Sepsis and Septic Shock Definitions in Patients With Cancer Admitted in ICU.

INTRODUCTION: In 2016, a new definition of sepsis and septic shock was adopted. Some studies based on the general population demonstrated that the Sequential Organ Failure Assessment (SOFA) score is more accurate than the systemic inflammatory response syndrome (SIRS) criteria to predict hospital mortality of infected patients requiring intensive care. PATIENTS AND METHOD: We have analyzed all the records of patients with cancer admitted for a suspected infection between January 1, 2013, and December 31, 2016, in our oncological intensive care unit (ICU). Sequential Organ Failure Assessment score and quick SOFA (qSOFA) score as well as SIRS criteria were calculated. We analyzed the accuracy of each score to predict hospital mortality in the setting of the new and old definitions of septic shock. RESULTS: Our study includes 241 patients with a solid tumor and 112 with a hematological malignancy. The hospital mortality rate is 37% (68% in patients with septic shock according to the new definition and 60% according to old definition) between 2013 and 2016. To predict hospital mortality, the SOFA score has an area under the receiver operating characteristic curve of 0.74 (95% confidence interval [CI], 0.68-0.79), the qSOFA of 0.65 (95% CI, 0.59-0.70), and the SIRS criteria of 0.58 (95% CI, 0.52-0.63). In multivariate analysis, a higher SOFA score or a higher qSOFA score indicates poor prognosis: odds ratio (OR) per 1-point increase by 1.28 (95% CI, 1.18-1.39) and 1.48 (95% CI, 1.04-2.11), respectively. Complete remission is a good prognostic factor for hospital mortality: OR 0.39 (95% CI, 0.22-0.67). CONCLUSION: The new definition of sepsis and septic shock is applicable in an ICU oncological population with the same reliability as in the general population. The SOFA score is more accurate than qSOFA and SIRS criteria to predict hospital mortality.

Deciphering heterogeneity of septic shock patients using immune functional assays: a proof of concept study.

The complexity of sepsis pathophysiology hinders patient management and therapeutic decisions. In this proof-of-concept study we characterised the underlying host immune response alterations using a standardised immune functional assay (IFA) in order to stratify a sepsis population. In septic shock patients, ex vivo LPS and SEB stimulations modulated, respectively, 5.3% (1/19) and 57.1% (12/21) of the pathways modulated in healthy volunteers (HV), highlighting deeper alterations induced by LPS than by SEB. SEB-based clustering, identified 3 severity-based groups of septic patients significantly different regarding mHLA-DR expression and TNFα level post-LPS, as well as 28-day mortality, and nosocomial infections. Combining the results from two independent cohorts gathering 20 HV and 60 patients, 1 cluster grouped all HV with 12% of patients. The second cluster grouped 42% of patients and contained all non-survivors. The third cluster grouped 46% of patients, including 78% of those with nosocomial infections. The molecular features of these clusters indicated a distinctive contribution of previously described genes defining a "healthy-immune response" and a "sepsis-related host response". The third cluster was characterised by potential immune recovery that underlines the possible added value of SEB-based IFA to capture the sepsis immune response and contribute to personalised management.

Modelagem PK/PD na terapia antimicrobiana com carbapenêmico em pacientes sépticos críticos grandes queimados. " Estudo da efetividade do meropenem administrado através de infusão intermitente versus estendida " / PK/PD modelling in antimicrobial therapy with carbapenem in critically burn septic patients. " Study of the effectiveness of meropenem administered by intermittent versus extended infusion "

