Hydrocortisone plus fludrocortisone for community acquired pneumonia-related septic shock: a subgroup analysis of the APROCCHSS phase 3 randomised trial.

BACKGROUND: Glucocorticoids probably improve outcomes in patients hospitalised for community acquired pneumonia (CAP). In this a priori planned exploratory subgroup analysis of the phase 3 randomised controlled Activated Protein C and Corticosteroids for Human Septic Shock (APROCCHSS) trial, we aimed to investigate responses to hydrocortisone plus fludrocortisone between CAP and non-CAP related septic shock. METHODS: APROCCHSS was a randomised controlled trial that investigated the effects of hydrocortisone plus fludrocortisone, drotrecogin-alfa (activated), or both on mortality in septic shock in a two-by-two factorial design; after drotrecogin-alfa was withdrawn on October 2011, from the market, the trial continued on two parallel groups. It was conducted in 34 centres in France. In this subgroup study, patients with CAP were a preselected subgroup for an exploratory secondary analysis of the APROCCHSS trial of hydrocortisone plus fludrocortisone in septic shock. Adults with septic shock were randomised 1:1 to receive, in a double-blind manner, a 7-day treatment with daily administration of intravenous hydrocortisone 50 mg bolus every 6h and a tablet of 50 µg of fludrocortisone via the nasogastric tube, or their placebos. The primary outcome was 90-day all-cause mortality. Secondary outcomes included all-cause mortality at intensive care unit (ICU) and hospital discharge, 28-day and 180-day mortality, the number of days alive and free of vasopressors, mechanical ventilation, or organ failure, and ICU and hospital free-days to 90-days. Analysis was done in the intention-to-treat population. The trial was registered at ClinicalTrials.gov (NCT00625209). FINDINGS: Of 1241 patients included in the APROCCHSS trial, CAP could not be ruled in or out in 31 patients, 562 had a diagnosis of CAP (279 in the placebo group and 283 in the corticosteroid group), and 648 patients did not have CAP (329 in the placebo group and 319 in the corticosteroid group). In patients with CAP, there were 109 (39%) deaths of 283 patients at day 90 with hydrocortisone plus fludrocortisone and 143 (51%) of 279 patients receiving placebo (odds ratio [OR] 0·60, 95% CI 0·43-0·83). In patients without CAP, there were 148 (46%) deaths of 319 patients at day 90 in the hydrocortisone and fludrocortisone group and 157 (48%) of 329 patients in the placebo group (OR 0·95, 95% CI 0·70-1·29). There was significant heterogeneity in corticosteroid effects on 90-day mortality across subgroups with CAP and without CAP (p=0·046 for both multiplicative and additive interaction tests; moderate credibility). Of 1241 patients included in the APROCCHSS trial, 648 (52%) had ARDS (328 in the placebo group and 320 in the corticosteroid group). There were 155 (48%) deaths of 320 patients at day 90 in the corticosteroid group and 186 (57%) of 328 patients in the placebo group. The OR for death at day 90 was 0·72 (95% CI 0·53-0·98) in patients with ARDS and 0·85 (0·61-1·20) in patients without ARDS (p=0·45 for multiplicative interaction and p=0·42 for additive interaction). The OR for observing at least one serious adverse event (corticosteroid group vs placebo) within 180 days post randomisation was 0·64 (95% CI 0·46-0·89) in the CAP subgroup and 1·02 (0·75-1·39) in the non-CAP subgroup (p=0·044 for multiplicative interaction and p=0·042 for additive interaction). INTERPRETATION: In a pre-specified subgroup analysis of the APROCCHSS trial of patients with CAP and septic shock, hydrocortisone plus fludrocortisone reduced mortality as compared with placebo. Although a large proportion of patients with CAP also met criteria for ARDS, the subgroup analysis was underpowered to fully discriminate between ARDS and CAP modifying effects on mortality reduction with corticosteroids. There was no evidence of a significant treatment effect of corticosteroids in the non-CAP subgroup. FUNDING: Programme Hospitalier de Recherche Clinique of the French Ministry of Health, by Programme d'Investissements d'Avenir, France 2030, and IAHU-ANR-0004.

Role of the interstitium during septic shock: a key to the understanding of fluid dynamics?

