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1.
N Engl J Med ; 378(9): 809-818, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29490185

RESUMO

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 After drotrecogin alfa (activated) was withdrawn from the market, the trial continued with a two-group parallel design.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


Assuntos
Anti-Inflamatórios/uso terapêutico , Fludrocortisona/uso terapêutico , Hidrocortisona/uso terapêutico , Choque Séptico/tratamento farmacológico , Idoso , Anti-Inflamatórios/efeitos adversos , Causas de Morte , Terapia Combinada , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Fludrocortisona/efeitos adversos , Humanos , Hidrocortisona/efeitos adversos , Masculino , Pessoa de Meia-Idade , Escores de Disfunção Orgânica , Recidiva , Terapia de Substituição Renal , Respiração Artificial , Choque Séptico/complicações , Choque Séptico/mortalidade , Choque Séptico/terapia , Escore Fisiológico Agudo Simplificado , Análise de Sobrevida , Resultado do Tratamento
2.
JAMA ; 322(3): 229-239, 2019 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-31310299

RESUMO

Importance: Keeping a diary for patients while they are in the intensive care unit (ICU) might reduce their posttraumatic stress disorder (PTSD) symptoms. Objectives: To assess the effect of an ICU diary on the psychological consequences of an ICU hospitalization. Design, Setting, and Participants: Assessor-blinded, multicenter, randomized clinical trial in 35 French ICUs from October 2015 to January 2017, with follow-up until July 2017. Among 2631 approached patients, 709 adult patients (with 1 family member each) who received mechanical ventilation within 48 hours after ICU admission for at least 2 days were eligible, 657 were randomized, and 339 were assessed 3 months after ICU discharge. Interventions: Patients in the intervention group (n = 355) had an ICU diary filled in by clinicians and family members. Patients in the control group (n = 354) had usual ICU care without an ICU diary. Main Outcomes and Measures: The primary outcome was significant PTSD symptoms, defined as an Impact Event Scale-Revised (IES-R) score greater than 22 (range, 0-88; a higher score indicates more severe symptoms), measured in patients 3 months after ICU discharge. Secondary outcomes, also measured at 3 months and compared between groups, included significant PTSD symptoms in family members; significant anxiety and depression symptoms in patients and family members, based on a Hospital Anxiety and Depression Scale score greater than 8 for each subscale (range, 0-42; higher scores indicate more severe symptoms; minimal clinically important difference, 2.5); and patient memories of the ICU stay, reported with the ICU memory tool. Results: Among 657 patients who were randomized (median [interquartile range] age, 62 [51-70] years; 126 women [37.2%]), 339 (51.6%) completed the trial. At 3 months, significant PTSD symptoms were reported by 49 of 164 patients (29.9%) in the intervention group vs 60 of 175 (34.3%) in the control group (risk difference, -4% [95% CI, -15% to 6%]; P = .39). The median (interquartile range) IES-R score was 12 (5-25) in the intervention group vs 13 (6-27) in the control group (difference, -1.47 [95% CI, -1.93 to 4.87]; P = .38). There were no significant differences in any of the 6 prespecified comparative secondary outcomes. Conclusions and Relevance: Among patients who received mechanical ventilation in the ICU, the use of an ICU diary filled in by clinicians and family members did not significantly reduce the number of patients who reported significant PTSD symptoms at 3 months. These findings do not support the use of ICU diaries for preventing PTSD symptoms. Trial Registration: ClinicalTrials.gov Identifier: NCT02519725.


Assuntos
Cuidados Críticos/psicologia , Unidades de Terapia Intensiva , Respiração Artificial/psicologia , Transtornos de Estresse Pós-Traumáticos/prevenção & controle , Idoso , Família/psicologia , Feminino , Pessoal de Saúde/psicologia , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Registros
3.
Am J Respir Crit Care Med ; 191(6): 637-45, 2015 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-25584431

