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Background: Critical-illness survivors may experience post-traumatic stress disorder (PTSD) and quality-of-life impairments. Resilience may protect against psychological trauma but has not been adequately studied after critical illness. We assessed resilience and its associations with PTSD and quality of life, and also identified factors associated with greater resilience., Methods: This prospective, multicentre, study in patients recruited at 41 French ICUs was done in parallel with the NUTRIREA-3 trial in patients given mechanical ventilation and vasoactive amines for shock. Three months to one year after intensive-care-unit admission, survivors completed the Connor-Davidson Resilience Scale (CD-RISC-25), Impact of Event-Revised scale for PTSD symptoms (IES-R), SF-36 quality-of-life scale, Multidimensional Scale of Perceived Social Support (MSPSS), and Brief Illness Perception Questionnaire (B-IPQ)., Results: Of the 382 included patients, 203 (53.1%) had normal or high resilience (CD-RISC-25 ≥ 68). Of these resilient patients, 26 (12.8%) had moderate to severe PTSD symptoms (IES-R ≥ 24) vs. 45 (25.4%) patients with low resilience (p = 0.002). Resilient patients had higher SF-36 scores. Factors independently associated with higher CD-RISC-25 scores were higher MSPSS score indicating stronger social support (OR, 1.027; 95%CI 1.008-1.047; p = 0.005) and lower B-IPQ scores indicating a more threatening perception of the illness (OR, 0.973; 95%CI 0.950-0.996; p = 0.02)., Conclusions: Resilient patients had a lower prevalence of PTSD symptoms and higher quality of life scores, compared to patients with low resilience. Higher scores for social support and illness perception were independently associated with greater resilience. Thus, our findings suggest that interventions to strengthen social support and improve illness perception may help to improve resilience. Such interventions should be evaluated in trials with PTSD mitigation and quality-of-life improvement as the target outcomes., (© 2024. The Author(s).)