BACKGROUND: While not traditionally included in the conceptual understanding of circulation, the interstitium plays a critical role in maintaining fluid homeostasis. Fluid balance regulation is a critical aspect of septic shock, with a well-known association between fluid balance and outcome. The regulation of transcapillary flow is the first key to understand fluid homeostasis during sepsis. MAIN TEXT: Capillary permeability is increased during sepsis, and was classically considered to be necessary and sufficient to explain the increase of capillary filtration during inflammation. However, on the other side of the endothelial wall, the interstitium may play an even greater role to drive capillary leak. Indeed, the interstitial extracellular matrix forms a complex gel-like structure embedded in a collagen skeleton, and has the ability to directly attract intravascular fluid by decreasing its hydrostatic pressure. Thus, interstitium is not a mere passive reservoir, as was long thought, but is probably major determinant of fluid balance regulation during sepsis. Up to this date though, the role of the interstitium during sepsis and septic shock has been largely overlooked. A comprehensive vision of the interstitium may enlight our understanding of septic shock pathophysiology. Overall, we have identified five potential intersections between septic shock pathophysiology and the interstitium: 1. increase of oedema formation, interacting with organ function and metabolites diffusion; 2. interstitial pressure regulation, increasing transcapillary flow; 3. alteration of the extracellular matrix; 4. interstitial secretion of inflammatory mediators; 5. decrease of lymphatic outflow. CONCLUSIONS: We aimed at reviewing the literature and summarizing the current knowledge along these specific axes, as well as methodological aspects related to interstitium exploration.

Differential effect on mortality of the timing of initiation of renal replacement therapy according to the criteria used to diagnose acute kidney injury: an IDEAL-ICU substudy.

BACKGROUND: This substudy of the randomized IDEAL-ICU trial assessed whether the timing of renal replacement therapy (RRT) initiation has a differential effect on 90-day mortality, according to the criteria used to diagnose acute kidney injury (AKI), in patients with early-stage septic shock. METHODS: Three groups were considered according to the criterion defining AKI: creatinine elevation only (group 1), reduced urinary output only (group 2), creatinine elevation plus reduced urinary output (group 3). Primary outcome was 90-day all-cause death. Secondary endpoints were RRT-free days, RRT dependence and renal function at discharge. We assessed the interaction between RRT strategy (early vs. delayed) and group, and the association between RRT strategy and mortality in each group by logistic regression. RESULTS: Of 488 patients enrolled, 205 (42%) patients were in group 1, 174 (35%) in group 2, and 100 (20%) in group 3. The effect of RRT initiation strategy on 90-day mortality across groups showed significant heterogeneity (adjusted interaction p = 0.021). Mortality was 58% vs. 42% for early vs. late RRT initiation, respectively, in group 1 (p = 0.028); 57% vs. 67%, respectively, in group 2 (p = 0.18); and 58% vs. 55%, respectively, in group 3 (p = 0.79). There was no significant difference in secondary outcomes. CONCLUSION: The timing of RRT initiation has a differential impact on outcome according to AKI diagnostic criteria. In patients with elevated creatinine only, early RRT initiation was associated with significantly increased mortality. In patients with reduced urine output only, late RRT initiation was associated with a nonsignificant, 10% absolute increase in mortality.

Epidemiology, clinical presentation, and outcomes of 620 patients with eosinophilia in the intensive care unit.

PURPOSE: Although eosinophil-induced manifestations can be life-threatening, studies focusing on the epidemiology and clinical manifestations of eosinophilia in the intensive care unit (ICU) are lacking. METHODS: A retrospective, national, multicenter (14 centers) cohort study over 6 years of adult patients who presented with eosinophilia ≥ 1 × 109/L on two blood samples performed from the day before admission to the last day of an ICU stay. RESULTS: 620 patients (0.9% of all ICU hospitalizations) were included: 40% with early eosinophilia (within the first 24 h of ICU admission, ICU-Eo1 group) and 56% with delayed (> 24 h after ICU admission, ICU-Eo2 group) eosinophilia. In ICU-Eo1, eosinophilia was mostly due to respiratory (14.9%) and hematological (25.8%) conditions, frequently symptomatic (58.1%, mainly respiratory and cardiovascular manifestations) requiring systemic corticosteroids in 32.2% of cases. In ICU-Eo2, eosinophil-related organ involvement was rare (25%), and eosinophilia was mostly drug-induced (46.8%). Survival rates at day 60 (D60) after ICU admission were 21.4% and 17.2% (p = 0.219) in ICU-Eo1 and ICU-Eo2 patients, respectively. For ICU-Eo1 patients, in multivariate analysis, risk factors for death at D60 were current immunosuppressant therapy at ICU admission, eosinophilia of onco-hematological origin and the use of vasopressors at ICU admission, whereas older age and the use of vasopressors or mechanical ventilation at the onset of eosinophilia were associated with a poorer prognosis for ICU-Eo2 patients. CONCLUSION: Eosinophilia ≥ 1 × 109/L is not uncommon in the ICU. According to the timing of eosinophilia, two subsets of patients requiring different etiological workups and management can be distinguished.

