Prior Exposure to Angiotensin II Receptor Blockers in Patients With Septic Shock to Individualize Mean Arterial Pressure Target? A Post Hoc Analysis of the Sepsis and Mean Arterial Pressure (SEPSISPAM) Trial.

OBJECTIVES: Individualizing a target mean arterial pressure is challenging during the initial resuscitation of patients with septic shock. The Sepsis and Mean Arterial Pressure (SEPSISPAM) trial suggested that targeting high mean arterial pressure might reduce the occurrence of acute kidney injury among those included patients with a past history of chronic hypertension. We investigated whether the class of antihypertensive medications used before the ICU stay in chronic hypertensive patients was associated with the severity of acute kidney injury occurring after inclusion, according to mean arterial pressure target. DESIGN: Post hoc analysis of the SEPSISPAM trial. SETTING: The primary outcome was the occurrence of severe acute kidney injury during the ICU stay defined as kidney disease improving global outcome stage 2 or higher. Secondary outcomes were mortality at day 28 and mortality at day 90. PATIENTS: All patients with chronic hypertension included in SEPSISPAM with available antihypertensive medications data in the hospitalization report were included. MEASUREMENTS AND MAIN RESULTS: We analyzed 297 patients. Severe acute kidney injury occurred in 184 patients, without difference according to pre-ICU exposure to antihypertensive medications. Patients with pre-ICU exposure to angiotensin II receptor blockers had significantly less severe acute kidney injury in the high mean arterial pressure target group (adjusted odd ratio 0.24 with 95% CI [0.09-0.66]; p = 0.006). No statistically significant association was found after adjustment for pre-ICU exposure to antihypertensive medications and survival. CONCLUSIONS: Our results suggest that patients with septic shock and chronic hypertension treated with angiotensin II receptor blocker may benefit from a high mean arterial pressure target to reduce the risk of acute kidney injury occurrence.

Enteral versus parenteral early nutrition in ventilated adults with shock: a randomised, controlled, multicentre, open-label, parallel-group study (NUTRIREA-2).

BACKGROUND: Whether the route of early feeding affects outcomes of patients with severe critical illnesses is controversial. We hypothesised that outcomes were better with early first-line enteral nutrition than with early first-line parenteral nutrition. METHODS: In this randomised, controlled, multicentre, open-label, parallel-group study (NUTRIREA-2 trial) done at 44 French intensive-care units (ICUs), adults (18 years or older) receiving invasive mechanical ventilation and vasopressor support for shock were randomly assigned (1:1) to either parenteral nutrition or enteral nutrition, both targeting normocaloric goals (20-25 kcal/kg per day), within 24 h after intubation. Randomisation was stratified by centre using permutation blocks of variable sizes. Given that route of nutrition cannot be masked, blinding of the physicians and nurses was not feasible. Patients receiving parenteral nutrition could be switched to enteral nutrition after at least 72 h in the event of shock resolution (no vasopressor support for 24 consecutive hours and arterial lactate <2 mmol/L). The primary endpoint was mortality on day 28 after randomisation in the intention-to-treat-population. This study is registered with ClinicalTrials.gov, number NCT01802099. FINDINGS: After the second interim analysis, the independent Data Safety and Monitoring Board deemed that completing patient enrolment was unlikely to significantly change the results of the trial and recommended stopping patient recruitment. Between March 22, 2013, and June 30, 2015, 2410 patients were enrolled and randomly assigned; 1202 to the enteral group and 1208 to the parenteral group. By day 28, 443 (37%) of 1202 patients in the enteral group and 422 (35%) of 1208 patients in the parenteral group had died (absolute difference estimate 2·0%; [95% CI -1·9 to 5·8]; p=0·33). Cumulative incidence of patients with ICU-acquired infections did not differ between the enteral group (173 [14%]) and the parenteral group (194 [16%]; hazard ratio [HR] 0·89 [95% CI 0·72-1·09]; p=0·25). Compared with the parenteral group, the enteral group had higher cumulative incidences of patients with vomiting (406 [34%] vs 246 [20%]; HR 1·89 [1·62-2·20]; p<0·0001), diarrhoea (432 [36%] vs 393 [33%]; 1·20 [1·05-1·37]; p=0·009), bowel ischaemia (19 [2%] vs five [<1%]; 3·84 [1·43-10·3]; p=0·007), and acute colonic pseudo-obstruction (11 [1%] vs three [<1%]; 3·7 [1·03-13·2; p=0·04). INTERPRETATION: In critically ill adults with shock, early isocaloric enteral nutrition did not reduce mortality or the risk of secondary infections but was associated with a greater risk of digestive complications compared with early isocaloric parenteral nutrition. FUNDING: La Roche-sur-Yon Departmental Hospital and French Ministry of Health.

Intra-Abdominal Hypertension Is Responsible for False Negatives to the Passive Leg Raising Test.