Background: Restoring plasma arginine levels through enteral administration of L-citrulline in critically ill patients may improve outcomes. We aimed to evaluate whether enteral L-citrulline administration reduced organ dysfunction based on the Sequential Organ Failure Assessment (SOFA) score and affected selected immune parameters in mechanically ventilated medical intensive care unit (ICU) patients., Methods: A randomized, double-blind, multicenter clinical trial of enteral administration of L-citrulline versus placebo for critically ill adult patients under invasive mechanical ventilation without sepsis or septic shock was conducted in four ICUs in France between September 2016 and February 2019. Patients were randomly assigned to receive enteral L-citrulline (5 g) every 12 h for 5 days or isonitrogenous, isocaloric placebo. The primary outcome was the SOFA score on day 7. Secondary outcomes included SOFA score improvement (defined as a decrease in total SOFA score by 2 points or more between day 1 and day 7), secondary infection acquisition, ICU length of stay, plasma amino acid levels, and immune biomarkers on day 3 and day 7 (HLA-DR expression on monocytes and interleukin-6)., Results: Of 120 randomized patients (mean age, 60 ± 17 years; 44 [36.7%] women; ICU stay 10 days [IQR, 7-16]; incidence of secondary infections 25 patients (20.8%)), 60 were allocated to L-citrulline and 60 were allocated to placebo. Overall, there was no significant difference in organ dysfunction as assessed by the SOFA score on day 7 after enrollment (4 [IQR, 2-6] in the L-citrulline group vs. 4 [IQR, 2-7] in the placebo group; Mann‒Whitney U test, p = 0.9). Plasma arginine was significantly increased on day 3 in the treatment group, while immune parameters remained unaffected., Conclusion: Among mechanically ventilated ICU patients without sepsis or septic shock, enteral L-citrulline administration did not result in a significant difference in SOFA score on day 7 compared to placebo., Trial Registration: ClinicalTrials.gov Identifier NCT02864017 (date of registration: 11 August 2016)., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Response to prophylactic platelet transfusion is suspected to be inconsistent in critically ill patients questioning how to optimize transfusion practices. This study aimed to describe prophylactic platelet transfusion response, to identify factors associated with a suboptimal response, to analyse the correlation between corrected count increment and platelet count increment and to determine the association between poor platelet transfusion response and clinical outcomes., Methods: This prospective multicentre observational study recruited patients who received at least one prophylactic platelet transfusion in one of the nine participating intensive care units for a period up to 16 months. Poor platelet transfusion response was defined as a corrected count increment (CCI) that adjusts for platelet dose and body surface area, less than 7 at 18-24 h after platelet transfusion. Factors associated with poor platelet transfusion response were assessed in a mixed-effect model. Sensitivity analyses were conducted in patients with and without haematology malignancy and chemotherapy., Results: Poor platelet transfusion response occurred in 349 of the 472 (73.9%) prophylactic platelet transfusions and in 141/181 (77.9%) patients. The mixed-effect model identified haemoglobin at ICU admission (odds ratio (OR): 0.79 [95% confidence interval (CI) 0.7-0.89]) and body mass index (BMI) (OR: 0.93 [0.89-0.98]) being positively and independently associated with platelet transfusion response, while a haematological malignancy (OR 1.93 [1.09-3.43]), sepsis as primary ICU admission diagnosis (OR: 2.81 [1.57-5.03]), SOFA score (OR 1.10 [1.03; 1.17]) and maximum storage duration of platelet (OR: 1.24 [1.02-1.52]) were independently associated with a suboptimal platelet increment. Clinical outcomes did not differ between groups, nor the requirement for red blood cells. Poor platelet transfusion response was found in 93.5% of patients with haematology malignancy and chemotherapy., Conclusions: In this study of critically ill patients, of whom more than half had bone marrow failure, almost three quarters of prophylactic platelet transfusions led to suboptimal platelet increment measured 18 to 24 h following platelet transfusion. Platelet storage duration was the only factor associated with poor platelet response that may be accessible to intervention. Trial registration in October 2017: ClinicalTrials.gov: NCT03325140., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Except in a few retrospective studies mainly including patients under chemotherapy, information regarding the impact of immunosuppressive therapy on the prognosis of patients admitted to the intensive care unit (ICU) for septic shock is scarce. Accordingly, the PACIFIC study aimed to asses if immunosuppressive therapy is associated with an increased mortality in patients admitted to the ICU for septic shock., Methods: This was a retrospective epidemiological multicentre study. Eight high enroller centres in septic shock randomised controlled trials (RCTs) participated in the study. Patients in the "exposed" group were selected from the screen failure logs of seven recent RCTs and excluded because of immunosuppressive treatment. The "non-exposed" patients were those included in the placebo arm of the same RCTs. A multivariate logistic regression model was used to estimate the risk of death., Results: Among the 433 patients enrolled, 103 were included in the "exposed" group and 330 in the "non-exposed" group. Reason for immunosuppressive therapy included organ transplantation (n = 45 [44%]) or systemic disease (n = 58 [56%]). ICU mortality rate was 24% in the "exposed" group and 25% in the "non-exposed" group (p = 0.9). Neither in univariate nor in multivariate analysis immunosuppressive therapy was associated with a higher ICU mortality (OR: 0.95; [95% CI 0.56-1.58]: p =  0.86 and 1.13 [95% CI 0.61-2.05]: p =  0.69, respectively) or 3-month mortality (OR: 1.13; [95% CI 0.69-1.82]: p =  0.62 and OR: 1.36 [95% CI 0.78-2.37]: p =  0.28, respectively)., Conclusions: In this study, long-term immunosuppressive therapy excluding chemotherapy was not associated with significantly higher or lower ICU and 3-month mortality in patients admitted to the ICU for septic shock., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Vascular leakage is a major feature of acute respiratory distress syndrome (ARDS). We aimed to evaluate the efficacy of FX06, a drug under development that stabilizes interendothelial cell junctions, at reducing vascular leakage during SARS-CoV-2-induced ARDS., Methods: This multicenter, double-blinded, randomized trial included adults with COVID-19-associated ARDS who had received invasive mechanical ventilation for < 5 days and were randomized to receive either intravenous FX06 (400 mg/d, for 5 days) or its vehicle as placebo. The primary endpoint was the lowering-from day 1 to day 7-of the transpulmonary thermodilution-derived extravascular lung-water index (EVLWi)., Results: Twenty-five patients were randomized to receive FX06 and 24 the placebo. Although EVLWi was elevated at baseline (median [IQR] 15.6 mL/kg [13.5; 18.5]), its declines from day 1 to day 7 were comparable for FX06 recipients and controls (respectively, - 1.9 [- 3.3; - 0.5] vs. - 0.8 [- 5.5; - 1.1] mL/kg; estimated effect - 0.8 [- 3.1; + 2.4], p = 0.51). Cardiac indexes, pulmonary vascular permeability indexes, and fluid balances were also comparable, as were PaO 2 /FiO 2 ratios and durations of mechanical ventilation. Adverse event rates were similar for the 2 groups, although more FX06 recipients developed ventilator-associated pneumonia (16/25 (64%) vs. 6/24 (24%), p = 0.009)., Conclusions: In this unique-dosing-regimen study, FX06 did not lower SARS-CoV-2-induced pulmonary vascular leakage. Future investigations will need to evaluate its efficacy at earlier times during the disease or using other regimens. Trial registration NCT04618042. Registered 5 November 2020., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Generalised convulsive status epilepticus (GCSE) is a medical emergency. Guidelines recommend a stepwise strategy of benzodiazepines followed by a second-line anti-seizure medicine (ASM). However, GCSE is uncontrolled in 20-40% patients and is associated with protracted hospitalisation, disability, and mortality. The objective was to determine whether valproic acid (VPA) as complementary treatment to the stepwise strategy improves the outcomes of patients with de novo established GCSE., Methods: This was a multicentre, double-blind, randomised controlled trial in 244 adults admitted to intensive care units for GCSE in 16 French hospitals between 2013 and 2018. Patients received standard care of benzodiazepine and a second-line ASM (except VPA). Intervention patients received a 30 mg/kg VPA loading dose, then a 1 mg/kg/h 12 h infusion, whilst the placebo group received an identical intravenous administration of 0.9% saline as a bolus and continuous infusion. Primary outcome was proportion of patients discharged from hospital by day 15. The secondary outcomes were seizure control, adverse events, and cognition at day 90., Results: A total of 126 (52%) and 118 (48%) patients were included in the VPA and placebo groups. 224 (93%) and 227 (93%) received a first-line and a second-line ASM before VPA or placebo infusion. There was no between-group difference for patients hospital-discharged at day 15 [VPA, 77 (61%) versus placebo, 72 (61%), adjusted relative risk 1.04; 95% confidence interval (0.89-1.19); p = 0.58]. There were no between-group differences for secondary outcomes., Conclusions: VPA added to the recommended strategy for adult GCSE is well tolerated but did not increase the proportion of patients hospital-discharged by day 15., Trial Registration No: NCT01791868 (ClinicalTrials.gov registry), registered: 15 February 2012., (© 2023. The Author(s).)

