Impella® implantation were independently associated with severe bleeding. CONCLUSIONS: Bleeding complications and coagulation disorders were frequent and severe in patients on VA-ECMO after AMI, leading of antiplatelet therapy withdrawal in one third of patients.

Geo-economic Influence on the Effect of Fluid Volume for Sepsis Resuscitation: A Meta-Analysis.

Rationale: Sepsis management relies on fluid resuscitation avoiding fluid overload and its related organ congestion. Objectives: To explore the influence of country income group on risk-benefit balance of fluid management strategies in sepsis. Methods: We searched e-databases for all randomized controlled trials on fluid resuscitation in patients with sepsis or septic shock up to January 2023, excluding studies on hypertonic fluids, colloids, and depletion-based interventions. The effect of fluid strategies (higher versus lower volumes) on mortality was analyzed per income group (i.e., low- and middle-income countries [LMICs] or high-income countries [HICs]). Measurements and Main Results: Twenty-nine studies (11,798 patients) were included in the meta-analysis. There was a numerically higher mortality in studies of LMICs as compared with those of HICs: median, 37% (interquartile range [IQR]: 26-41) versus 29% (IQR: 17-38; P = 0.06). Income group significantly interacted with the effect of fluid volume on mortality: Higher fluid volume was associated with higher mortality in LMICs but not in HICs: odds ratio (OR), 1.47; 95% confidence interval (95% CI): 1.14-1.90 versus 1.00 (95% CI: 0.87-1.16), P = 0.01 for subgroup differences. Higher fluid volume was associated with increased need for mechanical ventilation in LMICs (OR, 1.24 [95% CI: 1.08-1.43]) but not in HICs (OR, 1.02 [95% CI: 0.80-1.29]). Self-reported access to mechanical ventilation also significantly influenced the effect of fluid volume on mortality, which increased with higher volumes only in settings with limited access to mechanical ventilation (OR: 1.45 [95% CI: 1.09-1.93] vs. 1.09 [95% CI: 0.93-1.28], P = 0.02 for subgroup differences). Conclusions: In sepsis trials, the effect of fluid resuscitation approach differed by setting, with higher volume of fluid resuscitation associated with increased mortality in LMICs and in settings with restricted access to mechanical ventilation. The precise reason for these differences is unclear and may be attributable in part to resource constraints, participant variation between trials, or other unmeasured factors.

Potential of Multiplex Polymerase Chain Reaction Performed on Protected Telescope Catheter Samples for Early Adaptation of Antimicrobial Therapy in ARDS Patients.

BACKGROUND: Diagnosis of co/superinfection in patients with Acute Respiratory Distress Syndrome (ARDS) is challenging. The FilmArray Pneumonia plus Panel (bioMérieux, France), a new rapid multiplex Polymerase Chain Reaction (mPCR), has never been assessed on a blinded protected telescope catheter (PTC) samples, a very common diagnostic tool in patients under mechanical ventilation. We evaluated the performance of mPCR on PTC samples compared with conventional culture and its impact on antibiotic stewardship. METHODS: Observational study in two intensive care units, conducted between March and July 2020, during the first wave of the COVID-19 pandemic in France. RESULTS: We performed 125 mPCR on blinded PTC samples of 95 ARDS patients, including 73 (77%) SARS-CoV-2 cases and 28 (29%) requiring extracorporeal membrane oxygenation. Respiratory samples were drawn from mechanically ventilated patients either just after intubation (n = 48; 38%) or later for suspected ventilator-associated pneumonia (VAP) (n = 77; 62%). The sensitivity, specificity, positive, and negative predictive values of mPCR were 93% (95% CI 84-100), 99% (95% CI 99-100), 68% (95% CI 54-83), and 100% (95% CI 100-100), respectively. The overall coefficient of agreement between mPCR and standard culture was 0.80 (95% CI 0.68-0.89). Intensivists changed empirical antimicrobial therapy in only 14% (18/125) of cases. No new antibiotic was initiated in more than half of the CAP/HAP pneumonia-suspected cases (n = 29; 60%) and in more than one-third of those suspected to have VAP without affecting or delaying their antimicrobial therapy. CONCLUSIONS: Rapid mPCR was feasible on blinded PTC with good sensitivity and specificity. New antibiotics were not initiated in more than half of patients and more than one-third of VAP-suspected cases. Further studies are needed to assess mPCR potential in improving antibiotic stewardship.