OBJECTIVES: To compare the passive leg raising test ability to predict fluid responsiveness in patients with and without intra-abdominal hypertension. DESIGN: Observational study. SETTING: Medical ICU. PATIENTS: Mechanically ventilated patients monitored with a PiCCO2 device (Pulsion Medical Systems, Feldkirchen, Germany) in whom fluid expansion was planned, with (intra-abdominal hypertension+) and without (intra-abdominal hypertension-) intra-abdominal hypertension, defined by an intra-abdominal pressure greater than or equal to 12 mm Hg (bladder pressure). INTERVENTIONS: We measured the changes in cardiac index during passive leg raising and after volume expansion. The passive leg raising test was defined as positive if it increased cardiac index greater than or equal to 10%. Fluid responsiveness was defined by a fluid-induced increase in cardiac index greater than or equal to 15%. MEASUREMENTS AND MAIN RESULTS: We included 60 patients, 30 without intra-abdominal hypertension (15 fluid responders and 15 fluid nonresponders) and 30 with intra-abdominal hypertension (21 fluid responders and nine fluid nonresponders). The intra-abdominal pressure at baseline was 4 ± 3 mm Hg in intra-abdominal hypertension- and 20 ± 6 mm Hg in intra-abdominal hypertension+ patients (p < 0.01). In intra-abdominal hypertension- patients with fluid responsiveness, cardiac index increased by 25% ± 19% during passive leg raising and by 35% ± 14% after volume expansion. The passive leg raising test was positive in 14 patients. The passive leg raising test was negative in all intra-abdominal hypertension- patients without fluid responsiveness. In intra-abdominal hypertension+ patients with fluid responsiveness, cardiac index increased by 10% ± 14% during passive leg raising (p = 0.01 vs intra-abdominal hypertension- patients) and by 32% ± 18% during volume expansion (p = 0.72 vs intra-abdominal hypertension- patients). Among these patients, the passive leg raising test was negative in 15 patients (false negatives) and positive in six patients (true positives). Among the nine intra-abdominal hypertension+ patients without fluid responsiveness, the passive leg raising test was negative in all but one patient. The area under the receiver operating characteristic curve of the passive leg raising test for detecting fluid responsiveness was 0.98 ± 0.02 (p < 0.001 vs 0.5) in intra-abdominal hypertension- patients and 0.60 ± 0.11 in intra-abdominal hypertension+ patients (p = 0.37 vs 0.5). CONCLUSIONS: Intra-abdominal hypertension is responsible for some false negatives to the passive leg raising test.

The effects of passive leg raising may be detected by the plethysmographic oxygen saturation signal in critically ill patients.

BACKGROUND: A passive leg raising (PLR) test is positive if the cardiac index (CI) increased by > 10%, but it requires a direct measurement of CI. On the oxygen saturation plethysmographic signal, the perfusion index (PI) is the ratio between the pulsatile and the non-pulsatile portions. We hypothesised that the changes in PI could predict a positive PLR test and thus preload responsiveness in a totally non-invasive way. METHODS: In patients with acute circulatory failure, we measured PI (Radical-7) and CI (PiCCO2) before and during a PLR test and, if decided, before and after volume expansion (500-mL saline). RESULTS: Three patients were excluded because the plethysmography signal was absent and 3 other ones because it was unstable. Eventually, 72 patients were analysed. In 34 patients with a positive PLR test (increase in CI ≥ 10%), CI and PI increased during PLR by 21 ± 10% and 54 ± 53%, respectively. In the 38 patients with a negative PLR test, PI did not significantly change during PLR. In 26 patients in whom volume expansion was performed, CI and PI increased by 28 ± 14% and 53 ± 63%, respectively. The correlation between the PI and CI changes for all interventions was significant (r = 0.64, p < 0.001). During the PLR test, if PI increased by > 9%, a positive response of CI (≥ 10%) was diagnosed with a sensitivity of 91 (76-98%) and a specificity of 79 (63-90%) (area under the receiver operating characteristics curve 0.89 (0.80-0.95), p < 0.0001). CONCLUSION: An increase in PI during PLR by 9% accurately detects a positive response of the PLR test. TRIAL REGISTRATION: ID RCB 2016-A00959-42. Registered 27 June 2016.

High versus low blood-pressure target in patients with septic shock.

BACKGROUND: The Surviving Sepsis Campaign recommends targeting a mean arterial pressure of at least 65 mm Hg during initial resuscitation of patients with septic shock. However, whether this blood-pressure target is more or less effective than a higher target is unknown. METHODS: In a multicenter, open-label trial, we randomly assigned 776 patients with septic shock to undergo resuscitation with a mean arterial pressure target of either 80 to 85 mm Hg (high-target group) or 65 to 70 mm Hg (low-target group). The primary end point was mortality at day 28. RESULTS: At 28 days, there was no significant between-group difference in mortality, with deaths reported in 142 of 388 patients in the high-target group (36.6%) and 132 of 388 patients in the low-target group (34.0%) (hazard ratio in the high-target group, 1.07; 95% confidence interval [CI], 0.84 to 1.38; P=0.57). There was also no significant difference in mortality at 90 days, with 170 deaths (43.8%) and 164 deaths (42.3%), respectively (hazard ratio, 1.04; 95% CI, 0.83 to 1.30; P=0.74). The occurrence of serious adverse events did not differ significantly between the two groups (74 events [19.1%] and 69 events [17.8%], respectively; P=0.64). However, the incidence of newly diagnosed atrial fibrillation was higher in the high-target group than in the low-target group. Among patients with chronic hypertension, those in the high-target group required less renal-replacement therapy than did those in the low-target group, but such therapy was not associated with a difference in mortality. CONCLUSIONS: Targeting a mean arterial pressure of 80 to 85 mm Hg, as compared with 65 to 70 mm Hg, in patients with septic shock undergoing resuscitation did not result in significant differences in mortality at either 28 or 90 days. (Funded by the French Ministry of Health; SEPSISPAM ClinicalTrials.gov number, NCT01149278.).

