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.

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.

Timing of Renal-Replacement Therapy in Patients with Acute Kidney Injury and Sepsis.

BACKGROUND: Acute kidney injury is the most frequent complication in patients with septic shock and is an independent risk factor for death. Although renal-replacement therapy is the standard of care for severe acute kidney injury, the ideal time for initiation remains controversial. METHODS: In a multicenter, randomized, controlled trial, we assigned patients with early-stage septic shock who had severe acute kidney injury at the failure stage of the risk, injury, failure, loss, and end-stage kidney disease (RIFLE) classification system but without life-threatening complications related to acute kidney injury to receive renal-replacement therapy either within 12 hours after documentation of failure-stage acute kidney injury (early strategy) or after a delay of 48 hours if renal recovery had not occurred (delayed strategy). The failure stage of the RIFLE classification system is characterized by a serum creatinine level 3 times the baseline level (or ≥4 mg per deciliter with a rapid increase of ≥0.5 mg per deciliter), urine output less than 0.3 ml per kilogram of body weight per hour for 24 hours or longer, or anuria for at least 12 hours. The primary outcome was death at 90 days. RESULTS: The trial was stopped early for futility after the second planned interim analysis. A total of 488 patients underwent randomization; there were no significant between-group differences in the characteristics at baseline. Among the 477 patients for whom follow-up data at 90 days were available, 58% of the patients in the early-strategy group (138 of 239 patients) and 54% in the delayed-strategy group (128 of 238 patients) had died (P=0.38). In the delayed-strategy group, 38% (93 patients) did not receive renal-replacement therapy. Criteria for emergency renal-replacement therapy were met in 17% of the patients in the delayed-strategy group (41 patients). CONCLUSIONS: Among patients with septic shock who had severe acute kidney injury, there was no significant difference in overall mortality at 90 days between patients who were assigned to an early strategy for the initiation of renal-replacement therapy and those who were assigned to a delayed strategy. (Funded by the French Ministry of Health; IDEAL-ICU ClinicalTrials.gov number, NCT01682590 .).

Hydrocortisone plus Fludrocortisone for Adults with Septic Shock.

BACKGROUND: Septic shock is characterized by dysregulation of the host response to infection, with circulatory, cellular, and metabolic abnormalities. We hypothesized that therapy with hydrocortisone plus fludrocortisone or with drotrecogin alfa (activated), which can modulate the host response, would improve the clinical outcomes of patients with septic shock. METHODS: In this multicenter, double-blind, randomized trial with a 2-by-2 factorial design, we evaluated the effect of hydrocortisone-plus-fludrocortisone therapy, drotrecogin alfa (activated), the combination of the three drugs, or their respective placebos. The primary outcome was 90-day all-cause mortality. Secondary outcomes included mortality at intensive care unit (ICU) discharge and hospital discharge and at day 28 and day 180 and the number of days alive and free of vasopressors, mechanical ventilation, or organ failure. After drotrecogin alfa (activated) was withdrawn from the market, the trial continued with a two-group parallel design. The analysis compared patients who received hydrocortisone plus fludrocortisone with those who did not (placebo group). RESULTS: Among the 1241 patients included in the trial, the 90-day mortality was 43.0% (264 of 614 patients) in the hydrocortisone-plus-fludrocortisone group and 49.1% (308 of 627 patients) in the placebo group (P=0.03). The relative risk of death in the hydrocortisone-plus-fludrocortisone group was 0.88 (95% confidence interval, 0.78 to 0.99). Mortality was significantly lower in the hydrocortisone-plus-fludrocortisone group than in the placebo group at ICU discharge (35.4% vs. 41.0%, P=0.04), hospital discharge (39.0% vs. 45.3%, P=0.02), and day 180 (46.6% vs. 52.5%, P=0.04) but not at day 28 (33.7% and 38.9%, respectively; P=0.06). The number of vasopressor-free days to day 28 was significantly higher in the hydrocortisone-plus-fludrocortisone group than in the placebo group (17 vs. 15 days, P<0.001), as was the number of organ-failure-free days (14 vs. 12 days, P=0.003). The number of ventilator-free days was similar in the two groups (11 days in the hydrocortisone-plus-fludrocortisone group and 10 in the placebo group, P=0.07). The rate of serious adverse events did not differ significantly between the two groups, but hyperglycemia was more common in hydrocortisone-plus-fludrocortisone group. CONCLUSIONS: In this trial involving patients with septic shock, 90-day all-cause mortality was lower among those who received hydrocortisone plus fludrocortisone than among those who received placebo. (Funded by Programme Hospitalier de Recherche Clinique 2007 of the French Ministry of Social Affairs and Health; APROCCHSS ClinicalTrials.gov number, NCT00625209 .).

LDL apheresis as an alternate method for plasma LPS purification in healthy volunteers and dyslipidemic and septic patients.