RESUMO

RATIONALE: The occurrence of ventilator-associated pneumonia (VAP) is linked to the aspiration of contaminated pharyngeal secretions around the endotracheal tube. Tubes with cuffs made of polyurethane rather than polyvinyl chloride or with a conical rather than a cylindrical shape increase tracheal sealing. OBJECTIVES: To test whether using polyurethane and/or conical cuffs reduces tracheal colonization and VAP in patients with acute respiratory failure. METHODS: We conducted a multicenter, prospective, open-label, randomized study in four parallel groups in four intensive care units between 2010 and 2012. A cohort of 621 patients with expected ventilation longer than 2 days was included at intubation with a cuff composed of cylindrical polyvinyl chloride (n = 148), cylindrical polyurethane (n = 143), conical polyvinyl chloride (n = 150), or conical polyurethane (n = 162). We used Kaplan-Meier estimates and log-rank tests to compare times to events. MEASUREMENTS AND MAIN RESULTS: After excluding 17 patients who secondarily refused participation or had met an exclusion criterion, 604 were included in the intention-to-treat analysis. Cumulative tracheal colonization greater than 10(3) cfu/ml at Day 2 was as follows (median [interquartile range]): cylindrical polyvinyl chloride, 0.66 (0.58-0.74); cylindrical polyurethane, 0.61 (0.53-0.70); conical polyvinyl chloride, 0.67 (0.60-0.76); and conical polyurethane, 0.62 (0.55-0.70) (P = 0.55). VAP developed in 77 patients (14.4%), and postextubational stridor developed in 28 patients (6.4%) (P = 0.20 and 0.28 between groups, respectively). CONCLUSIONS: Among patients requiring mechanical ventilation, polyurethane and/or conically shaped cuffs were not superior to conventional cuffs in preventing tracheal colonization and VAP. Clinical trial registered with clinicaltrials.gov (NCT01114022).


Assuntos
Intubação Intratraqueal/instrumentação , Pneumonia Bacteriana/prevenção & controle , Idoso , Desenho de Equipamento , Feminino , Humanos , Unidades de Terapia Intensiva , Intubação Intratraqueal/efeitos adversos , Masculino , Pessoa de Meia-Idade , Poliuretanos , Cloreto de Polivinila , Estudos Prospectivos , Traqueia/microbiologia
4.
Am J Respir Crit Care Med ; 187(10): 1091-7, 2013 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-23525934

RESUMO

RATIONALE: A decade after drotrecogin alfa (activated) (DAA) was released on the market worldwide, its benefit-to-risk ratio remains a matter of debate. OBJECTIVES: The current investigator-led trial was designed to evaluate the efficacy and safety of DAA, in combination with low-dose steroids, in adults with persistent septic shock. METHODS: This was a multicenter (24 intensive care units), placebo-controlled, double-blind, 2 × 2 factorial design trial in which adults with persistent septic shock and no contraindication to DAA were randomly assigned to DAA alone (24 µg/kg/h for 96 h), hydrocortisone and fludrocortisone alone, their respective combinations, or their respective placebos. Primary outcome was mortality rate on Day 90. MEASUREMENTS AND MAIN RESULTS: On October 25, 2011, the trial was suspended after the withdrawal from the market of DAA. The Scientific Committee decided to continue the trial according to a two parallel group design comparing low-dose steroids with their placebos and to analyze the effects of DAA on patients included before trial suspension. At the time trial was suspended, 411 patients had been recruited, 208 had received DAA, and 203 had received its placebo. There was no significant interaction between DAA and low-dose steroids (P = 0.47). On Day 90, there were 99 deaths (47.6%) among the 208 patients receiving DAA and 94 deaths (46.3%) among the 203 patients receiving placebo (P = 0.79). There was no evidence of a difference between DAA and its placebo for any secondary outcomes or serious adverse events. CONCLUSIONS: In adults with established and severe septic shock, DAA showed no evidence of benefit or harm. Clinical trial registered with www.clinicaltrials.gov (NCT00625209).


Assuntos
Anti-Infecciosos/uso terapêutico , Proteína C/uso terapêutico , Choque Séptico/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Método Duplo-Cego , Quimioterapia Combinada/métodos , Feminino , Fludrocortisona/uso terapêutico , Humanos , Hidrocortisona/uso terapêutico , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/uso terapêutico , Retirada de Medicamento Baseada em Segurança , Resultado do Tratamento
5.
Lancet Respir Med ; 12(5): 366-374, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38310918

RESUMO

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


Assuntos
Infecções Comunitárias Adquiridas , Quimioterapia Combinada , Fludrocortisona , Hidrocortisona , Pneumonia , Choque Séptico , Humanos , Hidrocortisona/uso terapêutico , Hidrocortisona/administração & dosagem , Choque Séptico/tratamento farmacológico , Choque Séptico/mortalidade , Infecções Comunitárias Adquiridas/tratamento farmacológico , Infecções Comunitárias Adquiridas/mortalidade , Infecções Comunitárias Adquiridas/complicações , Masculino , Feminino , Fludrocortisona/uso terapêutico , Fludrocortisona/administração & dosagem , Idoso , Pessoa de Meia-Idade , Pneumonia/tratamento farmacológico , Pneumonia/mortalidade , Método Duplo-Cego , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/administração & dosagem , Resultado do Tratamento , Proteína C/uso terapêutico , Proteína C/administração & dosagem
6.
JAMA ; 310(17): 1809-17, 2013 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-24108515