Cardiac dysfunction induced by weaning from mechanical ventilation: incidence, risk factors, and effects of fluid removal.

BACKGROUND: Weaning-induced pulmonary oedema (WiPO) is a well-recognised cause of failure of weaning from mechanical ventilation, but its incidence and risk factors have not been reliably described. We wanted to determine the incidence and risk factors in a population of critically ill patients. In addition, we wanted to describe the effects of diuretics when they are administered in this context. METHODS: We monitored 283 consecutive spontaneous breathing trials (SBT; T-piece trial) performed in 81 patients. In cases with cardiac output monitoring (n = 85, 29 patients), a passive leg raising (PLR) test was performed before SBT. Three experts established the diagnosis of WiPO based on various patient characteristics. RESULTS: SBT failed in 128 cases (45 % of all SBT). WiPO occurred in 59 % of these failing cases. Compared to patients without WiPO (n = 52), patients with at least one WiPO (n = 29) had a higher prevalence of chronic obstructive pulmonary disease (COPD) (38 % vs. 12 %, respectively; p < 0.01), previous "structural" cardiopathy (dilated and/or hypertrophic and/or hypokinetic cardiopathy and/or significant valvular disease, 9 % vs. 25 %, respectively; p < 0.01), obesity (45 % vs. 17 %, respectively; p < 0.01), and low left ventricular ejection fraction (55 % vs. 21 %, respectively; p = 0.01). At logistic regression, COPD (odds ratio (OR) 8.7, 95 % confidence interval (CI) 2.0-37.3), previous structural cardiopathy (OR 4.5, 95 % CI 1.4-14.1), and obesity (OR 3.6, 95 % CI 1.2-12.6) were independent risk factors for experiencing at least one episode of WiPO. In 16 cases with WiPO and a negative PLR at baseline, treatment including diuretics was started. In 9 of these cases, the PLR remained negative before the following SBT. A new episode of WiPO occurred in 7 of these instances, while the two other were extubated. In 7 other cases, the PLR became positive before the following SBT. WiPO did not occur anymore in 6 of these 7 patients who were extubated, while the remaining one was not. CONCLUSIONS: In our population of critically ill patients, WiPO was responsible for 59 % of weaning failures. COPD, previous "structural" cardiopathy, and, to a lesser extent, obesity were the main risk factors. When a treatment including fluid removal had changed preload-independence to preload-dependence, the following SBT was very likely to succeed.

Outcomes of patients admitted to intensive care units for acute manifestation of small-vessel vasculitis: a multicenter, retrospective study.

BACKGROUND: The outcomes of patients admitted to the intensive care unit (ICU) for acute manifestation of small-vessel vasculitis are poorly reported. The aim of the present study was to determine the mortality rate and prognostic factors of patients admitted to the ICU for acute small-vessel vasculitis. METHODS: This retrospective, multicenter study was conducted from January 2001 to December 2014 in 20 ICUs in France. Patients were identified from computerized registers of each hospital using the International Classification of Diseases, Ninth Revision (ICD-9). Inclusion criteria were (1) known or highly suspected granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, microscopic polyangiitis (respectively, ICD-9 codes M31.3, M30.1, and M31.7), or anti-glomerular basement membrane antibody disease (ICD-9 codes N08.5X-005 or M31.0+); (2) admission to the ICU for the management of an acute manifestation of vasculitis; and (3) administration of a cyclophosphamide pulse in the ICU or within 48 h before admission to the ICU. The primary endpoint was assessment of mortality rate 90 days after admission to the ICU. RESULTS: Eighty-two patients at 20 centers were included, 94% of whom had a recent (<6 months) diagnosis of small-vessel vasculitis. Forty-four patients (54%) had granulomatosis with polyangiitis. The main reasons for admission were respiratory failure (34%) and pulmonary-renal syndrome (33%). Mechanical ventilation was required in 51% of patients, catecholamines in 31%, and renal replacement therapy in 71%. Overall mortality at 90 days was 18% and the mortality in ICU was 16 %. The main causes of death in the ICU were disease flare in 69% and infection in 31%. In univariable analysis, relevant factors associated with death in nonsurvivors compared with survivors were Simplified Acute Physiology Score II (median [interquartile range] 51 [38-82] vs. 36 [27-42], p = 0.005), age (67 years [62-74] vs. 58 years [40-68], p < 0.003), Sequential Organ Failure Assessment score on the day of cyclophosphamide administration (11 [6-12] vs. 6 [3-7], p = 0.0004), and delayed administration of cyclophosphamide (5 days [3-14] vs. 2 days [1-5], p = 0.0053). CONCLUSIONS: Patients admitted to the ICU for management of acute small-vessel vasculitis benefit from early, aggressive intensive care treatment, associated with an 18% death rate at 90 days.

