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Abstract Background Severe hypothyroidism (SH) is a rare but life-threatening endocrine emergency. Only a few data are available on its management and outcomes of the most severe forms requiring ICU admission. We aimed to describe the clinical manifestations, management, and in-ICU and 6-month survival rates of these patients. Methods We conducted a retrospective, multicenter study over 18 years in 32 French ICUs. The local medical records of patients from each participating ICU were screened using the International Classification of Disease 10th revision. Inclusion criteria were the presence of biological hypothyroidism associated with at least one cardinal sign among alteration of consciousness, hypothermia and circulatory failure, and at least one SH-related organ failure. Results Eighty-two patients were included in the study. Thyroiditis and thyroidectomy represented the main SH etiologies (29% and 19%, respectively), while hypothyroidism was unknown in 44 patients (54%) before ICU admission. The most frequent SH triggers were levothyroxine discontinuation (28%), sepsis (15%), and amiodarone-related hypothyroidism (11%). Clinical presentations included hypothermia (66%), hemodynamic failure (57%), and coma (52%). In-ICU and 6-month mortality rates were 26% and 39%, respectively. Multivariable analyses retained age > 70 years [odds ratio OR 6.01 (1.75–24.1)] Sequential Organ-Failure Assessment score cardiovascular component ≥ 2 [OR 11.1 (2.47–84.2)] and ventilation component ≥ 2 [OR 4.52 (1.27–18.6)] as being independently associated with in-ICU mortality. Conclusions SH is a rare life-threatening emergency with various clinical presentations. Hemodynamic and respiratory failures are strongly associated with worse outcomes. The very high mortality prompts early diagnosis and rapid levothyroxine administration with close cardiac and hemodynamic monitoring.

Abstract Background Sepsis prognosis correlates with antibiotic adequacy at the early phase. This adequacy is dependent on antibacterial spectrum, bacterial resistance profile and antibiotic dosage. Optimal efficacy of beta-lactams mandates concentrations above the minimal inhibitory concentration (MIC) of the targeted bacteria for the longest time possible over the day. Septic acute kidney injury (AKI) is the most common AKI syndrome in ICU and often mandates renal replacement therapy (RRT) initiation. Both severe AKI and RRT may increase outside target antibiotic concentrations and ultimately alter patient’s prognosis. Patients and methods This is a secondary analysis of a randomized controlled trial that compared an early RRT initiation strategy with a delayed one in 620 critically ill patients undergoing severe AKI (defined by KDIGO 3). We compared beta-lactam trough concentrations between the two RRT initiation strategies. The primary outcome was the proportion of patients with sufficient trough plasma concentration of beta-lactams defined by trough concentration above 4 times the MIC. We hypothesized that early initiation of RRT could be associated with an insufficient antibiotic plasma trough concentration compared to patients allocated to the delayed strategy. Results One hundred and twelve patients were included: 53 in the early group and 59 in the delayed group. Eighty-three patients (74%) had septic shock on inclusion. Trough beta-lactam plasma concentration was above 4 times the MIC breakpoint in 80.4% (n = 90) of patients of the whole population, without differences between the early and the delayed groups (79.2% vs. 81.4%, respectively, p = 0.78). On multivariate analysis, the presence of septic shock and a higher mean arterial pressure were significantly associated with a greater probability of adequate antibiotic trough concentration [OR 3.95 (1.14;13.64), p = 0.029 and OR 1.05 (1.01;1.10), p = 0.013, respectively). Evolution of procalcitonin level and catecholamine-free days as well as mortality did not differ whether beta-lactam trough concentration was above 4 times the MIC or not. Conclusions In this secondary analysis of a randomized controlled trial, renal replacement therapy initiation strategy did not significantly influence plasma trough concentrations of beta-lactams in ICU patients with severe AKI. Presence of septic shock on inclusion was the main variable associated with a sufficient beta-lactam concentration. Trial registration: The AKIKI trial was registered on ClinicalTrials.gov (Identifier: NCT01932190) before the inclusion of the first patient.