Background: Ventilator-associated pneumonia (VAP) is common in patients with severe SARS-CoV-2 pneumonia. The aim of this ancillary analysis of the coVAPid multicenter observational retrospective study is to assess the relationship between adjuvant corticosteroid use and the incidence of VAP., Methods: Planned ancillary analysis of a multicenter retrospective European cohort in 36 ICUs. Adult patients receiving invasive mechanical ventilation for more than 48 h for SARS-CoV-2 pneumonia were consecutively included between February and May 2020. VAP diagnosis required strict definition with clinical, radiological and quantitative microbiological confirmation. We assessed the association of VAP with corticosteroid treatment using univariate and multivariate cause-specific Cox's proportional hazard models with adjustment on pre-specified confounders., Results: Among the 545 included patients, 191 (35%) received corticosteroids. The proportional hazard assumption for the effect of corticosteroids on the incidence of VAP could not be accepted, indicating that this effect varied during ICU stay. We found a non-significant lower risk of VAP for corticosteroid-treated patients during the first days in the ICU and an increased risk for longer ICU stay. By modeling the effect of corticosteroids with time-dependent coefficients, the association between corticosteroids and the incidence of VAP was not significant (overall effect p = 0.082), with time-dependent hazard ratios (95% confidence interval) of 0.47 (0.17-1.31) at day 2, 0.95 (0.63-1.42) at day 7, 1.48 (1.01-2.16) at day 14 and 1.94 (1.09-3.46) at day 21., Conclusions: No significant association was found between adjuvant corticosteroid treatment and the incidence of VAP, although a time-varying effect of corticosteroids was identified along the 28-day follow-up., (© 2022. The Author(s).)

Rationale: Early corticosteroid treatment is used to treat COVID-19-related acute respiratory distress syndrome (ARDS). Infection is a well-documented adverse effect of corticosteroid therapy., Objectives: To determine whether early corticosteroid therapy to treat COVID-19 ARDS was associated with ventilator-associated pneumonia (VAP)., Methods: We retrospectively included adults with COVID-19-ARDS requiring invasive mechanical ventilation (MV) for ≥ 48 h at any of 15 intensive care units in 2020. We divided the patients into two groups based on whether they did or did not receive corticosteroids within 24 h. The primary outcome was VAP incidence, with death and extubation as competing events. Secondary outcomes were day 90-mortality, MV duration, other organ dysfunctions, and VAP characteristics., Measurements and Main Results: Of 670 patients (mean age, 65 years), 369 did and 301 did not receive early corticosteroids. The cumulative VAP incidence was higher with early corticosteroids (adjusted hazard ratio [aHR] 1.29; 95% confidence interval [95% CI] 1.05-1.58; P = 0.016). Antibiotic resistance of VAP bacteria was not different between the two groups (odds ratio 0.94, 95% CI 0.58-1.53; P = 0.81). 90-day mortality was 30.9% with and 24.3% without early corticosteroids, a nonsignificant difference after adjustment on age, SOFA score, and VAP occurrence (aHR 1.15; 95% CI 0.83-1.60; P = 0.411). VAP was associated with higher 90-day mortality (aHR 1.86; 95% CI 1.33-2.61; P = 0.0003)., Conclusions: Early corticosteroid treatment was associated with VAP in patients with COVID-19-ARDS. Although VAP was associated with higher 90-day mortality, early corticosteroid treatment was not. Longitudinal randomized controlled trials of early corticosteroids in COVID-19-ARDS requiring MV are warranted., (© 2022. The Author(s).)

Background: Recent multicenter studies identified COVID-19 as a risk factor for invasive pulmonary aspergillosis (IPA). However, no large multicenter study has compared the incidence of IPA between COVID-19 and influenza patients., Objectives: To determine the incidence of putative IPA in critically ill SARS-CoV-2 patients, compared with influenza patients., Methods: This study was a planned ancillary analysis of the coVAPid multicenter retrospective European cohort. Consecutive adult patients requiring invasive mechanical ventilation for > 48 h for SARS-CoV-2 pneumonia or influenza pneumonia were included. The 28-day cumulative incidence of putative IPA, based on Blot definition, was the primary outcome. IPA incidence was estimated using the Kalbfleisch and Prentice method, considering extubation (dead or alive) within 28 days as competing event., Results: A total of 1047 patients were included (566 in the SARS-CoV-2 group and 481 in the influenza group). The incidence of putative IPA was lower in SARS-CoV-2 pneumonia group (14, 2.5%) than in influenza pneumonia group (29, 6%), adjusted cause-specific hazard ratio (cHR) 3.29 (95% CI 1.53-7.02, p = 0.0006). When putative IPA and Aspergillus respiratory tract colonization were combined, the incidence was also significantly lower in the SARS-CoV-2 group, as compared to influenza group (4.1% vs. 10.2%), adjusted cHR 3.21 (95% CI 1.88-5.46, p < 0.0001). In the whole study population, putative IPA was associated with significant increase in 28-day mortality rate, and length of ICU stay, compared with colonized patients, or those with no IPA or Aspergillus colonization., Conclusions: Overall, the incidence of putative IPA was low. Its incidence was significantly lower in patients with SARS-CoV-2 pneumonia than in those with influenza pneumonia. Clinical trial registration The study was registered at ClinicalTrials.gov, number NCT04359693 ., (© 2022. The Author(s).)