Rituximab in anti-GBM disease: A retrospective study of 8 patients.

OBJECTIVES: Anti-glomerular basement membrane (GBM) disease is a rare autoantibody-mediated disorder presenting as rapidly progressive glomerulonephritis, and often with pulmonary hemorrhage. Antibody removal with plasmapheresis and immunosuppressive drugs are the cornerstones of the treatment. Data regarding the use of specific B-cell depleting therapy such as rituximab are lacking. METHODS: We conducted a retrospective observational study of 8 patients with severe and/or refractory GBM disease that received rituximab therapy. RESULTS: Eight patients (2 men, 6 women) with a mean age of 26 ± 13.1 years old were included. Seven had severe renal involvement [median creatinin level was 282 µmol/l, range (65-423)] requiring high immunosuppressive or plasmapheresis dependent, and two had relapse of pulmonary hemorrhage including one with renal failure. Patients received an initial immunosuppressive treatment including steroid and cyclosphosphamide (n = 8) and plasmapheresis (n = 5). Except one late relapse, rituximab therapy was started within two months after diagnosis. All patients except one received 4 weekly dose of rituximab (375 mg(2)). Anti-GBM antibodies were still present in 6/8 patients, at rituximab initiation. Complete remission was observed in 7 out of 8 patients, mostly 3 months after rituximab therapy. After a mean follow-up of 25.6 months (range 4-93), patient and renal survival were 100% and 75% respectively, but rituximab use did not improve GFR. Anti-GBM antibodies remained negative for all patients during follow-up. Only one patient developed a severe bacterial infection but no opportunistic or viral infections were reported. CONCLUSION: Rituximab may represent an additional and/or alternative therapy in the induction treatment of anti-GBM disease.

Rifampin use in acute community-acquired meningitis in intensive care units: the French retrospective cohort ACAM-ICU study.

INTRODUCTION: Bacterial meningitis among critically ill adult patients remains associated with both high mortality and frequent, persistent disability. Vancomycin was added to treatment with a third-generation cephalosporin as recommended by French national guidelines. Because animal model studies had suggested interest in the use of rifampin for treatment of bacterial meningitis, and after the introduction of early corticosteroid therapy (in 2002), there was a trend toward increasing rifampin use for intensive care unit (ICU) patients. The aim of this article is to report on this practice. METHODS: Five ICUs participated in the study. Baseline characteristics and treatment data were retrospectively collected from charts of patients admitted with a diagnosis of acute bacterial meningitis during a 5-year period (2004-2008). The ICU mortality was the main outcome measure; Glasgow Outcome Scale and 3-month mortality were also assessed. RESULTS: One hundred fifty-seven patients were included. Streptococcus pneumoniae and Neisseria meningitidis were the most prevalent causative microorganisms. The ICU mortality rate was 15%. High doses of a cephalosporin were the most prevalent initial antimicrobial treatment. The delay between admission and administration of the first antibiotic dose was correlated with ICU mortality. Rifampin was used with a cephalosporin for 32 patients (ranging from 8% of the cohort for 2004 to 30% in 2008). Administration of rifampin within the first 24 h of hospitalization could be associated with a lower ICU survival. Statistical association between such an early rifampin treatment and ICU mortality reached significance only for patients with pneumococcal meningitis (p=0.031) in univariate analysis, but not in the logistic model. CONCLUSIONS: We report on the role of rifampin use for patients with community-acquired meningitis, and the results of this study suggest that this practice may be associated with lower mortality in the ICU. Nevertheless, the only independent predictors of ICU mortality were organ failure and pneumococcal infection. Further studies are required to confirm these results and to explain how rifampin use would reduce mortality.

Extravascular lung water, B-type natriuretic peptide, and blood volume contraction enable diagnosis of weaning-induced pulmonary edema.

OBJECTIVE: We tested whether the changes in extravascular lung water indexed for ideal body weight could detect weaning-induced pulmonary edema. We also studied the diagnostic value of blood volume contraction indices and B-type natriuretic peptide variations. DESIGN: Prospective study. SETTING ICU PATIENTS: Twenty-one patients who failed a first spontaneous breathing trial. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We performed a second 60-minute T-tube spontaneous breathing trial. Before and at the end of spontaneous breathing trial, we recorded pulmonary artery occlusion pressure, the extravascular lung water indexed for ideal body weight, plasma B-type natriuretic peptide level, hemoglobin, and plasma protein concentrations. Weaning-induced pulmonary edema was defined by the association of signs of clinical intolerance and a pulmonary artery occlusion pressure greater than or equal to 18 mm Hg at the end of spontaneous breathing trial. Because some patients performed several spontaneous breathing trial, a primary analysis included all spontaneous breathing trial and a secondary analysis included only the first spontaneous breathing trial of each patient. In primary analysis, 36 spontaneous breathing trials were analyzed, 21 spontaneous breathing trial with weaning-induced pulmonary edema and 15 without. During spontaneous breathing trial, extravascular lung water indexed for ideal body weight increased only in cases with weaning-induced pulmonary edema (25% ± 23%). Plasma protein concentration, hemoglobin concentration, and B-type natriuretic peptide also significantly increased only in cases with weaning-induced pulmonary edema (9% ± 3%, 9% ± 4%, 21% ± 23%, respectively). The areas under the receiver operating characteristics curves to detect weaning-induced pulmonary edema were 0.89 (95% CI, 0.78-0.99) for extravascular lung water indexed for ideal body weight, 0.97 (0.93-1.01) for spontaneous breathing trial-induced changes in plasma protein concentration, 0.96 (0.90-1.01) for changes in hemoglobin concentration, and 0.76 (0.60-0.93) for changes in B-type natriuretic peptide. An increase in extravascular lung water indexed for ideal body weight greater than or equal to 14% diagnosed weaning-induced pulmonary edema with a sensitivity of 67% (95% CI, 43-85%) and a specificity of 100% (95% CI, 78-100%). The secondary analysis confirmed these results. CONCLUSIONS: Spontaneous breathing trial-induced increases in extravascular lung water indexed for ideal body weight, plasma protein concentrations, hemoglobin concentration, and B-type natriuretic peptide are reliable alternatives to the pulmonary artery catheter for diagnosing weaning-induced pulmonary edema.