Abstract Background The anatomic site for central venous catheter insertion influences the risk of central venous catheter-related intravascular complications. We developed and validated a predictive score of required catheter dwell time to identify critically ill patients at higher risk of intravascular complications. Methods We retrospectively conducted a cohort study from three multicenter randomized controlled trials enrolling consecutive patients requiring central venous catheterization. The primary outcome was the required catheter dwell time, defined as the period between the first catheter insertion and removal of the last catheter for absence of utility. Predictors were identified in the training cohort (3SITES trial; 2336 patients) through multivariable analyses based on the subdistribution hazard function accounting for death as a competing event. Internal validation was performed in the training cohort by 500 bootstraps to derive the CVC-IN score from robust risk factors. External validation of the CVC-IN score were performed in the testing cohort (CLEAN, and DRESSING2; 2371 patients). Results The analysis was restricted to patients requiring mechanical ventilation to comply with model assumptions. Immunosuppression (2 points), high creatinine > 100 micromol/L (2 points), use of vasopressor (1 point), obesity (1 point) and older age (40–59, 1 point; ≥ 60, 2 points) were independently associated with the required catheter dwell time. At day 28, area under the ROC curve for the CVC-IN score was 0.69, 95% confidence interval (CI) [0.66–0.72] in the training cohort and 0.64, 95% CI [0.61–0.66] in the testing cohort. Patients with a CVC-IN score ≥ 4 in the overall cohort had a median required catheter dwell time of 24 days (versus 11 days for CVC-IN score 7 days required catheter dwell time in the testing cohort. Conclusion The CVC-IN score, which can be used for the first catheter, had a modest ability to discriminate required catheter dwell time. Nevertheless, preference of the subclavian site may contribute to limit the risk of intravascular complications, in particular among ventilated patients with high CVC-IN score. Trials Registration NCT01479153, NCT01629550, NCT01189682

Abstract Background In patients with septic shock, the impact of the mean arterial pressure (MAP) target on the course of mottling remains uncertain. In this post hoc analysis of the SEPSISPAM trial, we investigated whether a low-MAP (65 to 70 mmHg) or a high-MAP target (80 to 85 mmHg) would affect the course of mottling and arterial lactate in patients with septic shock. Methods The presence of mottling was assessed every 2 h from 2 h after inclusion to catecholamine weaning. We compared mottling and lactate time course between the two MAP target groups. We evaluated the patient’s outcome according to the presence or absence of mottling. Results We included 747 patients, 374 were assigned to the low-MAP group and 373 to the high-MAP group. There was no difference in mottling and lactate evolution during the first 24 h between the two MAP groups. After adjustment for MAP and confounding factors, the presence of mottling ≥ 6 h during the first 24 h was associated with a significantly higher risk of death at day 28 and 90. Patients without mottling or with mottling

Abstract Background Valproic acid (VPA) poisoning is responsible for life-threatening neurological and metabolic impairments. Despite only low-level evidence of effectiveness, L-carnitine has been used for years to prevent or reverse VPA-related toxicity. We aimed to evaluate the effects of L-carnitine used to treat acute VPA poisoning on the time-course of plasma VPA concentrations and VPA-related toxicity. We designed a single-center cohort study including all VPA-poisoned patients admitted to the intensive care unit. We studied VPA toxicokinetics using a nonlinear mixed-effects model-based population approach and modeled individual plasma VPA/blood lactate concentration relationships. Then, we evaluated L-carnitine-attributed effects by comparing VPA elimination half-lives and time-courses of blood lactate levels and organ dysfunction [assessed by the Sequential Organ Failure Assessment (SOFA) score] between matched L-carnitine-treated and non-treated patients using a multivariate analysis including a propensity score. Results Sixty-nine VPA-poisoned patients (40F/29 M; age, 41 years [32–47]) (median [25th–75th percentiles]; SOFA score, 4 [1–6]) were included. The presumed VPA ingested dose was 15 g [10–32]. Plasma VPA concentration on admission was 231 mg/L [147–415]. The most common manifestations were coma (70%), hyperlactatemia (3.9 mmol/L [2.7–4.9]) and hyperammonemia (127 mmol/L [92–159]). VPA toxicokinetics well fitted a one-compartment linear model with a mean elimination half-life of 22.9 h (coefficient of variation, 28.1%). Plasma VPA (C)/blood lactate concentration (E) relationships were well described by an exponential growth equation [ $$E={E}_{0}\times {e}^{k\cdot C}$$ E = E 0 × e k · C ; with baseline E 0 = 1.3 mmol/L (43.9%) and rate constant of the effect, k = 0.003 L/mg (59.5%)]. Based on a multivariate analysis, peak blood lactate concentration was the only factor independently associated with L-carnitine administration (odds ratio, 1.9, 95% confidence interval, 1.2–2.8; P = 0.004). We found no significant contribution of L-carnitine to enhancing VPA elimination, accelerating blood lactate level normalization and/or preventing organ dysfunction. Conclusions VPA poisoning results in severe toxicity. While L-carnitine does not contribute to enhancing VPA clearance, its impact on accelerating blood lactate level normalization and/or preventing organ dysfunction remains uncertain. Investigating VPA toxicokinetics and concentration/effect relationships may help understanding how to improve VPA-poisoned patient management.