RESUMO

IMPORTANCE: Evidence supporting the choice of intravenous colloid vs crystalloid solutions for management of hypovolemic shock remains unclear. OBJECTIVE: To test whether use of colloids compared with crystalloids for fluid resuscitation alters mortality in patients admitted to the intensive care unit (ICU) with hypovolemic shock. DESIGN, SETTING, AND PARTICIPANTS: A multicenter, randomized clinical trial stratified by case mix (sepsis, trauma, or hypovolemic shock without sepsis or trauma). Therapy in the Colloids Versus Crystalloids for the Resuscitation of the Critically Ill (CRISTAL) trial was open label but outcome assessment was blinded to treatment assignment. Recruitment began in February 2003 and ended in August 2012 of 2857 sequential ICU patients treated at 57 ICUs in France, Belgium, North Africa, and Canada; follow-up ended in November 2012. INTERVENTIONS: Colloids (n = 1414; gelatins, dextrans, hydroxyethyl starches, or 4% or 20% of albumin) or crystalloids (n = 1443; isotonic or hypertonic saline or Ringer lactate solution) for all fluid interventions other than fluid maintenance throughout the ICU stay. MAIN OUTCOMES AND MEASURES: The primary outcome was death within 28 days. Secondary outcomes included 90-day mortality; and days alive and not receiving renal replacement therapy, mechanical ventilation, or vasopressor therapy. RESULTS: Within 28 days, there were 359 deaths (25.4%) in colloids group vs 390 deaths (27.0%) in crystalloids group (relative risk [RR], 0.96 [95% CI, 0.88 to 1.04]; P = .26). Within 90 days, there were 434 deaths (30.7%) in colloids group vs 493 deaths (34.2%) in crystalloids group (RR, 0.92 [95% CI, 0.86 to 0.99]; P = .03). Renal replacement therapy was used in 156 (11.0%) in colloids group vs 181 (12.5%) in crystalloids group (RR, 0.93 [95% CI, 0.83 to 1.03]; P = .19). There were more days alive without mechanical ventilation in the colloids group vs the crystalloids group by 7 days (mean: 2.1 vs 1.8 days, respectively; mean difference, 0.30 [95% CI, 0.09 to 0.48] days; P = .01) and by 28 days (mean: 14.6 vs 13.5 days; mean difference, 1.10 [95% CI, 0.14 to 2.06] days; P = .01) and alive without vasopressor therapy by 7 days (mean: 5.0 vs 4.7 days; mean difference, 0.30 [95% CI, -0.03 to 0.50] days; P = .04) and by 28 days (mean: 16.2 vs 15.2 days; mean difference, 1.04 [95% CI, -0.04 to 2.10] days; P = .03). CONCLUSIONS AND RELEVANCE: Among ICU patients with hypovolemia, the use of colloids vs crystalloids did not result in a significant difference in 28-day mortality. Although 90-day mortality was lower among patients receiving colloids, this finding should be considered exploratory and requires further study before reaching conclusions about efficacy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00318942.


Assuntos
Coloides/uso terapêutico , Estado Terminal/terapia , Hidratação/métodos , Soluções Isotônicas/uso terapêutico , Choque/terapia , Idoso , Soluções Cristaloides , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Respiração Artificial , Análise de Sobrevida , Resultado do Tratamento , Vasoconstritores/uso terapêutico
7.
Crit Care ; 16(3): R94, 2012 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-22624531

RESUMO

INTRODUCTION: Inadequate initial treatment and delayed hemodynamic stabilization (HDS) may be associated with increased risk of death in severe sepsis patients. METHODS: In order to compare the hemodynamic efficacy and safety of 6% HES 130/0.4 and NaCl 0.9% for HDS in patients with severe sepsis, we designed a prospective, multicenter, active-controlled, double-blind, randomized study in intensive care units. RESULTS: 174 out of 196 patients reached HDS (88 and 86 patients for HES and NaCl, respectively). Significantly less HES was used to reach HDS vs. NaCl (1,379 ± 886 ml in the HES group and 1,709 ± 1,164 ml in the NaCl group (mean difference = -331 ± 1,033, 95% CI -640 to -21, P = 0.0185). Time to reach HDS was 11.8 10.1 hours vs. 14.3 ± 11.1 hours for HES and NaCl, respectively. Total quantity of study drug infused over four consecutive days, ICU and hospital LOS, and area under the curve of SOFA score were comparable. Acute renal failure occurred in 24 (24.5%) and 19 (20%) patients for HES and NaCl, respectively (P = 0.454). There was no difference between AKIN and RIFLE criteria among groups and no difference in mortality, coagulation, or pruritus up to 90 days after treatment initiation. CONCLUSION: Significantly less volume was required to achieve HDS for HES vs. NaCl in the initial phase of fluid resuscitation in severe sepsis patients without any difference for adverse events in both groups. CLINICALTRIALSGOV: NCT00464204.