O meropenem é um carbapenêmico de amplo espectro e alta potência, largamente prescrito para tratamento de infecções graves causadas por bactérias sensíveis gram-negativas em pacientes críticos internados em Unidades de Terapia Intensiva. O objetivo do presente estudo foi avaliar a efetividade do antimicrobiano em pacientes grandes queimados, recebendo a dose recomendada 1 g q8h através da infusão intermitente de 0,5 hora que ocorreu até 2014 (grupo 1) comparada a infusão estendida de 3 horas que ocorreu após esse período (grupo 2). Investigaram-se 25 pacientes sépticos de ambos os sexos (6F/19M), 26 (21-34) anos, medianas (interquartil), 70 (60-75) kg, superfície corporal total queimada (SCTQ) 35 (16-42)%, SAPS 3: 55 (45-59) e Clcr 129 (95-152) ml/min que foram distribuídos em dois grupos. Registrou-se trauma térmico pelo fogo em 19/25 e trauma elétrico no restante dos pacientes (6/25), lesão inalatória (17/25), intubação orotraqueal e a necessidade de vasopressores em 18/25 pacientes. Duas amostras de sangue foram coletadas (3ª e 5ª horas) para dosagem sérica do meropenem por cromatografia líquida no período precoce do choque séptico. A farmacocinética foi investigada pela aplicação do modelo aberto de um compartimento e a abordagem PK/PD foi realizada com base no novo índice recomendado 100%fΔT>CIM. Evidenciou-se aumento do PCR 224 (179-286) versus 300 (264-339) mg/L, p=0,0411 e neutrofilia: 12 (8-17) versus 8 (2-15) células/mm3, p=0,1404, respectivamente nos grupos de infusão estendida versus infusão intermitente. Os níveis séricos obtidos mostraram diferença significativa entre grupos (p<0,0001) tanto para o pico 21 (21-22) mg/L versus 44 (42-45) mg/L, como para o vale 7,8 (7,3-9,5) mg/L versus 3,0 (2,6-3,7) mg/L. A farmacocinética mostrou-se alterada nos dois grupos frente aos dados de referência reportados em voluntários sadios. Significativa alteração ocorreu em diferentes proporções pela comparação entre os grupos relativamente à constante de eliminação 0,190 (0,157-0,211) versus 0,349 (0,334-0,382) h-1; meia-vida biológica 3,6 (3,3-4,4) versus 2,0 (1,8-2,1) h; depuração total corporal 8,6 (8,2-8,9) versus 5,3 (5,2-5,4) L/h; volume de distribuição 41,8 (39,9-44,5) versus 15,4 (14,1-16,2) L (p<0,0001). A infecção de ferida foi a mais prevalente nos dois grupos com 47% versus 38% dos isolados, sendo a Klebsiella pneumoniae, a principal enterobactéria. A abordagem PK/PD para patógenos CIM 1 a 4 mg/L mostrou cobertura até CIM 4 mg/L para a infusão estendida e até CIM 2 mg/L para infusão intermitente. Em conclusão, demonstrou-se a superioridade da infusão estendida decorrente de alterações na farmacocinética do meropenem em pacientes grandes queimados. O aumento do volume de distribuição contribuiu para o prolongamento da meia-vida e dos altos níveis de vale registrados, o justifica o impacto na cobertura antimicrobiana após infusão estendida e controle das infecções com cura desses pacientes

Meropenem is a broad-spectrum agent widely prescribed for the treatment of septic shock caused by gram-negative susceptible strains in critically ill patients from the Intensive Care Units. Subject of the present study was to evaluate the drug effectiveness in critically ill septic burn patients in SIRS at the early period of septic shock receiving the recommended dose of Meropenem 1 g q8h by intermittent 0.5 hour infusion or the extended 3 hour infusion. Twenty-five septic patients were: (6F/19M), 26 (21-34) years, medians (quartiles), 70 (60-75) kg, total burn body surface (SCTQ) 35 (16-42) %, SAPS 3: 55 (45-59) and Clcr 129 (95-152) ml/min. Thermal trauma was registered in 19/25 and electrical trauma in the remaining patients (6/25), inhalation injury (17/25), orotracheal intubation and vasopressor requirement in 18/25 patients. Patients were distributed in two groups on the basis of the duration of drug infusion that occurred for the patients of group 1 (1g q8h 0.5 hr) until 2014, December in the hospital. In addition, the extended 3 hours infusion occurred after that period for patients enrolled afterwards (group 2). Pharmacokinetics was investigated after blood sampling at the third (3rd) hour and the fifth (5th) hour of starting the meropenem infusion. Serum drug measurement was done by liquid chromatography. A one compartment open model was applied and kinetic parameters were estimated. PK/PD approach based on the new recommended index of drug effectiveness 100% fΔT>MIC was performed, on the basis on PK parameters and the minimum inhibitory concentration, PD parameter. It was demonstrated a significant difference between groups (p <0.0001) related to the trough levels 7.8 (7.3-9.5) mg/L versus 3.0 (2.6-3.7) mg/L, respectively after extended infusion or intermittent infusion. Concerning the pharmacokinetics, it was shown profound changes on meropenem kinetic parameters in both groups of burn patients by comparison with the reference data reported in healthy volunteers. In addition, it is important to highlight that significant changes occurred also by comparison of PK data between groups of patients related to the parameters: elimination constant 0.190 (0.157-0.211) versus 0.349 (0.334-0.382) h-1; biological half-life 3.6 (3.3-4.4) versus 2.0 (1.8-2.1) hr; total body clearance 8.6 (8.2-8.9) versus 5.3 (5.2-5.4) L/hr; volume of distribution 41.8 (39.9-44.5) versus 15.4 (14.1-16.2) L. Concerning the inflammatory biomarker an increase of C-reactive protein was registered in both groups of septic patients in SIRS: 224 versus 300 mg/L, p = 0.0411, after the extended infusion versus intermittent infusion, respectively. Wound and bone were the most prevalent sites of infection in those patients of both groups. It was shown in the isolates the prevalence of Gram-negative strains 54/83 (65%) that were distributed in Enterobacteriaceae, K. pneumoniae 7/30 (23%), and Non-Enterobacteriaceae, P. aeruginosa 13/54 (24%) followed by Acinetobacter baumannii 11/54 (20%). Drug effectiveness against susceptible strains was demonstrated by PK/PD approach up to 4 mg/L over 2 mg/L, after the extended infusion or after intermittent infusion, respectively. In conclusion, the superiority of the extended infusion in septic burn patients at the earlier period of septic shock was demonstrated, once considerable increases on volume of distribution impacted the drug effectiveness of these patients. Cure was obtained by meropenem monotherapy in 22/25 patients; only three patients (3/25) received meropenem - colistine combined therapy due to Acinetobacter baumannii isolated