Abstract The 2018 Paris Intensive Care symposium entitled “Update in Neurocritical Care” was organized in Paris, June 21–22, 2018, under the auspices of the French Intensive Care Society. This 2-day post-graduate educational symposium comprised several chapters, aiming first to provide all-board intensivists with current standards for the clinical assessment of altered consciousness states (including coma and delirium) and peripheral nervous system in critically ill patients, monitoring of brain function (specifically, electro-encephalography) and best practices for sedation—analgesia—delirium management. An update on the treatment of specific severe brain pathologies—including ischaemic/haemorrhagic stroke, cerebral venous thrombosis, hypoxic-ischaemic brain injury, immune-mediated and infectious encephalitis and refractory status epilepticus—was also provided. Finally, we discuss how to approach some difficult decisions, namely the role of decompressive craniectomy and prognostication models in patients with head injury. For each chapter, the scope of the present review was to provide important issues and key messages, provide most recent and relevant literature in the field, and briefly describe new developments in the field.

Abstract Background Little is known about the causes, clinical course and long-term outcome of comatose patients with prolonged hypoglycemic encephalopathy. Methods In a multicenter retrospective study conducted in patients hospitalized from July 1, 2004, to July 1, 2014, we investigated functional long-term prognosis and identified prognosis factors of patients admitted in an intensive care unit (ICU) with prolonged neurological manifestations related to hypoglycemia. Eligible patients were adults admitted to the ICU with a Glasgow Coma Score 3 improved enough to be in the good outcome group 1 year later. Twenty-two (45%) patients underwent therapeutic limitation, mainly related to no expected hope for improvement. On multivariate analysis, only low mRS prior to ICU admission (OR 2.6; 95% CI 1.1–6.3; P = 0.03) and normal brain imaging (OR 7.1; 95% CI 1.1–44; P = 0.03) were significantly predictive of a good outcome. All patients (n = 15) who remained hypoglycemic >480 min had a poor outcome. Conclusion Poor outcome was observed in about 60% of this population of hypoglycemic encephalopathy. However, some patients can recover satisfactorily over time.