Assuntos
Hidratação/métodos , Hemodinâmica/efeitos dos fármacos , Derivados de Hidroxietil Amido/administração & dosagem , Sepse/diagnóstico , Sepse/terapia , Cloreto de Sódio/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Feminino , Hemodinâmica/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sepse/metabolismo , Resultado do Tratamento
8.
Antioxid Redox Signal ; 37(13-15): 998-1029, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35287478

RESUMO

Significance: Endothelial barrier damage, which is in part caused by excess production of reactive oxygen, halogen and nitrogen species (ROHNS), especially peroxynitrite (ONOO-), is a major event in early sepsis and, with leukocyte hyperactivation, part of the generalized dysregulated immune response to infection, which may even become a complex maladaptive state. Selenoenzymes have major antioxidant functions. Their synthesis is related to the need to limit deleterious oxidant redox cycling by small selenocompounds, which may be of therapeutic cytotoxic interest. Plasma selenoprotein-P is crucial for selenium transport from the liver to the tissues and for antioxidant endothelial protection, especially against ONOO-. Above micromolar concentrations, sodium selenite (Na2SeO3) becomes cytotoxic, with a lower cytotoxicity threshold in activated cells, which has led to cancer research. Recent Advances: Plasma selenium (<2% of total body selenium) is mainly contained in selenoprotein-P, and concentrations decrease rapidly in the early phase of sepsis, because of increased selenoprotein-P binding and downregulation of hepatic synthesis and excretion. At low concentrations, Na2SeO3 acts as a selenium donor, favoring selenoprotein-P synthesis in physiology, but probably not in the acute phase of sepsis. Critical Issues: The cytotoxic effects of Na2SeO3 against hyperactivated leukocytes, especially the most immature forms that liberate ROHNS, may be beneficial, but they may also be harmful for activated endothelial cells. Endothelial protection against ROHNS by selenoprotein-P may reduce Na2SeO3 toxicity, which is increased in sepsis. Future Direction: The combination of selenoprotein-P for endothelial protection and the cytotoxic effects of Na2SeO3 against hyperactivated leukocytes may be a promising intervention for early sepsis. Antioxid. Redox Signal. 37, 998-1029.


Assuntos
Antineoplásicos , Selênio , Sepse , Humanos , Selênio/farmacologia , Selênio/uso terapêutico , Selênio/metabolismo , Antioxidantes/metabolismo , Células Endoteliais/metabolismo , Selenoproteína P/metabolismo , Oxirredução , Sepse/tratamento farmacológico
9.
J Trace Elem Med Biol ; 73: 127031, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35793609

RESUMO

BACKGROUND: In sepsis, neutrophil respiratory bursts participate in endothelium damage, the first step to multiple organ failure. In plasma two antioxidant selenoenzymes, which protect the endothelium, decrease: selenoprotein-P, and to a lesser extent glutathione peroxidase (GPX3). Sodium selenite (Na2SeO3) is a Se donor, but also an oxidant chemotherapy drug depending on its concentration. In a previous published study, Na2SeO3 continuous infusion in septic shock patients at a pharmacological dose of 4 mg1 Se/day on day-1, followed by a high nutritional dose of 1 mg Se/day during 9 days, showed no beneficial effect on weaning of catecholamine nor on survival. In this ancillary study, we report clinical and biological effects of such continuous infusion of Na2SeO3. METHODS: This was a multicenter, placebo-controlled, double-blind study on 60 patients. Na2SeO3 or placebo in continuous infusion as described above. Evolution with time of plasma Se, selenoprotein-P, GPX3, Organ dysfunction (sequential organ failure assessment SOFA scores, including PaO2/FiO2, for respiratory failure, and plasma lactate) and quality of life at 6 months (by SF36 scores) were analyzed using two-way (time, treatment) non-parametric repeated-measures analysis of variance (Friedman test). MAIN RESULTS: At baseline, plasma Se was about a quarter of reference values. From baseline to day-4 plasma Se, selenoprotein-P and GPX3 significantly increased by 3.9, 2.7 and 1.8 respectively in the Na2SeO3 group as compared with placebo and remained elevated by 2.3, 2.7 and 2.1 at day-14 respectively (p < 0.001). Na2SeO3 did not affect global and organ by organ SOFA Scores and plasma lactate concentration at day-1 and later up to day-14. The evolution of PaO2/FiO2 until day-14 was similar in the two groups. Quality of life in the surviving patients at 6 months was similar between the two groups. CONCLUSION: Continuous infusion of Na2SeO3 at 4 mg Se at day-1 seems to have neither beneficial nor toxic effect at day-1 or later and induces a late increase of selenoprotein-P at day-4. Preclinical studies are required to confirm the use of Na2SeO3 as a cytotoxic drug against neutrophils and protection of the endothelium by selenoprotein-P.