Definitions and pathophysiology of vasoplegic shock.

Vasoplegia is the syndrome of pathological low systemic vascular resistance, the dominant clinical feature of which is reduced blood pressure in the presence of a normal or raised cardiac output. The vasoplegic syndrome is encountered in many clinical scenarios, including septic shock, post-cardiac bypass and after surgery, burns and trauma, but despite this, uniform clinical definitions are lacking, which renders translational research in this area challenging. We discuss the role of vasoplegia in these contexts and the criteria that are used to describe it are discussed. Intrinsic processes which may drive vasoplegia, such as nitric oxide, prostanoids, endothelin-1, hydrogen sulphide and reactive oxygen species production, are reviewed and potential for therapeutic intervention explored. Extrinsic drivers, including those mediated by glucocorticoid, catecholamine and vasopressin responsiveness of the blood vessels, are also discussed. The optimum balance between maintaining adequate systemic vascular resistance against the potentially deleterious effects of treatment with catecholamines is as yet unclear, but development of novel vasoactive agents may facilitate greater understanding of the role of the differing pathways in the development of vasoplegia. In turn, this may provide insights into the best way to care for patients with this common, multifactorial condition.

Reclassificando o espectro de pacientes septicos com o uso do lactato: sepse grave, choque criptico, choque vasoplegico e choque disoxico / Reclassifying the spectrum of septic patients using lactate: severe sepsis, cryptic shock, vasoplegic shock and dysoxic shock

Objetivo: A definição atual de sepse grave e choque séptico inclui um perfil heterogêneo de pacientes. Embora o valor prognóstico de hiperlactatemia seja bem estabelecido, ela está presente em pacientes com ou sem choque. Nosso objetivo foi comparar o prognóstico de pacientes sépticos estratificando-os segundo dois fatores: hiperlactatemia e hipotensão persistente. Métodos: Este estudo é uma análise secundária de um estudo observacional conduzido em dez hospitais no Brasil (Rede Amil - SP). Pacientes sépticos com valor inicial de lactato das primeiras 6 horas do diagnóstico foram incluídos e divididos em 4 grupos segundo hiperlactatemia (lactato >4mmol/L) e hipotensão persistente: (1) sepse grave (sem ambos os critérios); (2) choque críptico (hiperlactatemia sem hipotensão persistente); (3) choque vasoplégico (hipotensão persistente sem hiperlactatemia); e (4) choque disóxico (ambos os critérios). Resultados: Foram analisados 1.948 pacientes, e o grupo sepse grave constituiu 52% dos pacientes, seguido por 28% com choque vasoplégico, 12% choque disóxico e 8% com choque críptico. A sobrevida em 28 dias foi diferente entre os grupos (p<0,001), sendo maior para o grupo sepse grave (69%; p<0,001 versus outros), semelhante entre choque críptico e vasoplégico (53%; p=0,39) e menor para choque disóxico (38%; p<0,001 versus outros). Em análise ajustada, a sobrevida em 28 dias permaneceu diferente entre os grupos (p<0,001), sendo a maior razão de risco para o grupo choque disóxico (HR=2,99; IC95% 2,21-4,05). Conclusão: A definição de pacientes com sepse inclui quatro diferentes perfis, se considerarmos a presença de hiperlactatemia. Novos estudos são necessários para melhor caracterizar pacientes sépticos e gerar conhecimento ...