Abstract Background The influence of socioeconomic deprivation on health inequalities is established, but its effect on critically ill patients remains unclear, due to inconsistent definitions in previous studies. Methods Prospective multicenter cohort study conducted from March to June 2018 in eight ICUs in the Greater Paris area. All admitted patients aged ≥ 18 years were enrolled. Socioeconomic phenotypes were identified using hierarchical clustering, based on education, health insurance, income, and housing. Association of phenotypes with 180-day mortality was assessed using Cox proportional hazards models. Results A total of 1,748 patients were included. Median age was 62.9 [47.4–74.5] years, 654 (37.4%) patients were female, and median SOFA score was 3 [1–6]. Study population was clustered in five phenotypes with increasing socioeconomic deprivation. Patients from phenotype A (n = 958/1,748, 54.8%) were without socioeconomic deprivation, patients from phenotype B (n = 273/1,748, 15.6%) had only lower education levels, phenotype C patients (n = 117/1,748, 6.7%) had a cumulative burden of 1[1–2] deprivations and all had housing deprivation, phenotype D patients had 2 [1–2] deprivations, all of them with income deprivation, and phenotype E patients (n = 93/1,748, 5.3%) included patients with 3 [2–4] deprivations and included all patients with health insurance deprivation. Patients from phenotypes D and E were younger, had fewer comorbidities, more alcohol and opiate use, and were more frequently admitted due to self-harm diagnoses. Patients from phenotype C (predominant housing deprivation), were more frequently admitted with diagnoses related to chronic respiratory diseases and received more non-invasive positive pressure ventilation. Following adjustment for age, sex, alcohol and opiate use, socioeconomic phenotypes were not associated with increased 180-day mortality: phenotype A (reference); phenotype B (hazard ratio [HR], 0.85; 95% confidence interval CI 0.65–1.12); phenotype C (HR, 0.56; 95% CI 0.34–0.93); phenotype D (HR, 1.09; 95% CI 0.78–1.51); phenotype E (HR, 1.20; 95% CI 0.73–1.96). Conclusions In a universal health care system, the most deprived socioeconomic phenotypes were not associated with increased 180-day mortality. The most disadvantaged populations exhibit distinct characteristics and medical conditions that may be addressed through targeted public health interventions.

Abstract Background Inhaled nitric oxide (iNO) has been widely used in patients with COVID-19-related acute respiratory distress syndrome (C-ARDS), though its physiological effects and outcome are debated in this setting. The objective of this cohort study was to describe the modalities of iNO use, clinical response, and outcomes in a large cohort of C-ARDS patients. Methods Multicentre, retrospective cohort study conducted in France. Results From end February to December 2020, 300 patients (22.3% female) were included, 84.5% were overweight and 69.0% had at least one comorbidity. At ICU admission, their median (IQR) age, SAPS II, and SOFA score were 66 (57–72) years, 37 (29–48), and 5 (3–8), respectively. Patients were all ventilated according to a protective ventilation strategy, and 68% were prone positioned before iNO initiation. At iNO initiation, 2%, 37%, and 61% of patients had mild, moderate, and severe ARDS, respectively. The median duration of iNO treatment was 2.8 (1.1–5.5) days with a median dosage of 10 (7–13) ppm at initiation. Responders (PaO2/FiO2 ratio improving by 20% or more) represented 45.7% of patients at 6 h from iNO initiation. The severity of ARDS was the only predictive factor associated with iNO response. Among all evaluable patients, the crude mortality was not significantly different between responders at 6 h and their counterparts. Of the 62 patients with refractory ARDS (who fulfilled extracorporeal membrane oxygenation criteria before iNO initiation), 32 (51.6%) no longer fulfilled these criteria after 6 h of iNO. The latter showed significantly lower mortality than the other half (who remained ECMO eligible), including after confounder adjustment (adjusted OR: 0.23, 95% CI 0.06, 0.89, p = 0.03). Conclusions Our study reports the benefits of iNO in improving arterial oxygenation in C-ARDS patients. This improvement seems more relevant in the most severe cases. In patients with ECMO criteria, an iNO-driven improvement in gas exchange was associated with better survival. These results must be confirmed in well-designed prospective studies.