Assuntos
Síndrome do Desconforto Respiratório , Selênio , Choque Séptico , Glutationa Peroxidase , Humanos , Lactatos/uso terapêutico , Qualidade de Vida , Selenoproteína P , Selenoproteínas , Choque Séptico/tratamento farmacológico , Selenito de Sódio/farmacologia , Selenito de Sódio/uso terapêutico
11.
Antioxid Redox Signal ; 35(2): 113-138, 2021 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-33567962

RESUMO

Significance: Sepsis is a health disaster. In sepsis, an initial, beneficial local immune response against infection evolves rapidly into a generalized, dysregulated response or a state of chaos, leading to multiple organ failure. Use of life-sustaining supportive therapies creates an unnatural condition, enabling the complex cascades of the sepsis response to develop in patients who would otherwise die. Multiple attempts to control sepsis at an early stage have been unsuccessful. Recent Advances: Major events in early sepsis include activation and binding of leukocytes and endothelial cells in the microcirculation, damage of the endothelial surface layer (ESL), and a decrease in the plasma concentration of the antioxidant enzyme, selenoprotein-P. These events induce an increase in intracellular redox potential and lymphocyte apoptosis, whereas apoptosis is delayed in monocytes and neutrophils. They also induce endothelial mitochondrial and cell damage. Critical Issues: Neutrophil production increases dramatically, and aggressive immature forms are released. Leukocyte cross talk with other leukocytes and with damaged endothelial cells amplifies the inflammatory response. The release of large quantities of reactive oxygen, halogen, and nitrogen species as a result of the leukocyte respiratory burst, endothelial mitochondrial damage, and ischemia/reperfusion processes, along with the marked decrease in selenoprotein-P concentrations, leads to peroxynitrite damage of the ESL, reducing flow and damaging the endothelial barrier. Future Directions: Endothelial barrier damage by activated leukocytes is a time-sensitive event in sepsis, occurring within hours and representing the first step toward organ failure and death. Reducing or stopping this event is necessary before irreversible damage occurs.


Assuntos
Células Endoteliais/metabolismo , Leucócitos/metabolismo , Selenoproteína P/sangue , Sepse/diagnóstico , Comunicação Celular , Diagnóstico Precoce , Humanos , Neutrófilos/metabolismo , Oxirredução , Sepse/sangue , Sepse/tratamento farmacológico
12.
Brain Sci ; 11(5)2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33922414

RESUMO

Brain dysfunction is associated with poor outcome in critically ill patients. In a post hoc analysis of the Intensive Care over Nations (ICON) database, we investigated the effect of brain dysfunction on hospital mortality in critically ill patients. Brain failure was defined as a neurological sequential organ failure assessment (nSOFA) score of 3-4, based on the assumed Glasgow Coma Scale (GCS) score. Multivariable analyses were performed to assess the independent roles of nSOFA and change in nSOFA from admission to day 3 (ΔnSOFA) for predicting hospital mortality. Data from 7192 (2096 septic and 5096 non-septic) patients were analyzed. Septic patients were more likely than non-septic patients to have brain failure on admission (434/2095 (21%) vs. 617/4665 (13%), p < 0.001) and during the ICU stay (625/2063 (30%) vs. 736/4665 (16%), p < 0.001). The presence of sepsis (RR 1.66 (1.31-2.09)), brain failure (RR 4.85 (3.33-7.07)), and both together (RR 5.61 (3.93-8.00)) were associated with an increased risk of in-hospital death, but nSOFA was not. In the 3280 (46%) patients in whom ΔnSOFA was available, sepsis (RR 2.42 (1.62-3.60)), brain function deterioration (RR 6.97 (3.71-13.08)), and the two together (RR 10.24 (5.93-17.67)) were associated with an increased risk of in-hospital death, whereas improvement in brain function was not.