Lipopolysaccharide (LPS) is a key player for innate immunity activation. It is therefore a prime target for sepsis treatment, as antibiotics are not sufficient to improve outcome during septic shock. An extracorporeal removal method by polymyxin (PMX) B direct hemoperfusion (PMX-DHP) is used in Japan, but recent trials failed to show a significant lowering of circulating LPS levels after PMX-DHP therapy. PMX-DHP has a direct effect on LPS molecules. However, LPS is not present in a free form in the circulation, as it is mainly carried by lipoproteins, including LDLs. Lipoproteins are critical for physiological LPS clearance, as LPSs are carried by LDLs to the liver for elimination. We hypothesized that LDL apheresis could be an alternate method for LPS removal. First, we demonstrated in vitro that LDL apheresis microbeads are almost as efficient as PMX beads to reduce LPS concentration in LPS-spiked human plasma, whereas it is not active in PBS. We found that PMX was also adsorbing lipoproteins, although less specifically. Then, we found that endogenous LPS of patients treated by LDL apheresis for familial hypercholesterolemia is also removed during their LDL apheresis sessions, with both electrostatic-based devices and filtration devices. Finally, LPS circulating in the plasma of septic shock and severe sepsis patients with gram-negative bacteremia was also removed in vitro by LDL adsorption. Overall, these results underline the importance of lipoproteins for LPS clearance, making them a prime target to study and treat endotoxemia-related conditions.

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.

CAPS criteria fail to identify most severely-ill thrombotic antiphospholipid syndrome patients requiring intensive care unit admission.

PURPOSE: Catastrophic antiphospholipid syndrome (CAPS), the most severe manifestation of antiphospholipid syndrome (APS), is characterised by simultaneous thromboses in multiple organs. Diagnosing CAPS can be challenging but its early recognition and management is crucial for a favourable outcome. This study was undertaken to evaluate the frequencies, distributions and ability to predict mortality of "definite/probable" or "no-CAPS" categories of thrombotic APS patients requiring admission to the intensive care unit (ICU). METHODS: This French national multicentre retrospective study, conducted from January 2000 to September 2018, included all APS patients with any new thrombotic manifestation(s) admitted to 24 ICUs. RESULTS: One hundred and thirty-four patients (male/female ratio: 0.4; mean age at admission: 45.4 ±â€¯15.0 years), who experienced 152 CAPS episodes, required ICU admission. The numbers of definite, probable or no-CAPS episodes, respectively, were: 11 (7.2%), 60 (39.5%) and 81 (53.3%). No histopathological proof of microvascular thrombosis was the most frequent reason for not being classified as definite CAPS. Overall, 35/152 (23.0%) episodes were fatal, with comparable rates for definite/probable CAPS and no CAPS (23% vs. 28.8% respectively, p = 0.4). The Kaplan-Meier curve of estimated probability of survival showed no between-group survival difference (log-rank test p = 0.5). CONCLUSIONS: In this study, CAPS criteria were not associated with mortality of thrombotic APS patients requiring ICU admission. Further studies are need evaluate the adequacy of CAPS criteria for critically-ill APS patients.

Exploration of COVID-19 associated bradycardia using heart rate variability analysis in a case-control study of ARDS patients.

BACKGROUND: Bradycardia and dysautonomia observed during SARS-Cov2 infection suggests involvement of the autonomic nervous system (ANS). Limited data exists on ANS dysregulation and its association with outcomes in patients with acute respiratory distress syndrome (ARDS) related to COVID-19 (C-ARDS) or other etiologies (NC-ARDS). OBJECTIVES: We aimed to explore sympathovagal balance, assessed by heart rate variability (HRV), and its clinical prognostic value in C-ARDS compared with NC-ARDS. METHODS: A single-center, prospective case-control study was conducted. Consecutive patients meeting ARDS criteria between 2020 and 2022 were included. HRV was assessed using 1-hour electrographic tracing during a stable, daytime period. RESULTS: Twenty-four patients with C-ARDS and 19 with NC-ARDS were included. Age, sex and ARDS severity were similar between groups. The median heart rate was markedly lower in the C-ARDS group than in the NC-ARDS group (60 [53-72] versus 101 [91-112] bpm, p<.001). Most of HRV parameters were significantly increased in patients with C-ARDS. HRV correlated with heart rate only in patients with C-ARDS. A positive correlation was found between the low-to high-frequency ratio (LF/HF) and length of intensive care unit stay (r = 0.576, p<.001). CONCLUSION: This study confirmed that C-ARDS was associated with marked bradycardia and severe ANS impairment, suggesting a sympathovagal imbalance with vagal overtone. Poor outcomes appeared to be more related to sympathetic rather than parasympathetic hyperactivation.

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.

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.

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.

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.

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.

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.

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.