Abstract Background The extent of the consequences of an episode of severe acute kidney injury (AKI) on long-term outcome of critically ill patients remain debated. We conducted a prospective follow-up of patients included in a large multicenter clinical trial of renal replacement therapy (RRT) initiation strategy during severe AKI (the Artificial Kidney Initiation in Kidney Injury, AKIKI) to investigate long-term survival, renal outcome and health related quality of life (HRQOL). We also assessed the influence of RRT initiation strategy on these outcomes. Results Follow-up of patients extended from 60 days to a median of 3.35 years [interquartile range (IQR), 1.89 to 4.09] after the end of initial study. Of the 619 patients included in the AKIKI trial, 316 survived after 60 days. The overall survival rate at 3 years from inclusion was 39.4% (95% CI 35.4 to 43.4). A total of 46 patients (on the 175 with available data on long-term kidney function) experienced worsening of renal function (WRF) at the time of follow-up [overall incidence of 26%, cumulative incidence at 4 years: 20.6% (CI 95% 13.0 to 28.3)]. Fifteen patients required chronic dialysis (5% of patients who survived after day 90). Among the 226 long-term survivors, 80 (35%) answered the EQ-5D questionnaire. The median index value reported was 0.67 (IQR 0.40 to 1.00) indicating a noticeable alteration of quality of life. Initiation strategy for RRT had no effect on any long-term outcome. Conclusion Severe AKI in critically ill patients was associated with a high proportion of death within the first 2 months but less so during long-term follow-up. A quarter of long-term survivors experienced a WRF and suffered from a noticeable impairment of quality of life. Renal replacement therapy initiation strategy was not associated with mortality outcome. Graphical Abstract

Abstract Background The presence of bacteraemia in pneumococcal pneumonia in critically ill patients does not appear to be a strong independent prognostic factor in the existing literature. However, there may be a specific pattern of factors associated with mortality for ICU patients with bacteraemic pneumococcal community-acquired pneumonia (CAP). We aimed to compare the factors associated with mortality, according to the presence of bacteraemia or not on admission, for patients hospitalised in intensive care for severe pneumococcal CAP. Methods This was a post hoc analysis of data from the prospective, observational, multicentre STREPTOGENE study in immunocompetent Caucasian adults admitted to intensive care in France between 2008 and 2012 for pneumococcal CAP. Patients were divided into two groups based on initial blood culture (positive vs. negative) for Streptococcus pneumoniae. The primary outcome was hospital mortality, which was compared between the two groups using odds ratios according to predefined variables to search for a prognostic interaction present in bacterial patients but not non-bacteraemic patients. Potential differences in the distribution of serotypes between the two groups were assessed. The prognostic consequences of the presence or not of initial bi-antibiotic therapy were assessed, specifically in bacteraemic patients. Results Among 614 included patients, 274 had a blood culture positive for S. pneumoniae at admission and 340 did not. The baseline difference between the groups was more frequent leukopaenia (26% vs. 14%, p = 0.0002) and less frequent pre-hospital antibiotic therapy (10% vs. 16.3%, p = 0.024) for the bacteraemic patients. Hospital mortality was not significantly different between the two groups (p = 0.11). We did not observe any prognostic factors specific to the bacteraemic patient population, as the statistical comparison of the odds ratios, as an indication of the association between the predefined prognostic parameters and mortality, showed them to be similar for the two groups. Bacteraemic patients more often had invasive serotypes but less often serotypes associated with high case fatality rates (p = 0.003). The antibiotic regimens were similar for the two groups. There was no difference in mortality for patients in either group given a beta-lactam alone vs. a beta-lactam combined with a macrolide or fluoroquinolone. Conclusion Bacteraemia had no influence on the mortality of immunocompetent Caucasian adults admitted to intensive care for severe pneumococcal CAP, regardless of the profile of the associated prognostic factors.

Abstract Background Vascular access for renal replacement therapy (RRT) is routine question in the intensive care unit. Randomized trials comparing jugular and femoral sites have shown similar rate of nosocomial events and catheter dysfunction. However, recent prospective observational data on RRT catheters use are scarce. We aimed to assess the site of RRT catheter, the reasons for catheter replacement, and the complications according to site in a large population of critically ill patients with acute kidney injury. Patients and methods We performed an ancillary study of the AKIKI study, a pragmatic randomized controlled trial, in which patients with severe acute kidney injury (KDIGO 3 classification) with invasive mechanical ventilation, catecholamine infusion or both were randomly assigned to either an early or a delayed RRT initiation strategy. The present study involved all patients who underwent at least one RRT session. Number of RRT catheters, insertion sites, factors potentially associated with the choice of insertion site, duration of catheter use, reason for catheter replacement, and complications were prospectively collected. Results Among the 619 patients included in AKIKI, 462 received RRT and 459 were finally included, with 598 RRT catheters. Femoral site was chosen preferentially (n = 319, 53%), followed by jugular (n = 256, 43%) and subclavian (n = 23, 4%). In multivariate analysis, continuous RRT modality was significantly associated with femoral site (OR = 2.33 (95% CI (1.34–4.07), p = 0.003) and higher weight with jugular site [88.9 vs 83.2 kg, OR = 0.99 (95% CI 0.98–1.00), p = 0.03]. Investigator site was also significantly associated with the choice of insertion site (p = 0.03). Cumulative incidence of catheter replacement did not differ between jugular and femoral site [sHR 0.90 (95% CI 0.64—1.25), p = 0.67]. Catheter dysfunction was the main reason for replacement (n = 47), followed by suspected infection (n = 29) which was actually seldom proven (n = 4). No mechanical complication (pneumothorax or hemothorax) occurred. Conclusion Femoral site was preferentially used in this prospective study of RRT catheters in 31 French intensive care units. The choice of insertion site depended on investigating center habits, weight, RRT modality. A high incidence of catheter infection suspicion led to undue replacement.