14.
Crit Care ; 11(4): R73, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17617901

RESUMO

INTRODUCTION: Sepsis is associated with the generation of oxygen free radicals and (lacking) decreased selenium plasma concentrations. High doses of sodium selenite might reduce inflammation by a direct pro-oxidative effect and may increase antioxidant cell capacities by selenium incorporation into selenoenzymes. We investigated the effects of a continuous administration of high doses of selenium in septic shock patients. METHODS: A prospective, multicentre, placebo-controlled, randomized, double-blind study was performed with an intention-to-treat analysis in severe septic shock patients with documented infection. Patients received, for 10 days, selenium as sodium selenite (4,000 microg on the first day, 1,000 microg/day on the nine following days) or matching placebo using continuous intravenous infusion. The primary endpoint was the time to vasopressor therapy withdrawal. The duration of mechanical ventilation, the mortality rates in the intensive care unit, at hospital discharge, and at 7, 14, 28 and 180 days and 1 year after randomization, and adverse events were recorded. RESULTS: Sixty patients were included (placebo, n = 29; selenium, n = 31). The median time to vasopressor therapy withdrawal was 7 days in both groups (95% confidence interval = 5-8 and 6-9 in the placebo and selenium groups, respectively; log-rank, P = 0.713). The median duration of mechanical ventilation was 14 days and 19 days in the placebo and selenium groups, respectively (P = 0.762). Mortality rates did not significantly differ between groups at any time point. Rates of adverse events were similar in the two groups. CONCLUSION: Continuous infusion of selenium as sodium selenite (4,000 microg on the first day, 1,000 microg/day on the nine following days) had no obvious toxicity but did not improve the clinical outcome in septic shock patients. Trial Registration = NCT00207844.


Assuntos
Antioxidantes/uso terapêutico , Choque Séptico/tratamento farmacológico , Selenito de Sódio/uso terapêutico , Idoso , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Infusões Intravenosas , Masculino , Estudos Prospectivos , Índice de Gravidade de Doença , Resultado do Tratamento
15.
J Trace Elem Med Biol ; 21 Suppl 1: 62-5, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-18039501

RESUMO

Selenium has a double action. (i) Seleno-compounds, among them sodium selenite have a direct pro-oxidant action leading to acute toxicity but may be also beneficial as drug. (ii) Selenium is an essential anti-oxidant required for anti-oxidant seleno-enzymes. Septic shock is a common severe syndrome leading to endothelium damage and multiple organ failure, with increased data suggesting the principle role of oxidative stress. Selenoprotein P, main selenium constituent of the plasma, may decrease dramatically and specifically in septic shock patients and may be involved in the endothelium protection. A prospective, multi-center placebo-controlled, randomized, double-blind study in severe septic shock patients with documented infection has been preformed. Patients received, for 10 days, selenium as sodium selenite (4000 microg on the first day, 1000 microg/day on the 9 following days) or matching placebo using continuous intravenous infusion. Mortality rates did not significantly differ between groups at any time point. Adverse events rates were similar in the two groups. However, high-dose selenium administration has been associated with a tendency to decrease the mortality in septic shock animal and patients, especially when using a bolus administration, whereas studies using a continuous administration failed to find any benefit on mortality. The interest of the successive use of pro-oxidant action of seleno-compounds, followed by anti-oxidant action need to be the further studied in cellular and animal models, preceding new dose-effect phase II. The interest of the selenoprotein-P as a marker of septic shock and for endothelium protection needs also to be studied further.


Assuntos
Selênio/uso terapêutico , Choque Séptico/tratamento farmacológico , Selenito de Sódio/uso terapêutico , Método Duplo-Cego , Humanos
16.
BMJ Open ; 7(10): e016736, 2017 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-28988172

RESUMO

OBJECTIVE: To compare the haemodynamic effect of crystalloids and colloids during acute severe hypovolaemic shock. DESIGN: Exploratory subgroup analysis of a multicentre randomised controlled trial (Colloids Versus Crystalloids for the Resuscitation of the Critically Ill, CRISTAL, ClinicalTrials.gov NCT00318942). SETTING: CRISTAL was conducted in intensive care units in Europe, North Africa and Canada. PARTICIPANTS: Current analysis included all patients who had a pulmonary artery catheter in place at randomisation. 220 patients (117 received crystalloids vs 103 colloids) underwent pulmonary artery catheterisation. INTERVENTION: Crystalloids versus colloids for fluid resuscitation in hypovolaemic shock. OUTCOME MEASURES: Haemodynamic data were collected at the time of randomisation and subsequently on days 1, 2, 3, 4, 5, 6 and 7. RESULTS: Median cumulative volume of fluid administered during the first 7 days was higher in the crystalloids group than in the colloids group (3500 (2000-6000) vs 2500 (1000-4000) mL, p=0.01). Patients in the colloids arm exhibited a lower heart rate over time compared with those allocated to the crystalloids arm (p=0.014). There was no significant difference in Cardiac Index (p=0.053), mean blood pressure (p=0.4), arterial lactates (p=0.9) or global Sequential Organ Failure Assessment score (p=0.3) over time between arms. CONCLUSIONS: During acute severe hypovolaemic shock, patients monitored by a pulmonary artery catheter achieved broadly similar haemodynamic outcomes, using lower volumes of colloids than crystalloids. The heart rate was lower in the colloids arm.