Oxygen (O 2 ) toxicity remains a concern, particularly to the lung. This is mainly related to excessive production of reactive oxygen species (ROS). Supplemental O 2 , i.e. inspiratory O 2 concentrations (F I O 2 ) > 0.21 may cause hyperoxaemia (i.e. arterial (a) PO 2  > 100 mmHg) and, subsequently, hyperoxia (increased tissue O 2 concentration), thereby enhancing ROS formation. Here, we review the pathophysiology of O 2 toxicity and the potential harms of supplemental O 2 in various ICU conditions. The current evidence base suggests that PaO 2  > 300 mmHg (40 kPa) should be avoided, but it remains uncertain whether there is an "optimal level" which may vary for given clinical conditions. Since even moderately supra-physiological PaO 2 may be associated with deleterious side effects, it seems advisable at present to titrate O 2 to maintain PaO 2 within the normal range, avoiding both hypoxaemia and excess hyperoxaemia., (© 2021. The Author(s).)

Background: Patients with SARS-CoV-2 infection are at higher risk for ventilator-associated pneumonia (VAP). No study has evaluated the relationship between VAP and mortality in this population, or compared this relationship between SARS-CoV-2 patients and other populations. The main objective of our study was to determine the relationship between VAP and mortality in SARS-CoV-2 patients., Methods: Planned ancillary analysis of a multicenter retrospective European cohort. VAP was diagnosed using clinical, radiological and quantitative microbiological criteria. Univariable and multivariable marginal Cox's regression models, with cause-specific hazard for duration of mechanical ventilation and ICU stay, were used to compare outcomes between study groups. Extubation, and ICU discharge alive were considered as events of interest, and mortality as competing event., Findings: Of 1576 included patients, 568 were SARS-CoV-2 pneumonia, 482 influenza pneumonia, and 526 no evidence of viral infection at ICU admission. VAP was associated with significantly higher risk for 28-day mortality in SARS-CoV-2 (adjusted HR 1.70 (95% CI 1.16-2.47), p = 0.006), and influenza groups (1.75 (1.03-3.02), p = 0.045), but not in the no viral infection group (1.07 (0.64-1.78), p = 0.79). VAP was associated with significantly longer duration of mechanical ventilation in the SARS-CoV-2 group, but not in the influenza or no viral infection groups. VAP was associated with significantly longer duration of ICU stay in the 3 study groups. No significant difference was found in heterogeneity of outcomes related to VAP between the 3 groups, suggesting that the impact of VAP on mortality was not different between study groups., Interpretation: VAP was associated with significantly increased 28-day mortality rate in SARS-CoV-2 patients. However, SARS-CoV-2 pneumonia, as compared to influenza pneumonia or no viral infection, did not significantly modify the relationship between VAP and 28-day mortality., Clinical Trial Registration: The study was registered at ClinicalTrials.gov, number NCT04359693.

Background: Anemia is a significant problem in patients on ICU. Its commonest cause, iron deficiency (ID), is difficult to diagnose in the context of inflammation. Hepcidin is a new marker of ID. We aimed to assess whether hepcidin levels would accurately guide treatment of ID in critically ill anemic patients after a prolonged ICU stay and affect the post-ICU outcomes., Methods: In a controlled, single-blinded, multicenter study, anemic (WHO definition) critically ill patients with an ICU stay ≥ 5 days were randomized when discharge was expected to either intervention by hepcidin treatment protocol or control. In the intervention arm, patients were treated with intravenous iron (1 g of ferric carboxymaltose) when hepcidin was < 20 μg/l and with intravenous iron and erythropoietin for 20 ≤ hepcidin < 41 μg/l. Control patients were treated according to standard care (hepcidin quantification remained blinded). Primary endpoint was the number of days spent in hospital 90 days after ICU discharge (post-ICU LOS). Secondary endpoints were day 15 anemia, day 30 fatigue, day 90 mortality and 1-year survival., Results: Of 405 randomized patients, 399 were analyzed (201 in intervention and 198 in control arm). A total of 220 patients (55%) had ID at discharge (i.e., a hepcidin < 41 μg/l). Primary endpoint was not different (medians (IQR) post-ICU LOS 33(13;90) vs. 33(11;90) days for intervention and control, respectively, median difference - 1(- 3;1) days, p = 0.78). D90 mortality was significantly lower in intervention arm (16(8%) vs 33(16.6%) deaths, absolute risk difference - 8.7 (- 15.1 to - 2.3)%, p = 0.008, OR 95% IC, 0.46, 0.22-0.94, p = 0.035), and one-year survival was improved (p = 0.04)., Conclusion: Treatment of ID diagnosed according to hepcidin levels did not reduce the post-ICU LOS, but was associated with a significant reduction in D90 mortality and with improved 1-year survival in critically ill patients about to be discharged after a prolonged stay., Trial Registration: www.clinicaltrial.gov NCT02276690 (October 28, 2014; retrospectively registered).