Transpulmonary thermodilution enables to detect small short-term changes in extravascular lung water induced by a bronchoalveolar lavage.

OBJECTIVE: To take the opportunity of a bronchoalveolar lavage to challenge the transpulmonary thermodilution for detecting the time course of changes in extravascular lung water. DESIGN: Observational study. SETTING: Medical ICU. PATIENTS: Mechanically ventilated patients in whom a bronchoalveolar lavage by bronchoscopy was performed. INTERVENTION: Transpulmonary thermodilution before and after bronchoalveolar lavage. MEASUREMENTS AND MAIN RESULTS: Before and at different times after bronchoalveolar lavage, transpulmonary thermodilution was performed to record the value of indexed extravascular lung water. For each measurement, the values of three thermodilution measurements were averaged at the following steps: before bronchoalveolar lavage, after bronchoalveolar lavage, and 1 hour, 2 hours, 4 hours, and 6 hours after bronchoalveolar lavage. The amount of saline infusion left in the lungs after bronchoalveolar lavage was also recorded. Twenty-five patients with suspicion of pneumonia were included. Twenty-eight bronchoalveolar lavages were finally analyzed. On average, 200 mL (180-200 mL) of saline were injected and 130 mL (100-160 mL) were left in the lungs. Between before and immediately after bronchoalveolar lavage, indexed extravascular lung water significantly increased from 12 ± 4 to 15 ± 5 mL/kg, respectively, representing a 169 ± 166 mL increase in nonindexed extravascular lung water. After bronchoalveolar lavage, the value of indexed extravascular lung water was significantly different from the baseline value until 2 hours after bronchoalveolar lavage and became similar to the baseline value thereafter. CONCLUSIONS: Transpulmonary thermodilution enabled to detect small short-term changes of indexed extravascular lung water secondary to bronchoalveolar lavage.

Beneficial hemodynamic effects of prone positioning in patients with acute respiratory distress syndrome.

RATIONALE: The effects of prone positioning during acute respiratory distress syndrome on all the components of cardiac function have not been investigated under protective ventilation and maximal alveolar recruitment. OBJECTIVES: To investigate the hemodynamic effects of prone positioning. METHODS: We included 18 patients with acute respiratory distress syndrome ventilated with protective ventilation and an end-expiratory positive pressure titrated to a plateau pressure of 28-30 cm H2O. Before and within 20 minutes of starting prone positioning, hemodynamic, respiratory, intraabdominal pressure, and echocardiographic data were collected. Before prone positioning, preload reserve was assessed by a passive leg raising test. MEASUREMENTS AND MAIN RESULTS: In all patients, prone positioning increased the ratio of arterial oxygen partial pressure over inspired oxygen fraction, the intraabdominal pressure, and the right and left cardiac preload. The pulmonary vascular resistance decreased along with the ratio of the right/left ventricular end-diastolic areas suggesting a decrease of the right ventricular afterload. In the nine patients with preload reserve, prone positioning significantly increased cardiac index (3.0 [2.3-3.5] to 3.6 [3.2-4.4] L/min/m(2)). In the remaining patients, cardiac index did not change despite a significant decrease in the pulmonary vascular resistance. CONCLUSIONS: In patients with acute respiratory distress syndrome under protective ventilation and maximal alveolar recruitment, prone positioning increased the cardiac index only in patients with preload reserve, emphasizing the important role of preload in the hemodynamic effects of prone positioning.

Heart involvement: A neglected manifestation of haemophagocytic syndrome associated with high mortality.

Secondary haemophagocytic lymphohistiocytosis (sHLH) proceeds from uncontrolled and inefficient immune activation leading to hyper-inflammation and multi-organ damage. sHLH proceeds from a wide panel of infectious, auto immune and malignant conditions and bears high mortality despite treatment. Literature on sHLH does not mention heart involvement. We sought to describe occurrence of reversible heart dysfunction in the setting of HLH in order to motivate larger prospective studies assessing the causality link between both conditions. We identified 11 cases in our hospital, systematically searched the PubMed database for publications on HLH and heart involvement and reviewed 36 publications with a total of 18 cases. Amongst these 29 cases, 25 presented with myocardial dysfunction and 14 with pericardial effusion. Twenty-six patients required intensive care management, and 14 patients died. This leads us to hypothesize that heart involvement confers worse prognosis to HLH. Formal accountability of HLH in the occurrence of cardiac manifestations is difficult to establish given the numerous differential diagnoses but reversibility of myocardial dysfunction in 14 survivors and results of two necropsies supported it. These data, and the current knowledge on the pathophysiology of both HLH and heart failure lead us to suggest that such a link may exist.