Systematic review of locking solutions for non-tunneled hemodialysis catheters.

BACKGROUND: We conducted a systematic review of studies investigating lock solutions for use in non-tunneled hemodialysis catheters. METHODS: We searched PubMed and Cochrane databases from inception to June 11, 2021. Study inclusion criteria were: randomized trial or observational study, adults (>18 years), with acute kidney injury (AKI); and temporary non-tunneled catheters. We recorded bleeding events, catheter dysfunction and complications. RESULTS: Of 649 studies identified, 6 were included (4 randomized, 1 non-randomized trial, 1 retrospective cohort study; sample sizes 78-1496 patients). Citrate was compared to heparin in 4 studies, to saline in 1, and ethanol versus saline in 1. Event-free survival of non-tunneled catheters did not differ between groups. Catheter-related infections and adverse events were less frequent with citrate locks, but reached statistical significance in only two studies. CONCLUSION: Existing data are too heterogeneous to enable recommending one type of catheter lock over any other for non-tunneled hemodialysis catheters.

Tetanus-induced rhythmic seizures mimicking the clinical and electroencephalographic presentation of status epilepticus.

We describe the case of a woman in her 60s admitted to the intensive care unit after a first generalised tonic-clonic seizure in the context of alcohol withdrawal. She was placed under invasive mechanical ventilation due to persistence of coma despite antiepileptic treatment. Despite continuous sedation with propofol, the frequency and intensity of seizure increased. Seizures were very similar to epileptic tonic-clonic seizures and were recorded with video and electroencephalogram (EEG). A diagnosis of tetanus was considered after a scalp wound was discovered. The patient's husband revealed that a trismus had appeared a few days before hospital admission after a head trauma. EEG showed a pattern of diffuse spikes, which disappeared after a cisatracurium bolus. The diagnosis of tetanus was later confirmed by cultures from wound samples. Therefore, severe tetanus can mimic both the clinical and EEG features of status epilepticus and could be added to the differential diagnosis of epilepsy.

Prevalence, characteristics and outcome of cardiac manifestations in critically-ill antiphospholipid syndrome patients.

AIMS: Antiphospholipid syndrome (APS) is a rare autoimmune disease defined by thrombotic events occurring in patients with persistent antiphospholipid antibodies. Cardiac manifestations in critically-ill APS patients are poorly investigated. We conducted a study to assess the prevalence, the characteristics and the prognosis of cardiac manifestations in thrombotic APS patients admitted to intensive care unit (ICU). METHODS AND RESULTS: A French, national, multicentre, retrospective study, conducted, from January 2000 to September 2018, including all APS patients admitted to 24 participating centres' ICUs with any new thrombotic (arterial, venous or microvascular) manifestation. Cardiac manifestations were defined as any new cardiac abnormalities relying on clinical examination, cardiac biomarkers, echocardiography, cardiac magnetic resonance (CMR) and coronarography. One hundred and thirty-six patients (female 72%) were included. Mean age at ICU admission was 46 ± 15years. Cardiac manifestations were present in 71 patients (53%). In patients with cardiac involvement, median left ventricular ejection fraction (LVEF) was 40% [28-55], troponin was elevated in 93% patients, coronary angiogram (n = 19, 27%) disclosing a coronary obstruction in 21%. CMR (n = 21) was abnormal in all cases, with late gadolinium enhancement in 62% of cases. Cardiac manifestations were associated with a non-significant increase of mortality (32% vs. 19%, p = 0.08). After 1-year follow-up, median LVEF was 57% [44-60] in patients with cardiac involvement. CONCLUSION: Cardiac involvement is frequent in critically-ill thrombotic APS patients and may be associated to more severe outcome. Increased awareness on this rare cause of myocardial infarction with or without obstructive coronary artery is urgently needed.

Dexmedetomidine to reduce vasopressor resistance in refractory septic shock: Protocol for a double-blind randomized controlled pilot trial (ADRESS Pilot study).