Background: There is wide variability between intensivists in the decisions to forgo life-sustaining treatment (DFLST). Advance directives (ADs) allow patients to communicate their end-of-life wishes to physicians. We assessed whether ADs reduced variability in DFLSTs between intensivists., Methods: We conducted a multicenter, prospective, simulation study. Eight patients expressed their wishes in ADs after being informed about DFLSTs by an intensivist-investigator. The participating intensivists answered ten questions about the DFLSTs of each patient in two scenarios, referring to patients' characteristics without ADs (round 1) and then with (round 2). DFLST score ranged from 0 (no-DFLST) to 10 (DFLST for all questions). The main outcome was variability in DFLSTs between intensivists, expressed as relative standard deviation (RSD)., Results: A total of 19,680 decisions made by 123 intensivists from 27 ICUs were analyzed. The DFLST score was higher with ADs than without (6.02 95% CI [5.85; 6.19] vs 4.92 95% CI [4.75; 5.10], p < 0.001). High inter-intensivist variability did not change with ADs (RSD: 0.56 (round 1) vs 0.46 (round 2), p = 0.84). Inter-intensivist agreement on DFLSTs was weak with ADs (intra-class correlation coefficient: 0.28). No factor associated with DFLSTs was identified. A qualitative analysis of ADs showed focus on end-of-life wills, unwanted things and fear of pain., Conclusions: ADs increased the DFLST rate but did not reduce variability between the intensivists. In the decision-making process using ADs, the intensivist's decision took priority. Further research is needed to improve the matching of the physicians' decision with the patient's wishes. Trial registration ClinicalTrials.gov Identifier: NCT03013530. Registered 6 January 2017; https://clinicaltrials.gov/ct2/show/NCT03013530 .

Hyperoxia is common practice in the acute management of circulatory shock, and observational studies report that it is present in more than 50 % of mechanically ventilated patients during the first 24 h after intensive care unit (ICU) admission. On the other hand, "oxygen toxicity" due to the increased formation of reactive oxygen species limits its use due to serious deleterious side effects. However, formation of reactive oxygen species to boost bacterial killing is one of the body's anti-microbial auto-defense mechanisms and, hence, O2 has been referred to as an antibiotic. Consequently, hyperoxia during the peri-operative period has been advocated for surgical patients in order to reduce surgical site infection. However, there is ample evidence that long-term exposure to hyperoxia impaired bacterial phagocytosis and thereby aggravated both bacterial burden and dissemination. Moreover, a recent retrospective study identified the number of days with hyperoxia, defined as a PaO2 > 120 mmHg only, as an independent risk factor of ventilator-associated pneumonia in patients needing mechanical ventilation for more than 48 h. Since so far the optimal oxygenation target is unknown for ICU patients, "conservative" O2 therapy represents the treatment of choice to avoid exposure to both hypoxemia and excess hyperoxemia.

In perioperative cardiac surgery period, supra-physiological arterial oxygen partial pressures is common practice, although there is no clear evidence of any benefit. Smit et al. have shown that a "conservative" approach did not improve hemodynamics, decrease oxidative stress or myocardial tissue damage, but was not associated with major deleterious event either. Here, we outline major oxygen friend or foes properties, which may partly explain the study results, and place the clinical trial from Smit et al. in a global context.

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.

Guidelines recommend that a mean arterial pressure (MAP) value greater than 65 mm Hg should be the initial blood pressure target in septic shock, but what evidence is there to support this statement? We searched Pubmed and Google Scholar by using the key words 'arterial pressure', 'septic shock', and 'norepinephrine' and retrieved human studies published between 1 January 2000 and 31 July 2014. We identified seven comparative studies: two randomized clinical trials and five observational studies. The results of the literature review suggest that a MAP target of 65 mm Hg is usually sufficient in patients with septic shock. However, a MAP of around 75 to 85 mm Hg may reduce the development of acute kidney injury in patients with chronic arterial hypertension. Because of the high prevalence of chronic arterial hypertension in patients who develop septic shock, this finding is of considerable importance. Future studies should assess interactions between time, fluid volumes administered, and doses of vasopressors.

Introduction: The relationships between systemic hemodynamics and renal blood flow and renal microcirculation are poorly known in sepsis. Norepinephrine (NE) infusion may add another level of complexity., Methods: Ventilated and anesthetized rats were submitted to various mean arterial pressure (MAP) steps by blood removal, in presence and absence of sepsis and/or NE. Renal blood flow (RBF) and blood velocity (Vm) in renal cortical capillaries (using Sidestream Dark Field Imaging) were measured. Data were analyzed using linear mixed models enabling us to display the effects of both the considered explanatory variables and their interactions., Results: Positive correlations were found between MAP and RBF. Sepsis had no independent impact on RBF whereas norepinephrine decreased RBF, regardless of the presence of sepsis. The relationship between MAP and RBF was weaker above a MAP of 100 mmHg as opposed to below 100 mmHg, with RBF displaying a relative "plateau" above this threshold. Sepsis and NE impacted carotid blood flow (CBF) differently compared to RBF, demonstrating organ specificity. A positive relationship was observed between MAP and Vm. Sepsis increased Vm while nNE decreased Vm irrespective of MAP. Sepsis was associated with an increase in serum creatinine determined at the end of the experiments, which was prevented by NE infusion., Conclusion: In our model, sepsis at an early phase did not impact RBF over a large range of MAP. NE elicited a renal vasoconstrictive effect. Autoregulation of RBF appeared conserved in sepsis. Conversely, sepsis was associated with "hypervelocity" of blood flow in cortical peritubular capillaries reversed by NE infusion.