Protocol for fever control using external cooling in mechanically ventilated patients with septic shock: SEPSISCOOL II randomised controlled trial.

INTRODUCTION: Fever treatment is commonly applied in patients with sepsis but its impact on survival remains undetermined. Patients with respiratory and haemodynamic failure are at the highest risk for not tolerating the metabolic cost of fever. However, fever can help to control infection. Treating fever with paracetamol has been shown to be less effective than cooling. In the SEPSISCOOL pilot study, active fever control by external cooling improved organ failure recovery and early survival. The main objective of this confirmatory trial is to assess whether fever control at normothermia can improve the evolution of organ failure and mortality at day 60 of febrile patients with septic shock. This study will compare two strategies within the first 48 hours of septic shock: treatment of fever with cooling or no treatment of fever. METHODS AND ANALYSIS: SEPSISCOOL II is a pragmatic, investigator-initiated, adaptive, multicentre, open-label, randomised controlled, superiority trial in patients admitted to the intensive care unit with febrile septic shock. After stratification based on the acute respiratory distress syndrome status, patients will be randomised between two arms: (1) cooling and (2) no cooling. The primary endpoint is mortality at day 60 after randomisation. The secondary endpoints include the evolution of organ failure, early mortality and tolerance. The target sample size is 820 patients. ETHICS AND DISSEMINATION: The study is funded by the French health ministry and was approved by the ethics committee CPP Nord Ouest II (Amiens, France). The results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04494074.

Extravascular lung water is an independent prognostic factor in patients with acute respiratory distress syndrome.

OBJECTIVE: Acute respiratory distress syndrome might be associated with an increase in extravascular lung water index and pulmonary vascular permeability index, which can be measured by transpulmonary thermodilution. We tested whether extravascular lung water index and pulmonary vascular permeability index are independent prognostic factors in patients with acute respiratory distress syndrome. DESIGN: Retrospective study. SETTING: Medical intensive care unit. PATIENTS: Two hundred consecutive acute respiratory distress syndrome patients (age = 57 ± 17, Simplified Acute Physiology Score II = 57 ± 20, overall day-28 mortality = 54%). MEASUREMENTS: Extravascular lung water index and pulmonary vascular permeability index were collected (PiCCO device, Pulsion Medical Systems) at each day of the acute respiratory distress syndrome episode. MAIN RESULTS: The maximum values of extravascular lung water index and pulmonary vascular permeability index recorded during the acute respiratory distress syndrome episode (maximum value of extravascular lung water index and maximum value of pulmonary vascular permeability index, respectively) were significantly higher in nonsurvivors than in survivors at day-28 (mean ± SD: 24 ± 10 mL/kg vs. 19 ± 7 mL/kg of predicted body weight, p < 0.001 [t-test] for maximum value of extravascular lung water index and median [interquartile range]: 4.4 [3.3-6.1] vs. 3.5 [2.8-4.4], p = 0.001 for maximum value of pulmonary vascular permeability index, Wilcoxon's test). In multivariate analyses, maximum value of extravascular lung water index or maximum value of pulmonary vascular permeability index, Simplified Acute Physiology Score II, maximum blood lactate, mean positive end-expiratory pressure, mean cumulative fluid balance, and the minimal ratio of arterial oxygen pressure over the inspired oxygen fraction were all independently associated with day-28 mortality. A maximum value of extravascular lung water index >21 mL/kg predicted day-28 mortality with a sensitivity of (mean [95% confidence interval]) 54% (44-63)% and a specificity of 73% (63-82)%. The mortality rate was 70% in patients with a maximum value of extravascular lung water index >21 mL/kg and 43% in the remaining patients (p = 0.0003). A maximum value of pulmonary vascular permeability index >3.8 predicted day-28 mortality with a sensitivity of (mean [95% confidence interval]) 67% (57-76)% and a specificity of 65% (54-75)%. The mortality rate was 69% in patients with a maximum value of pulmonary vascular permeability index >3.8 and 37% in the group with a maximum value of pulmonary vascular permeability index ≤ 3.8 (p < 0.0001). CONCLUSIONS: Extravascular lung water index and pulmonary vascular permeability index measured by transpulmonary thermodilution are independent risk factors of day-28 mortality in patients with acute respiratory distress syndrome.

Lactate and venoarterial carbon dioxide difference/arterial-venous oxygen difference ratio, but not central venous oxygen saturation, predict increase in oxygen consumption in fluid responders.