Acute Kidney Injury in Critically-Ill COVID-19 Patients.

Purpose: Acute kidney injury (AKI) is common in patients with COVID-19, however, its mechanism is still controversial, particularly in ICU settings. Urinary proteinuria profile could be a non-invasive tool of interest to scrutinize the pathophysiological process underlying AKI in COVID-19 patients. Material and Methods: We conducted a retrospective study between March 2020 and April 2020. All patients with laboratory-confirmed COVID-19 and without end-stage kidney disease requiring renal replacement therapy before ICU admission were included. Our objectives were to assess the incidence and risk factors for AKI and to describe its clinical and biological characteristics, particularly its urinary protein profile. Results: Seventy patients were included; 87% needed mechanical ventilation and 61% needed vasopressor during their ICU stay; 64.3% of patients developed AKI and half of them needed dialysis. Total and tubular proteinuria on day 1 were higher in patients with AKI, whereas glomerular proteinuria was similar in both groups. The main risk factor for AKI was shock at admission (OR = 5.47 (1.74−17.2), p < 0.01). Mortality on day 28 was higher in AKI (23/45, 51.1%) than in no-AKI patients (1/25, 4%), p < 0.001. Risk factors for 28-days mortality were AKI with need for renal replacement therapy, non-renal SOFA score and history of congestive heart failure. Conclusions: AKI is common in COVID-19 patients hospitalized in ICU; it seems to be related to tubular lesions rather than glomerular injury and is related to shock at ICU admission.

Comparison of standard prophylactic, intermediate prophylactic and therapeutic anticoagulation in patients with severe COVID-19: protocol for the ANTICOVID multicentre, parallel-group, open-label, randomised controlled trial.

INTRODUCTION: COVID-19 induces venous, arterial and microvascular thrombosis, involving several pathophysiological processes. In patients with severe COVID-19 without macrovascular thrombosis, escalating into high-dose prophylactic anticoagulation (HD-PA) or therapeutic anticoagulation (TA) could be beneficial in limiting the extension of microvascular thrombosis and forestalling the evolution of lung and multiorgan microcirculatory dysfunction. In the absence of data from randomised trials, clinical practice varies widely. METHODS AND ANALYSIS: This is a French multicentre, parallel-group, open-label, randomised controlled superiority trial to compare the efficacy and safety of three anticoagulation strategies in patients with COVID-19. Patients with oxygen-treated COVID-19 showing no pulmonary artery thrombosis on computed tomography with pulmonary angiogram will be randomised to receive either low-dose PA, HD-PA or TA for 14 days. Patients attaining the extremes of weight and those with severe renal failure will not be included. We will recruit 353 patients. Patients will be randomised on a 1:1:1 basis, and stratified by centre, use of invasive mechanical ventilation, D-dimer levels and body mass index. The primary endpoint is a hierarchical criterion at day 28 including all-cause mortality, followed by the time to clinical improvement defined as the time from randomisation to an improvement of at least two points on the ordinal clinical scale. Secondary outcomes include thrombotic and major bleeding events at day 28, individual components of the primary endpoint, number of oxygen-free, ventilator-free and vasopressor-free days at day 28, D-dimer and sepsis-induced coagulopathy score at day 7, intensive care unit and hospital stay at day 28 and day 90, and all-cause death and quality of life at day 90. ETHICS AND DISSEMINATION: The study has been approved by an ethical committee (Ethics Committee, Ile de France VII, Paris, France; reference 2020-A03531-38). Patients will be included after obtaining their signed informed consent. The results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04808882.

The role of acute hypercapnia on mortality and short-term physiology in patients mechanically ventilated for ARDS: a systematic review and meta-analysis.