Introduction: Haemorrhagic shock is associated with an inflammatory response consecutive to ischaemia-reperfusion (I/R) that leads to cardiovascular failure and organ injury. The role of and the timing of administration of hydrogen sulphide (H2S) remain uncertain. Vascular effects of H2S are mainly mediated through K+ATP-channel activation. Herein, we compared the effects of D,L-propargylglycine (PAG), an inhibitor of H2S production, as well as sodium hydrosulphide (NaHS), an H2S donor, on haemodynamics, vascular reactivity and cellular pathways in a rat model of I/R. We also compared the haemodynamic effects of NaHS administered before and 10 minutes after reperfusion., Methods: Mechanically ventilated and instrumented rats were bled during 60 minutes in order to maintain mean arterial pressure at 40 ± 2 mmHg. Ten minutes prior to retransfusion, rats randomly received either an intravenous bolus of NaHS (0.2 mg/kg) or vehicle (0.9% NaCl) or PAG (50 mg/kg). PNU, a pore-forming receptor inhibitor of K+ATP channels, was used to assess the role of K+ATP channels., Results: Shock and I/R induced a decrease in mean arterial pressure, lactic acidosis and ex vivo vascular hyporeactivity, which were attenuated by NaHS administered before reperfusion and PNU but not by PAG and NaHS administered 10 minutes after reperfusion. NaHS also prevented aortic inducible nitric oxide synthase expression and nitric oxide production while increasing Akt and endothelial nitric oxide synthase phosphorylation. NaHS reduced JNK activity and p-P38/P38 activation, suggesting a decrease in endothelial cell activation without variation in ERK phosphorylation. PNU + NaHS increased mean arterial pressure when compared with NaHS or PNU alone, suggesting a dual effect of NaHS on vascular reactivity., Conclusion: NaHS when given before reperfusion protects against the effects of haemorrhage-induced I/R by acting primarily through a decrease in both proinflammatory cytokines and inducible nitric oxide synthase expression and an upregulation of the Akt/endothelial nitric oxide synthase pathway.

The optimal target blood pressure in septic shock is still unknown. Therefore, in a long-term, resuscitated porcine model of fecal peritonitis-induced septic shock, Corrêa and colleagues tested whether different titrations of mean arterial pressure (50 to 60 and 75 to 85 mm Hg) would produce different effects on sepsis-related organ dysfunction. The higher blood pressure window was associated with increased needs for fluid resuscitation and norepinephrine support. However, titrating the lower blood pressure range coincided with an increased incidence of acute kidney injury. In contrast, neither the inflammatory response nor tissue mitochondrial activity showed any difference. This research paper in a clinically relevant model elegantly demonstrates that any standard resuscitation strategy may be a double-edged sword with respect to various therapeutic endpoints. Furthermore, it adds an important piece to the puzzle of the complex pathophysiology of sepsis-related acute kidney injury.

N-acetylcysteine is the classical antidote for acetaminophen overdose-induced hepatotoxicity, but its efficacy is limited by the need for early and only temporary treatment. Therefore, Yang and colleagues tested the hypothesis of whether ethyl pyruvate--another anti-inflammatory and antioxidant compound, which they had previously shown to protect against liver injury of various other etiologies--may allow circumventing these limitations. While ethyl pyruvate improved liver regeneration when administered early and during a limited period only, the opposite response was present both after delayed as well as prolonged treatment. The authors concluded that prolonged anti-inflammatory treatment is detrimental after acetaminophen intoxication-induced liver damage. On the one hand, this research paper confirms the need for biomarkers to monitor organ recovery after acetaminophen. On the other hand, this paper adds to the ongoing discussion on the usefulness of ethyl pyruvate as a resuscitation fluid in the critically ill.

Whether the hydrogen sulfide (H2S)-induced metabolic depression observed in awake rodents exists in larger species is controversial. Therefore, Derwall and colleagues exposed anesthetized and ventilated sheep to incremental H2S concentrations by means of an extracorporeal membrane oxygenator. H2S caused pulmonary vasoconstriction and metabolic acidosis at the highest concentration studied. Oxygen uptake and carbon dioxide production remained in the physiological range. The authors concluded that, beyond the effect of temperature, H2S hardly modifies metabolism at all. Since the highest H2S concentration caused toxic side effects (possibly due to an inhibition of mitochondrial respiration), the therapeutic use of inhaled H2S should be cautioned.