OBJECTIVES: During circulatory failure, the ultimate goal of treatments that increase cardiac output is to reduce tissue hypoxia. This can only occur if oxygen consumption depends on oxygen delivery. We compared the ability of central venous oxygen saturation and markers of anaerobic metabolism to predict whether a fluid-induced increase in oxygen delivery results in an increase in oxygen consumption. DESIGN: Prospective study. SETTING: ICU. PATIENTS: Fifty-one patients with an acute circulatory failure (78% of septic origin). MEASUREMENTS: Before and after a volume expansion (500 mL of saline), we measured cardiac index, o2- and Co2-derived variables and lactate. MAIN RESULTS: Volume expansion increased cardiac index ≥ 15% in 49% of patients ("volume-responders"). Oxygen delivery significantly increased in these 25 patients (+32% ± 16%, p < 0.0001). An increase in oxygen consumption ≥ 15% concomitantly occurred in 56% of these 25 volume-responders (+38% ± 28%). Compared with the volume-responders in whom oxygen consumption did not increase, the volume-responders in whom oxygen consumption increased ≥ 15% were characterized by a higher lactate (2.3 ± 1.1 mmol/L vs. 5.5 ± 4.0 mmol/L, respectively) and a higher ratio of the veno-arterial carbon dioxide tension difference (P(v - a)Co2) over the arteriovenous oxygen content difference (C(a - v)o2). A fluid-induced increase in oxygen consumption greater than or equal to 15% was not predicted by baseline central venous oxygen saturation but by high baseline lactate and (P(v - a)Co2/C(a - v)o2 ratio (areas under the receiving operating characteristics curves: 0.68 ± 0.11, 0.94 ± 0.05, and 0.91 ± 0.06). In volume-nonresponders, volume expansion did not significantly change cardiac index, but the oxygen delivery decreased due to a hemodilution-induced decrease in hematocrit. CONCLUSIONS: In volume-responders, unlike markers of anaerobic metabolism, central venous oxygen saturation did not allow the prediction of whether a fluid-induced increase in oxygen delivery would result in an increase in oxygen consumption. This suggests that along with indicators of volume-responsiveness, the indicators of anaerobic metabolism should be considered instead of central venous oxygen saturation for starting hemodynamic resuscitation.

Prospective evaluation of the efficacy, safety, and optimal biomarker enrichment strategy for nangibotide, a TREM-1 inhibitor, in patients with septic shock (ASTONISH): a double-blind, randomised, controlled, phase 2b trial.

BACKGROUND: Activation of the triggering receptor expressed on myeloid cells-1 (TREM-1) pathway is associated with septic shock outcomes. Data suggest that modulation of this pathway in patients with activated TREM-1 might improve survival. Soluble TREM-1 (sTREM-1), a potential mechanism-based biomarker, might facilitate enrichment of patient selection in clinical trials of nangibotide, a TREM-1 modulator. In this phase 2b trial, we aimed to confirm the hypothesis that TREM1 inhibition might improve outcomes in patients with septic shock. METHODS: This double-blind, randomised, placebo-controlled, phase 2b trial assessed the efficacy and safety of two different doses of nangibotide compared with placebo, and aimed to identify the optimum treatment population, in patients across 42 hospitals with medical, surgical, or mixed intensive care units (ICUs) in seven countries. Non-COVID-19 patients (18-85 years) meeting the standard definition of septic shock, with documented or suspected infection (lung, abdominal, or urinary [in patients ≥65 years]), were eligible within 24 h of vasopressor initiation for the treatment of septic shock. Patients were randomly assigned in a 1:1:1 ratio to intravenous nangibotide 0·3 mg/kg per h (low-dose group), nangibotide 1·0 mg/kg per h (high-dose group), or matched placebo, using a computer-generated block randomisation scheme (block size 3). Patients and investigators were masked to treatment allocation. Patients were grouped according to sTREM-1 concentrations at baseline (established from sepsis observational studies and from phase 2a change to data) into high sTREM-1 (≥ 400 pg/mL). The primary outcome was the mean difference in total Sequential Organ Failure Assessment (SOFA) score from baseline to day 5 in the low-dose and high-dose groups compared with placebo, measured in the predefined high sTREM-1 (≥ 400 pg/mL) population and in the overall modified intention-to-treat population. Secondary endpoints included all-cause 28-day mortality, safety, pharmacokinetics, and evaluation of the relationship between TREM-1 activation and treatment response. This study is registered with EudraCT, 2018-004827-36, and Clinicaltrials.gov, NCT04055909. FINDINGS: Between Nov 14, 2019, and April 11, 2022, of 402 patients screened, 355 were included in the main analysis (116 in the placebo group, 118 in the low-dose group, and 121 in the high-dose group). In the preliminary high sTREM-1 population (total 253 [71%] of 355; placebo 75 [65%] of 116; low-dose 90 [76%] of 118; high-dose 88 [73%] of 121), the mean difference in SOFA score from baseline to day 5 was 0·21 (95% CI -1·45 to 1·87, p=0·80) in the low-dose group and 1·39 (-0·28 to 3·06, p=0·104) in the high-dose group versus placebo. In the overall population, the difference in SOFA score from baseline to day 5 between the placebo group and low-dose group was 0·20 (-1·09 to 1·50; p=0·76),and between the placebo group and the high-dose group was 1·06 (-0·23 to 2·35, p=0·108). In the predefined high sTREM-1 cutoff population, 23 (31%) patients in the placebo group, 35 (39%) in the low-dose group, and 25 (28%) in the high-dose group had died by day 28. In the overall population, 29 (25%) patients in the placebo, 38 (32%) in the low-dose, and 30 (25%) in the high-dose group had died by day 28. The number of treatment-emergent adverse events (111 [96%] patients in the placebo group, 113 [96%] in the low-dose group, and 115 [95%] in the high-dose group) and serious treatment-emergent adverse events (28 [24%], 26 [22%], and 31 [26%]) was similar between all three groups. High-dose nangibotide led to a clinically relevant improvement in SOFA score (of two points or more) from baseline to day 5 over placebo in those with higher cutoff concentrations (≥532 pg/mL) of sTREM-1 at baseline. Low dose nangibotide displayed a similar pattern with lower magnitude of effect across all cutoff values. INTERPRETATION: This trial did not achieve the primary outcome of improvement in SOFA score at the predefined sTREM-1 value. Future studies are needed to confirm the benefit of nangibotide at higher concentrations of TREM-1 activation. FUNDING: Inotrem.