PURPOSE: Hypercapnia is frequent during mechanical ventilation for acute respiratory distress syndrome (ARDS), but its effects on morbidity and mortality are still controversial. We conducted a systematic review and meta-analysis to explore clinical consequences of acute hypercapnia in adult patients ventilated for ARDS. METHODS: We searched Medline, Embase, and the Cochrane Library via the OVID platform for studies published from 1946 to 2021. "Permissive hypercapnia" defined hypercapnia in studies where the group with hypercapnia was ventilated with a protective ventilation (PV) strategy (lower VT targeting 6 ml/kg predicted body weight) while the group without hypercapnia was managed with a non-protective ventilation (NPV); "imposed hypercapnia" defined hypercapnia in studies where hypercapnic and non-hypercapnic patients were managed with a similar ventilation strategy. RESULTS: Twenty-nine studies (10,101 patients) were included. Permissive hypercapnia, imposed hypercapnia under PV, and imposed hypercapnia under NPV were reported in 8, 21 and 1 study, respectively. Studies testing permissive hypercapnia reported lower mortality in hypercapnic patients receiving PV as compared to non-hypercapnic patients receiving NPV: OR = 0.26, 95% CI [0.07-0.89]. By contrast, studies reporting imposed hypercapnia under PV reported increased mortality in hypercapnic patients receiving PV as compared to non-hypercapnic patients also receiving PV: OR = 1.54, 95% CI [1.15-2.07]. There was a significant interaction between the mechanism of hypercapnia and the effect on mortality. CONCLUSIONS: Clinical effects of hypercapnia are conflicting depending on its mechanism. Permissive hypercapnia was associated with improved mortality contrary to imposed hypercapnia under PV, suggesting a major role of PV strategy on the outcome.

Effects of corticosteroids in patients with sickle cell disease and acute complications: a systematic review and meta-analysis.

Whether corticosteroids improve outcome in patients with acute complications of sickle cell disease (SCD) is still debated. We performed a systematic review of the literature with the aim of estimating effects of corticosteroids on the clinical course of vaso-occlusive crisis (VOC) or acute chest syndrome (ACS) in patients with SCD. The primary outcome was transfusion requirement during hospitalization. Studies were identified by search of MEDLINE and CENTRAL database. Three randomized clinical trials (RCT) and three retrospective cohort studies (RCS) were included, involving 3,304 participants and 5,562 VOC or ACS episodes. There was no difference between corticosteroids and standard treatment regarding transfusion requirement overall (odds ratio [OR]=0.98, 95% confidence interval [CI]: 0.38-2.53) but there was a significant interaction of the study type (P<0.0001): corticosteroid therapy was associated with a lower risk of transfusion in RCT (OR=0.13, 95% CI: 0.04-0.45) and a higher risk of transfusion in RCS (OR=2.12, 95% CI: 1.33-3.40. In RCT, the length of hospital stay was lower with corticosteroids as compared with standard treatment: mean difference - 24 hours (95% CI: -35 to -14). Corticosteroids were associated with an increased risk of hospital readmission as compared with standard treatment, in RCT, RCS, and the entire cohort: OR=5.91, 95% CI: 1.40-24.83; OR=3.28, 95% CI: 1.46-7.36 and OR=3.21, 95% CI: 1.97-5.24, respectively. Corticosteroids were associated with reduced number of transfusions and length of stay in RCT but not in RCS, with more rehospitalizations overall. Additional RCT should be conducted while minimizing the risk of rehospitalizations.

Prediction of extubation outcome in critically ill patients: a systematic review and meta-analysis.

BACKGROUND: Extubation failure is an important issue in ventilated patients and its risk factors remain a matter of research. We conducted a systematic review and meta-analysis to explore factors associated with extubation failure in ventilated patients who passed a spontaneous breathing trial and underwent planned extubation. This systematic review was registered in PROPERO with the Registration ID CRD42019137003. METHODS: We searched the PubMed, Web of Science and Cochrane Controlled Register of Trials for studies published from January 1998 to December 2018. We included observational studies involving risk factors associated with extubation failure in adult intensive care unit patients who underwent invasive mechanical ventilation. Two authors independently extracted data and assessed the validity of included studies. RESULTS: Sixty-seven studies (involving 26,847 participants) met the inclusion criteria and were included in our meta-analysis. We analyzed 49 variables and, among them, we identified 26 factors significantly associated with extubation failure. Risk factors were distributed into three domains (comorbidities, acute disease severity and characteristics at time of extubation) involving mainly three functions (circulatory, respiratory and neurological). Among these, the physiological respiratory characteristics at time of extubation were the most represented. The individual topic of secretion management was the one with the largest number of variables. By Bayesian multivariable meta-analysis, twelve factors were significantly associated with extubation failure: age, history of cardiac disease, history of respiratory disease, Simplified Acute Physiologic Score II score, pneumonia, duration of mechanical ventilation, heart rate, Rapid Shallow Breathing Index, negative inspiratory force, lower PaO2/FiO2 ratio, lower hemoglobin level and lower Glasgow Coma Scale before extubation, with the latest factor having the strongest association with extubation outcome. CONCLUSIONS: Numerous factors are associated with extubation failure in critically ill patients who have passed a spontaneous breathing trial. Robust multiparametric clinical scores and/or artificial intelligence algorithms should be tested based on the selected independent variables in order to improve the prediction of extubation outcome in the clinical scenario.