Introduction: Hydrogen sulfide (H2S) has been shown to improve survival in rodent models of lethal hemorrhage. Conversely, other authors have reported that inhibition of endogenous H2S production improves hemodynamics and reduces organ injury after hemorrhagic shock. Since all of these data originate from unresuscitated models and/or the use of a pre-treatment design, we therefore tested the hypothesis that the H2S donor, sodium hydrosulfide (NaHS), may improve hemodynamics in resuscitated hemorrhagic shock and attenuate oxidative and nitrosative stresses., Methods: Thirty-two rats were mechanically ventilated and instrumented to measure mean arterial pressure (MAP) and carotid blood flow (CBF). Animals were bled during 60 minutes in order to maintain MAP at 40 ± 2 mm Hg. Ten minutes prior to retransfusion of shed blood, rats randomly received either an intravenous bolus of NaHS (0.2 mg/kg) or vehicle (0.9% NaCl). At the end of the experiment (T = 300 minutes), blood, aorta and heart were harvested for Western blot (inductible Nitric Oxyde Synthase (iNOS), Nuclear factor-κB (NF-κB), phosphorylated Inhibitor κB (P-IκB), Inter-Cellular Adhesion Molecule (I-CAM), Heme oxygenase 1(HO-1), Heme oxygenase 2(HO-2), as well as nuclear respiratory factor 2 (Nrf2)). Nitric oxide (NO) and superoxide anion (O2(-)) were also measured by electron paramagnetic resonance., Results: At the end of the experiment, control rats exhibited a decrease in MAP which was attenuated by NaHS (65 ± 32 versus 101 ± 17 mmHg, P < 0.05). CBF was better maintained in NaHS-treated rats (1.9 ± 1.6 versus 4.4 ± 1.9 ml/minute P < 0.05). NaHS significantly limited shock-induced metabolic acidosis. NaHS also prevented iNOS expression and NO production in the heart and aorta while significantly reducing NF-kB, P-IκB and I-CAM in the aorta. Compared to the control group, NaHS significantly increased Nrf2, HO-1 and HO-2 and limited O2(-) release in both aorta and heart (P < 0.05)., Conclusions: NaHS is protective against the effects of ischemia reperfusion induced by controlled hemorrhage in rats. NaHS also improves hemodynamics in the early resuscitation phase after hemorrhagic shock, most likely as a result of attenuated oxidative stress. The use of NaHS hence appears promising in limiting the consequences of ischemia reperfusion (IR).

In sepsis, inflammation and thrombosis are both the cause and the result of interactions between circulating (for example, leukocytes and platelets), endothelial and smooth muscle cells. Microparticles are proinflammatory and procoagulant fragments originating from plasma membrane generated after cellular activation and released in body fluids. In the vessel, they constitute a pool of bioactive effectors pulled from diverse cellular origins and may act as intercellular messengers. Microparticles expose phosphatidylserine, a procoagulant phospholipid made accessible after membrane remodelling, and tissue factor, the initiator of blood coagulation at the endothelial and leukocyte surface. They constitute a secretion pathway for IL-1β and up-regulate the proinflammatory response of target cells. Microparticles circulate at low levels in healthy individuals, but undergo phenotypic and quantitative changes that could play a pathophysiological role in inflammatory diseases. Microparticles may participate in the pathogenesis of sepsis through multiple ways. They are able to regulate vascular tone and are potent vascular proinflammatory and procoagulant mediators. Microparticles' abilities are of increasing interest in deciphering the mechanisms underlying the multiple organ dysfunction of septic shock.

During advanced vasodilatory shock, arginine vasopressin (AVP) is increasingly used to restore blood pressure and thus to reduce catecholamine requirements. The AVP-related rise in mean arterial pressure is due to systemic vasoconstriction, which, depending on the infusion rate, may also reduce coronary blood flow despite an increased coronary perfusion pressure. In a murine model of myocardial ischaemia, Indrambarya and colleagues now report that a 3-day infusion of AVP decreased the left ventricular ejection fraction, ultimately resulting in increased mortality, and thus compared unfavourably with a standard treatment using dobutamine. The AVP-related impairment myocardial dysfunction did not result from the increased left ventricular afterload but from a direct effect on cardiac contractility. Consequently, the authors conclude that the use of AVP should be cautioned in patients with underlying cardiac disease.

Hydrogen sulfide (H2S), a gas with the characteristic odor of rotten eggs, is known for its toxicity and as an environmental hazard, inhibition of mitochondrial respiration resulting from blockade of cytochrome c oxidase being the main toxic mechanism. Recently, however, H2S has been recognized as a signaling molecule of the cardiovascular, inflammatory and nervous systems, and therefore, alongside nitric oxide and carbon monoxide, is referred to as the third endogenous gaseous transmitter. Inhalation of gaseous H2S as well as administration of inhibitors of its endogenous production and compounds that donate H2S have been studied in various models of shock. Based on the concept that multiorgan failure secondary to shock, inflammation and sepsis may represent an adaptive hypometabolic response to preserve ATP homoeostasis, particular interest has focused on the induction of a hibernation-like suspended animation with H2S. It must be underscored that currently only a limited number of data are available from clinically relevant large animal models. Moreover, several crucial issues warrant further investigation before the clinical application of this concept. First, the impact of hypothermia for any H2S-related organ protection remains a matter of debate. Second, similar to the friend and foe character of nitric oxide, no definitive conclusions can be made as to whether H2S exerts proinflammatory or anti-inflammatory properties. Finally, in addition to the question of dosing and timing (for example, bolus administration versus continuous intravenous infusion), the preferred route of H2S administration remains to be settled--that is, inhaling gaseous H2S versus intra-venous administration of injectable H2S preparations or H2S donors. To date, therefore, while H2S-induced suspended animation in humans may still be referred to as science fiction, there is ample promising preclinical data that this approach is a fascinating new therapeutic perspective for the management of shock states that merits further investigation.