Clinical Added Value of SARS-CoV-2 Antigen Detection in Blood Samples.

This study evaluated the performances of immunoassays (LFIA and ELISA) designed for SARS-CoV-2 Antigen (Ag)-detection in nasopharyngeal (NP) and serum samples in comparison to RT-PCR. NP samples from patients with respiratory symptoms (183 RT-PCR-positive and 74 RT-PCR-negative samples) were collected from March to April and November to December 2020. Seroconversion and antigen dynamics were assessed by symptom onset and day of RT-PCR diagnosis. Serum samples from 87 COVID-19 patients were used to investigate the added value of Ag quantification, at diagnosis and during follow-up. The sensitivity of COVID-VIRO-LFIA on samples with Ct ≤ 33, considered as the contagious threshold, was 86% on NPs (CI 95%: 79-90.5) and 76% on serum samples (CI 95%: 59.4-88), with a specificity of 100%. Serum N-Ag was detected during active infection as early as day two from symptom onset, with a diagnostic sensitivity of 81.5%. Within one week of symptom onset, diagnostic sensitivity and specificity reached 90.9% (95% CI, 85.1%-94.6%) and 98.3% (95% CI, 91.1%-99.9%), respectively. Serum N-Ag concentration closely correlated with disease severity. Longitudinal analysis revealed the simultaneous increase of antibodies and decrease of N-Ag. Sensitivities of COVID-VIRO-LFIA and COV-QUANTO-ELISA tests on NP and serum samples were close to 80%. They are suitable COVID-19-laboratory diagnostic tests, particularly when blood samples are available, thus reducing the requirement for NP sampling, and subsequent PCR analysis. ELISA titers may help to identify patients at risk of poor outcomes.

Healthcare trajectory of critically ill patients with necrotizing soft tissue infections: a multicenter retrospective cohort study using the clinical data warehouse of Greater Paris University Hospitals.

BACKGROUND: Necrotizing skin and soft tissue infections (NSTIs) are rare but serious and rapidly progressive infections characterized by necrosis of subcutaneous tissue, fascia and even muscle. The care pathway of patients with NSTIs is poorly understood. A better characterization of the care trajectory of these patients and a better identification of patients at risk of a complicated evolution, requiring prolonged hospitalization, multiple surgical re-interventions, or readmission to the intensive care unit (ICU), is an essential prerequisite to improve their care. The main objective of this study is to obtain large-scale data on the care pathway of these patients. We performed a retrospective multicenter observational cohort study in 13 Great Paris area hospitals, including patients hospitalized between January 1, 2015 and December 31, 2019 in the ICU for surgically confirmed NSTIs. RESULTS: 170 patients were included. The median duration of stay in ICU and hospital was 8 (3-17) and 37 (14-71) days, respectively. The median time from admission to first surgical debridement was 1 (0-2) day but 69.9% of patients were re-operated with a median of 1 (0-3) additional debridement. Inter-hospital transfer was necessary in 52.4% of patients. 80.2% of patients developed organ failures during the course of ICU stay with 51.8% of patients requiring invasive mechanical ventilation, 77.2% needing vasopressor support and 27.7% renal replacement therapy. In-ICU and in-hospital mortality rates were 21.8% and 28.8%, respectively. There was no significant difference between patients with abdomino-perineal NSTIs (n = 33) and others (n = 137) in terms of in-hospital or ICU mortality. Yet, immunocompromised patients (n = 43) showed significantly higher ICU and in-hospital mortality rates than non-immunocompromised patients (n = 127) (37.2% vs. 16.5%, p = 0.009, and 53.5% vs. 20.5%, p < 0.001). Factors associated with a complicated course were the presence of a polymicrobial infection (adjusted odds ratio [aOR = 3.18 (1.37-7.35); p = 0.007], of a bacteremia [aOR = 3.29 (1.14-9.52); p = 0.028] and a higher SAPS II score [aOR = 1.05 (1.02-1.07); p < 0.0001]. 62.3% of patients were re-hospitalized within 6 months. CONCLUSION: In this retrospective multicenter study, we showed that patients with NSTI required complex management and are major consumers of care. Two-thirds of them underwent a complicated hospital course, associated with a higher SAPS II score, a polymicrobial NSTI and a bacteremia.