Assuntos
Coloides/uso terapêutico , Hidratação/métodos , Hemodinâmica , Soluções Isotônicas/uso terapêutico , Ressuscitação/métodos , Choque/terapia , África do Norte , Idoso , Canadá , Estado Terminal/terapia , Soluções Cristaloides , Europa (Continente) , Feminino , Frequência Cardíaca , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Choque/fisiopatologia
17.
Trials ; 18(1): 542, 2017 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-29141694

RESUMO

BACKGROUND: Post-intensive care syndrome includes the multiple consequences of an intensive care unit (ICU) stay for patients and families. It has become a new challenge for intensivists. Prevention programs have been disappointing, except for ICU diaries, which report the patient's story in the ICU. However, the effectiveness of ICU diaries for patients and families is still controversial, as the interpretation of the results of previous studies was open to criticism hampering an expanded use of the diary. The primary objective of the study is to evaluate the post-traumatic stress syndrome in patients. The secondary objectives are to evaluate the post-traumatic stress syndrome in families, anxiety and depression symptoms in patients and families, and the recollected memories of patients. Endpoints will be evaluated 3 months after ICU discharge or death. METHODS: A prospective, multicenter, randomized, assessor-blind comparative study of the effect of an ICU diary on patients and families. We will compare two groups: one group with an ICU diary written by staff and family and given to the patient at ICU discharge or to the family in case of death, and a control group without any ICU diary. Each of the 35 participating centers will include 20 patients having at least one family member who will likely visit the patient during their ICU stay. Patients must be ventilated within 48 h after ICU admission and not have any previous chronic neurologic or acute condition responsible for cognitive impairments that would hamper their participation in a phone interview. Three months after ICU discharge or death of the patient, a psychologist will contact the patient and family by phone. Post-traumatic stress syndrome will be evaluated using the Impact of Events Scale-Revised questionnaire, anxiety and depression symptoms using the Hospital Anxiety and Depression Scale questionnaire, both in patients and families, and memory recollection using the ICU Memory Tool Questionnaire in patients. The content of a randomized sample of diaries of each center will be analyzed using a grid. An interview of the patients in the intervention arm will be conducted 6 months after ICU discharge to analyze in depth how they use the diary. DISCUSSION: This study will provide new insights on the impact of ICU diaries on post-traumatic stress disorders in patients and families after an ICU stay. TRIAL REGISTRATION: ClinicalTrial.gov, ID: NCT02519725 . Registered on 13 July 2015.


Assuntos
Ansiedade/psicologia , Cuidados Críticos , Depressão/psicologia , Relações Familiares , Unidades de Terapia Intensiva , Prontuários Médicos , Pacientes/psicologia , Qualidade de Vida , Transtornos de Estresse Pós-Traumáticos/psicologia , Ansiedade/diagnóstico , Efeitos Psicossociais da Doença , Depressão/diagnóstico , França , Nível de Saúde , Humanos , Memória , Saúde Mental , Narração , Estudos Prospectivos , Projetos de Pesquisa , Transtornos de Estresse Pós-Traumáticos/diagnóstico , Inquéritos e Questionários , Síndrome , Fatores de Tempo
18.
Crit Care ; 10(6): 180, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-17184558

RESUMO

Selenium protects cells and inhibits many inflammatory cell mechanisms through antioxidant seleno-enzymes. Immunity improvement is illustrated by the study of Berger and colleagues, with reduction of nosocomial pneumonia in burnt patients under multi-trace-element supplementation. As seleno-compounds (especially sodium selenite) are pro-oxidant, however, administration above 800 microg/day may be dangerous in septic shock. Paradoxically, direct reversible pro-oxidative effects of seleno-compounds may also be beneficial for reduction of inflammation (genomic action, apoptosis), and may even be bactericidal or virucidal. These facts need to be further examined, as well as the possible dramatic drop of plasma selenoprotein P in septic shock and its role in endothelium protection.