Introduction: Infusing arginine vasopressin (AVP) in vasodilatory shock usually decreases cardiac output and thus systemic oxygen transport. It is still a matter of debate whether this vasoconstriction impedes visceral organ blood flow and thereby causes organ dysfunction and injury. Therefore, we tested the hypothesis whether low-dose AVP is safe with respect to liver, kidney, and heart function and organ injury during resuscitated septic shock., Methods: After intraperitoneal inoculation of autologous feces, 24 anesthetized, mechanically ventilated, and instrumented pigs were randomly assigned to noradrenaline alone (increments of 0.05 microg/kg/min until maximal heart rate of 160 beats/min; n = 12) or AVP (1 to 5 ng/kg/min; supplemented by noradrenaline if the maximal AVP dosage failed to maintain mean blood pressure; n = 12) to treat sepsis-associated hypotension. Parameters of systemic and regional hemodynamics (ultrasound flow probes on the portal vein and hepatic artery), oxygen transport, metabolism (endogenous glucose production and whole body glucose oxidation derived from blood glucose isotope and expiratory 13CO2/12CO2 enrichment during 1,2,3,4,5,6-13C6-glucose infusion), visceral organ function (blood transaminase activities, bilirubin and creatinine concentrations, creatinine clearance, fractional Na+ excretion), nitric oxide (exhaled NO and blood nitrate + nitrite levels) and cytokine production (interleukin-6 and tumor necrosis factor-alpha blood levels), and myocardial function (left ventricular dp/dtmax and dp/dtmin) and injury (troponin I blood levels) were measured before and 12, 18, and 24 hours after peritonitis induction. Immediate post mortem liver and kidney biopsies were analysed for histomorphology (hematoxylin eosin staining) and apoptosis (TUNEL staining)., Results: AVP decreased heart rate and cardiac output without otherwise affecting heart function and significantly decreased troponin I blood levels. AVP increased the rate of direct, aerobic glucose oxidation and reduced hyperlactatemia, which coincided with less severe kidney dysfunction and liver injury, attenuated systemic inflammation, and decreased kidney tubular apoptosis., Conclusions: During well-resuscitated septic shock low-dose AVP appears to be safe with respect to myocardial function and heart injury and reduces kidney and liver damage. It remains to be elucidated whether this is due to the treatment per se and/or to the decreased exogenous catecholamine requirements.

In patients with hyperdynamic hemodynamics, infusing arginine vasopressin (AVP) in advanced vasodilatory shock is usually accompanied by a decrease in cardiac output and in visceral organ blood flow. Depending on the infusion rate, this vasoconstriction also reduces coronary blood flow despite an increased coronary perfusion pressure. In a porcine model of transitory myocardial ischemia-induced left ventricular dysfunction, Müller and colleagues now report that the AVP-related coronary vaso-constriction may impede diastolic relaxation while systolic contraction remains unaffected. Although any AVP-induced myocardial ischemia undoubtedly is a crucial safety issue, these findings need to be discussed in the context of the model design, the dosing of AVP as well as the complex direct, afterload-independent and systemic, vasoconstriction-related effects on the heart.

Infusing arginine vasopressin (AVP) in advanced vasodilatory shock is usually accompanied by a decrease in cardiac index and systemic oxygen transport. Whether or not such a vasoconstriction impedes regional blood flow and thus visceral organ function, even when low AVP is used, is still a matter of debate. Krejci and colleagues now report, in this issue of Critical Care, that infusing 'low-dose' AVP during early, short-term, normotensive and normodynamic fecal peritonitis-induced porcine septicemia markedly reduced both renal and portal blood flow, and consequently total hepatic blood flow, whereas hepatic arterial flow was not affected. This macrocirculatory response was concomitant with reduced kidney microcirculatory perfusion, whereas liver micro-circulation remained unchanged. From these findings the authors conclude that the use of AVP to treat hypotension should be cautioned against in patients with septic shock. Undoubtedly, given its powerful vasoconstrictor properties, which are not accompanied by positive inotropic qualities (in contrast with most of the equally potent standard care 'competitors', namely catecholamines), the safety of AVP is still a matter of concern. Nevertheless, the findings reported by Krejci and colleagues need to be discussed in the context of the model design, the timing and dosing of AVP as well as the complex interaction between visceral organ perfusion and function.

The organs of the hepatosplanchnic system are considered to play a key role in the development of multiorgan failure during septic shock. Impaired oxygenation of the intestinal mucosa can lead to disruption of the intestinal barrier, which may promote a vicious cycle of inflammatory response, increased oxygen demand and inadequate oxygen supply. Standard septic shock therapy includes supportive treatment such as fluid resuscitation, administration of vasopressors (adrenergic and nonadrenergic drugs), and respiratory and renal support. These therapies may have beneficial or detrimental effects not only on systemic haemodynamics but also on splanchnic haemodynamics, at both the macrocirculatory and microcirculatory levels. This clinical review focuses on the splanchnic haemodynamic and metabolic effects of standard therapies used in patients with septic shock, as well as on the recently described nonconventional therapies such as vasopressin, prostacyclin and N-acetyl cysteine.