Introduction: Refractory septic shock (RSS) is characterized by high vasopressor requirements, as a consequence of vasopressor resistance, which may be caused or enhanced by sympathetic hyperactivation. Experimental models and clinical trials show a reduction in vasopressor requirements and improved microcirculation compared to conventional sedation. Dexmedetomidine did not reduce mortality in clinical trials, but few septic shock patients were enrolled. This pilot trial aims to evaluate vasopressor re-sensitization with dexmedetomidine and assess the effect size, in order to design a larger trial. Methods: This is an investigator-initiated, multicenter, randomized, double-blind, placebo-controlled trial, comparing dexmedetomidine versus placebo in RSS patients with norepinephrine dose ≥0.5µg/kg/min. The primary outcome is blood pressure response to phenylephrine challenge, 6 hours after completion of a first challenge, after study treatment initiation. Secondary outcomes include feasibility and safety outcomes (bradycardia), mortality, vasopressor requirements, heart rate variability, plasma and urine catecholamines levels. The sample size is estimated at 32 patients to show a 20% improvement in blood pressure response to phenylephrine. Randomization (1:1) will be stratified by center, sedation type and presence of liver cirrhosis. Blood pressure and ECG will be continuously recorded for the first 24 h, enabling high-quality data collection for the primary and secondary endpoints. The study was approved by the ethics committee "Sud-Est VI" (2019-000726-22) and patients will be included after informed consent. Discussion: The present study will be the first randomized trial to specifically address the hemodynamic effects of dexmedetomidine in patients with septic shock. We implement a high-quality process for data acquisition and recording in the first 24 h, ensuring maximal quality for the evaluation of both efficacy and safety outcomes, as well as transparency of results. The results of the study will be used to elaborate a full-scale randomized controlled trial with mortality as primary outcome in RSS patients. Trial registration: Registered with ClinicalTrials.gov (NCT03953677). Registered 16 May 2019, https://clinicaltrials.gov/ct2/show/NCT03953677.

Feasibility of non-invasive respiratory drive and breathing pattern evaluation using CPAP in COVID-19 patients.

PURPOSE: Increased respiratory drive and respiratory effort are major features of acute hypoxemic respiratory failure (AHRF) and might help to predict the need for intubation. We aimed to explore the feasibility of a non-invasive respiratory drive evaluation and describe how these parameters may help to predict the need for intubation. MATERIALS AND METHODS: We conducted a prospective observational study. All consecutive patients with COVID-19-related AHRF requiring high-flow nasal cannula (HFNC) were screened for inclusion. Physiologic data (including: occlusion pressure (P0.1), tidal volume (Vt), inspiratory time (Ti), peak and mean inspiratory flow (Vt/Ti)) were collected during a short continuous positive airway pressure (CPAP) session. Measurements were repeated once, 12-24 h later. RESULTS: Measurements were completed in 31 patients after the screening of 45 patients (70%). P0.1 was high (4.4 [2.7-5.1]), but it was not significantly higher in patients who were intubated. The Vt (p = .006), Vt/Ti (p = .019), minute ventilation (p = .006), and Ti/Ttot (p = .003) were higher among intubated patients compared to non-intubated patients. Intubated patients had a significant increase in their diaphragm thickening fraction, Vt, and Vt/Ti over time. CONCLUSIONS: Non-invasive assessment of respiratory drive was feasible in patients with AHRF and showed an increased P0.1, although it was not predictive of intubation.

Family perceptions of clinical research and the informed consent process in the ICU.

PURPOSE: We investigated experiences of families who provide consent for research on behalf of a loved-one hospitalized in intensive care (ICU). METHODS: Multicentre, qualitative, descriptive study using semi-directive interviews in 3 ICUs. Eligible relatives were aged >18 years, and had provided informed consent for a clinical trial on behalf of a patient hospitalized in ICU. Interviews were conducted from 06/2018 to 06/2019 by a qualified sociologist, recorded and transcribed. RESULTS: Fifteen relatives were interviewed; average age 50.3 ±â€¯15 years. All emphasized their interest in clinical research, seeing it as a duty. Involving their loved-one in research allowed them to find meaning in the events. Participants underlined that trust in caregivers and communication are determinant. The strict regulation of research was perceived as a guarantee of safety. Participants felt they lacked the intellectual capacity and knowledge to question explanations. The greatest fear was not that they might incur a risk for the patient, but rather, that they might deprive the patient of a chance at a cure. CONCLUSION: Acceptance of research opportunities by relatives on behalf of decisionally-incapacitated patients is underpinned by trust in the physicians and the legislative framework. Communication and the quality of information provided by the caregivers are key.

Lung ultrasound score as a tool to monitor disease progression and detect ventilator-associated pneumonia during COVID-19-associated ARDS.