Assuntos
Selênio/uso terapêutico , Choque Séptico/complicações , Apoptose/efeitos dos fármacos , Queimaduras/complicações , Relação Dose-Resposta a Droga , Humanos , Inflamação , Pneumonia/etiologia , Pneumonia/prevenção & controle , Compostos de Selênio/administração & dosagem , Compostos de Selênio/efeitos adversos , Compostos de Selênio/farmacologia , Selenito de Sódio/administração & dosagem , Selenito de Sódio/efeitos adversos , Selenito de Sódio/farmacologia
19.
Intensive Care Med ; 28(7): 857-63, 2002 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12122522

RESUMO

OBJECTIVE: Protected specimen brush (PSB) and bronchoalveolar lavage (BAL) are proposed in combination to optimize antimicrobial treatment. Nevertheless, they are only validated for immediate laboratory processing. This study was therefore conducted to determine whether 48 h conservation at a mere 4 degrees C enables good culture reproducibility for both PSB and BAL. DESIGN AND SETTING: Prospective study, evaluation of a conservation procedure for PSB and BAL, from February 1994 to February 1995, in the 12 bed ICU of a general hospital (938 beds). SAMPLES: Ninety-nine PSB and 86 BAL samples, obtained from 100 bronchoscopic procedures, were analyzed. Thresholds were 10(3) and 10(4) cfu/ml for PSB and BAL, respectively. MEASUREMENTS AND RESULTS: Qualitative comparison between the immediate and 48 h procedures were, for PSB, specificity 100%, sensitivity 78%, positive predictive value 100%, negative predictive value 84% and overall accuracy 90%; and for BAL: 100%, 89%, 100%, 89% and 94%. Lowered 10(2) and 10(3) cfu/ml thresholds at the 48 h procedure for PSB and BAL reduce the false negatives from 10 to 3 and 5 to 1, respectively. Microorganism results were comparable for PSB and BAL ( r = 0.63 and 0.67), especially for the most resistant strains: Staphylococcus, Enterobacteriaceae and Pseudomonas. However, there was a decrease in the Neisseria and Haemophilus group ( p < 0.01). CONCLUSION: There is a good culture reproducibility for both PSB and BAL after 48 h conservation at 4 degrees C, especially with lowered thresholds; this technique is therefore appropriate for routine use.


Assuntos
Lavagem Broncoalveolar , Infecção Hospitalar/microbiologia , Pneumonia Bacteriana/microbiologia , Manejo de Espécimes/métodos , Temperatura , Adulto , Idoso , Bactérias/classificação , Infecção Hospitalar/diagnóstico , Feminino , França , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Pneumonia Bacteriana/diagnóstico , Estudos Prospectivos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Manejo de Espécimes/estatística & dados numéricos
20.
J Trace Elem Med Biol ; 28(3): 303-10, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24813451

RESUMO

PROJECT: Both septic shock and sodium selenite (Na2SeO3) lead to multiple organ failure through oxidation. Na2SeO3 has direct oxidant effects above the nutritional level and indirect anti-oxidant properties. In a lipopolysaccharide (LPS) rat model we assessed margin of safety, toxicity and beneficial effect of pentahydrate Na2SeO3 (5H2O·Na2SeO3) at oxidant doses. PROCEDURE: In a three-step study on 204 rats we: (i) observed toxic effects of Na2SeO3 injected intraperitoneously (IP) and determined its Minimum Dose Without Toxic effect (MDWT) 0.25-0.35 mg/kg selenium (Se) content; (ii) injected IP LPS at 70% lethal dose (LD) followed, or not, one hour later by IP Na2SeO3 at MDWT and (iii) by doses>MDWT. At 48 h, in survivors, we measured plasma creatinine, lactate, aspartate and alanine aminotransferase (AST, ALT), nitric oxide (NO) and Se concentrations. RESULTS: (i) Na2SeO3 alone did not increase NO and lactate. Encephalopathy appeared at 1mg Se/kg. Creatinine increased at 1-1.75 mg Se/kg, AST, ALT at 3-4.5 mg Se/kg, and the minimum LD was 3 mg Se/kg. (ii) Mortality after LPS was 37/50 (74%, [62-86%]) vs. 20/30 (67%, [50-84%]) when followed by Na2SeO3 at MDWT (p=0.483) with a decreased in NO (-31%, p=0.038) a trend for lactate decrease (-19%, p=0.068) and an increased Se in plasma of survivals. (iii) All rats died at doses ≥0.6 mg/kg (p<0.001). CONCLUSION: Mechanisms of LPS and Na2SeO3 toxicity differ (i.e. NO, lactate). In septic shock 5H2O·Na2SeO3 toxicity increased, margin of safety decrease, but IP administration of dose considered as oxidant of 5H2O·Na2SeO3 showed beneficial effects.


Assuntos
Insuficiência de Múltiplos Órgãos/induzido quimicamente , Selenito de Sódio/farmacologia , Animais , Masculino , Ratos , Selênio/farmacologia
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