Abstract Background Guidelines for the management of diabetic ketoacidosis (DKA) do not consider the type of underlying diabetes. We aimed to compare the occurrence of metabolic adverse events and the recovery time for DKA according to diabetes type. Methods Multicentre retrospective study conducted at five adult intermediate and intensive care units in Paris and its suburbs, France. All patients admitted for DKA between 2013 and 2014 were included. Patients were grouped and compared according to the underlying type of diabetes into three groups: type 1 diabetes, type 2 or secondary diabetes, and DKA as the first presentation of diabetes. Outcomes of interest were the rate of metabolic complications (hypoglycaemia or hypokalaemia) and the recovery time. Results Of 122 patients, 60 (49.2%) had type 1 diabetes, 28 (22.9%) had type 2 or secondary diabetes and 34 (27.9%) presented with DKA as the first presentation of diabetes (newly diagnosed diabetes). Despite having received lower insulin doses, hypoglycaemia was more frequent in patients with type 1 diabetes (76.9%) than in patients with type 2 or secondary diabetes (50.0%) and in patients with newly diagnosed diabetes (54.6%) (p = 0.026). In contrast, hypokalaemia was more frequent in the latter group (82.4%) than in patients with type 1 diabetes (57.6%) and type 2 or secondary diabetes (51.9%) (p = 0.022). The median recovery times were not significantly different between groups. Conclusions Rates of metabolic complications associated with DKA treatment differ significantly according to underlying type of diabetes. Decreasing insulin dose may limit those complications. DKA treatment recommendations should take into account the type of diabetes.

Abstract Background It is unknown whether the recommended mean arterial pressure (MAP) target of 65 mmHg during initial resuscitation of septic shock is sufficient to maintain cerebral perfusion. Thus, we tested the hypothesis that a higher MAP target in patients with septic shock may improve level of arousal. Methods We performed a post hoc exploratory analysis of the SEPSISPAM trial, which assessed the effect of a “high-target” level of MAP (80–85 mmHg) versus the recommended “low-target” MAP (65–70 mm Hg) on mortality in patients with septic shock. Among the 776 patients originally recruited in SEPSISPAM trial, we selected those who were mechanically ventilated and sedated and with available evaluation of arousal level assessed by the Richmond Agitation and Sedation Scale (RASS). Results We restricted our analysis to the period in which patients were treated with vasoactive drugs. Cumulative sedative drugs were assessed daily. A total of 532 patients were included in this study: 253 (47.6%) in the low-target group and 279 (52.4%) in the high-target group. Daily cumulative sedative drugs were similar in both groups. Compared to the low-target group, minimal and maximal RASS were significantly higher in the high-target group at day 2, 4 and 5. Furthermore, in order to consider the fact that multiple measures were done for each patient and to consider the global effect of time on these measures, we used a mixed linear regression and multivariate models: we confirmed that maximal RASS values were significantly higher in the high-target group. Conclusion In patients with septic shock who were mechanically ventilated and sedated, resuscitation with MAP target between 80 and 85 mmHg was associated with higher arousal level as compared to a MAP target between 65 and 70 mmHg.