BACKGROUND: Lung ultrasound can accurately detect pandemic coronavirus disease (COVID-19) pulmonary lesions. A lung ultrasound score (LUS) was developed to improve reproducibility of the technique. OBJECTIVES: To evaluate the clinical value of LUS monitoring to guide COVID-19-associated acute respiratory distress syndrome (ARDS) management. METHODS: We conducted a single center, prospective observational study, including all patients admitted with COVID-19-associated ARDS between March and April 2020. A systematic daily LUS evaluation was performed. RESULTS: Thirty-three consecutive patients were included. LUS was significantly and negatively correlated to PaO2/FIO2. LUS increased significantly over time in non-survivors compared to survivors. LUS increased in 83% of ventilatory associated pneumonia (VAP) episodes, when compared to the previous LUS evaluation. LUS was not significantly higher in patients presenting post-extubation respiratory failure. CONCLUSIONS: In conclusion, our study demonstrates that LUS variations are correlated to disease severity and progression, and LUS monitoring could contribute to the early diagnosis of VAPs.

Non-readmission decisions in the intensive care unit: A qualitative study of physicians' experience in a multicentre French study.

PURPOSE: Deciding not to re-admit a patient to the intensive care unit (ICU) poses an ethical dilemma for ICU physicians. We aimed to describe and understand the attitudes and perceptions of ICU physicians regarding non-readmission of patients to the ICU. MATERIALS AND METHODS: Multicenter, qualitative study using semi-directed interviews between January and May 2019. All medical staff working full-time in the ICU of five participating centres (two academic and three general, non-academic hospitals) were invited to participate. Participants were asked to describe how they experienced non-readmission decisions in the ICU, and to expand on the manner in which the decision was made, but also on the traceability and timing of the decision. Interviews were recorded, transcribed and analyzed using textual content analysis. RESULTS: In total, 22 physicians participated. Interviews lasted on average 26±7 minutes. There were 14 men and 8 women, average age was 35±9 years, and average length of ICU experience was 7±5 years. The majority of respondents said that they regretted that the question of non-readmission was not addressed before the initial ICU admission. They acknowledged that the ICU stay did lead to more thorough contemplation of the overall goals of care. Multidisciplinary team meetings could help to anticipate the question of readmission within the patient's care pathway. Participants reported that there is a culture of collegial decision-making in the ICU, although the involvement of patients, families and other healthcare professionals in this process is not systematic. The timing and traceability of non-readmission decisions are heterogeneous. CONCLUSIONS: Non-readmission decisions are a major issue that raises ethical questions surrounding the fact that there is no discussion of the patient's goals of care in advance. Better anticipation, and better communication with the patients, families and other healthcare providers are suggested as areas that could be targeted for improvement.

The dysregulated innate immune response in severe COVID-19 pneumonia that could drive poorer outcome.

BACKGROUND: Although immune modulation is a promising therapeutic avenue in coronavirus disease 2019 (COVID-19), the most relevant targets remain to be found. COVID-19 has peculiar characteristics and outcomes, suggesting a unique immunopathogenesis. METHODS: Thirty-six immunocompetent non-COVID-19 and 27 COVID-19 patients with severe pneumonia were prospectively enrolled in a single center, most requiring intensive care. Clinical and biological characteristics (including T cell phenotype and function and plasma concentrations of 30 cytokines) and outcomes were compared. RESULTS: At similar baseline respiratory severity, COVID-19 patients required mechanical ventilation for significantly longer than non-COVID-19 patients (15 [7-22] vs. 4 (0-15) days; p = 0.0049). COVID-19 patients had lower levels of most classical inflammatory cytokines (G-CSF, CCL20, IL-1ß, IL-2, IL-6, IL-8, IL-15, TNF-α, TGF-ß), but higher plasma concentrations of CXCL10, GM-CSF and CCL5, compared to non-COVID-19 patients. COVID-19 patients displayed similar T-cell exhaustion to non-COVID-19 patients, but with a more unbalanced inflammatory/anti-inflammatory cytokine response (IL-6/IL-10 and TNF-α/IL-10 ratios). Principal component analysis identified two main patterns, with a clear distinction between non-COVID-19 and COVID-19 patients. Multivariate regression analysis confirmed that GM-CSF, CXCL10 and IL-10 levels were independently associated with the duration of mechanical ventilation. CONCLUSION: We identified a unique cytokine response, with higher plasma GM-CSF and CXCL10 in COVID-19 patients that were independently associated with the longer duration of mechanical ventilation. These cytokines could represent the dysregulated immune response in severe COVID-19, as well as promising therapeutic targets. ClinicalTrials.gov: NCT03505281.