Characteristics and risk factors for poor outcome in patients with systemic vasculitis involving the gastrointestinal tract.

BACKGROUND: Gastrointestinal (GI) involvement was described to be a poor prognostic factor in systemic necrotizing vasculitis. Its prognostic significance may vary according to clinical presentation and vasculitis subtype. AIMS: This study investigated risk-factors associated to poor outcome in GI-involvement of vasculitis. METHODS: Patients with systemic vasculitis as defined by the 2012 Chapel Hill Consensus Conference and presenting with GI involvement were retrospectively included. Baseline characteristics, treatments and outcome were recorded. Primary endpoint was a composite of admission to intensive care unit (ICU), emergency surgical procedure, or death. RESULTS: Two hundred and thirteen patients were included. Vasculitis were distributed as follows: 41% IgA vasculitis, 27% ANCA-associated vasculitis, 17% polyarteritis nodosa (PAN), and 15% other vasculitis. Eighty-three (39%) patients fulfilled the composite primary endpoint within 6 months. Predictive factors associated with the primary endpoint included PAN subtype (OR 3.08, 95% CI 1.29-7.34), performance status (OR 1.40, 1.05-1.87), use of morphine (OR 2.51, 0.87-7.24), abdominal guarding (OR 3.08, 1.01-9.37), ileus (OR 2.29, 0.98-5.32), melena (OR 2.74, 1.17-6.42), increased leukocytes (per G/L, OR 1.05, 1.00-1.10), low hemoglobin (per g/dL, OR 0.80, 0.71-0.91) and increased CRP (log mg/L, OR 1.21, 0.94-1.56). A risk prediction model for the achievement of primary endpoint had a very good performance [C-statistics 0.853 (0.810 to 0.895], and for overall survival as well. CONCLUSIONS: Vasculitis presenting with GI involvement have a poor outcome in more than one third of cases. An easy-to-use risk prediction model had a very good performance to predict the admission to ICU, emergency surgical procedure, or death.

Procalcitonin to Reduce Antibiotic Exposure during Acute Chest Syndrome in Adult Patients with Sickle-Cell Disease.

Acute chest syndrome (ACS) is a major complication of sickle-cell disease. Bacterial infection is one cause of ACS, so current guidelines recommend the routine use of antibiotics. We performed a prospective before-after study in medical wards and an intensive-care unit (ICU). During the control phase, clinicians were blinded to procalcitonin concentration results. We built an algorithm using the obtained measurements to hasten antibiotic cessation after three days of treatment if bacterial infection was not documented, and procalcitonin concentrations were all <0.5 µg/L. During the intervention period, the procalcitonin algorithm was suggested to physicians as a guide for antibiotic therapy. The primary endpoint was the number of days alive without antibiotics at Day 21. One-hundred patients were analyzed (103 ACS episodes, 60 in intervention phase). Possible or proven lung infection was diagnosed during 13% of all ACS episodes. The number of days alive without antibiotics at Day 21 was higher during the intervention phase: 15 [14-18] vs. 13 [13,14] days (p = 0.001). More patients had a short (≤3 days) antibiotic course during intervention phase: 31% vs 9% (p = 0.01). There was neither infection relapse nor pulmonary superinfection in the entire cohort. A procalcitonin-guided strategy to prescribe antibiotics in patients with ACS may reduce antibiotic exposure with no apparent adverse outcomes.