Objective: The current definition of severe sepsis and septic shock includes a heterogeneous profile of patients. Although the prognostic value of hyperlactatemia is well established, hyperlactatemia is observed in patients with and without shock. The present study aimed to compare the prognosis of septic patients by stratifying them according to two factors: hyperlactatemia and persistent hypotension. Methods: The present study is a secondary analysis of an observational study conducted in ten hospitals in Brazil (Rede Amil - SP). Septic patients with initial lactate measurements in the first 6 hours of diagnosis were included and divided into 4 groups according to hyperlactatemia (lactate >4mmol/L) and persistent hypotension: (1) severe sepsis (without both criteria); (2) cryptic shock (hyperlactatemia without persistent hypotension); (3) vasoplegic shock (persistent hypotension without hyperlactatemia); and (4) dysoxic shock (both criteria). Results: In total, 1,948 patients were analyzed, and the sepsis group represented 52% of the patients, followed by 28% with vasoplegic shock, 12% with dysoxic shock and 8% with cryptic shock. Survival at 28 days differed among the groups (p<0.001). Survival was highest among the severe sepsis group (69%, p<0.001 versus others), similar in the cryptic and vasoplegic shock groups (53%, p=0.39), and lowest in the dysoxic shock group (38%, p<0.001 versus others). In the adjusted analysis, the survival at 28 days remained different among the groups (p<0.001) and the dysoxic shock group exhibited the highest hazard ratio (HR=2.99, 95%CI 2.21-4.05). Conclusion: The definition of sepsis includes four different profiles if we consider the presence of hyperlactatemia. Further studies are needed to better characterize septic patients, to understand the etiology and to design adequate targeted treatments. .

Shock séptico en pediatría I: enfoque actual en el diagnóstico y tratamiento / Septic shock in pediatrics I: current approach in diagnosis and therapeutics

El shock séptico es una de las principales causas de mortalidad infantil a nivel mundial y representa una compleja y progresiva vía inflamatoria secundaria a una enfermedad infecciosa, la cual origina disfunción cardiovascular aguda, no necesariamente hipotensión arterial, condicionando disoxia tisular y eventualmente falla celular y orgánica. Los paquetes de medidas de resucitación propuestos enfatizan el reconocimiento clínico y un tratamiento precoz. Estas intervenciones se basan en la pronta y agresiva resucitación con fluidos intravenosos para una adecuada perfusión tisular, administración de antibióticos, remoción del foco infeccioso y el uso de drogas vasoactivas en caso de ser necesario. La terapia debe evaluarse permanentemente según la normalización de metas clínicas y de laboratorio. En la presente publicación se actualiza el conocimiento de las características epidemiológicas y fisiopatológicas de la sepsis, una puesta al día en definiciones operacionales, campañas internacionales y referentes a las iniciativas propuestas para disminuir su morbimortalidad. Se aborda el enfoque terapéutico inicial en el servicio de urgencia. El objetivo de este artículo es dar a conocer el estado actual del conocimiento en el diagnóstico y tratamiento del paciente con shock séptico especialmente en su fase inicial previo al ingreso a UCI.

Septic shock is a major cause of infant mortality worldwide and represents the progressive underlying inflammatory pathway secondary to an infectious disease, which causes acute cardiovascular dysfunction, not necessarily hypotension, tissue dysoxia and eventually cellular and organ failure. Standard resuscitative measures emphasize clinical recognition and early treatment. These interventions are based on early and aggressive resuscitation with intravenous fluids to optimize tissue perfusion, antibiotics, removal of the source of infection and the use of vasoactive drugs if necessary. Therapy should be permanently evaluated according to the standardized laboratory and clinical targets. This publication is an update on the epidemiology and pathophysiology of sepsis, operational definitions, current international campaigns and initiatives concerning proposals to decrease the morbidity and mortality of this condition. It also addresses initial therapeutic approaches in the emergency room. The aim of this study is to present the current state of knowledge in the diagnosis and treatment of patients with septic shock especially in the initial phase before admissions to intensive care units.

Clasificación PIRO en sepsis grave y shock séptico pediátrico: Nuevo modelo de estratificación y su utilidad en pronóstico / PIRO classification in pediatric severe sepsis and septic shock: A new model for staging and its potential usefulness in prognoses

Background: Sepsis is a dynamic process that involves complex interactions between the pathogenic micro-organisms and the host. The understanding of this heterogeneous disease has led to the development of a new system for stratification of septic patients: the PIRO system: Predisposition (P) -Insult/Infection (I) -Response (R) -Organ disfunction (O), a classification aimed to determine the risk of death in patients with sepsis. Only a few studies have validated this classification system in children. Objective: To empirically test the accuracy of the PIRO system in pediatric patients with septic shock and severe sepsis and associate its individual components to predict mortality. Patients and Method: A retrospective chart review was performed in a 13 bed PICU during 24 months (January 2006 to December 2007) Demographic, clinical and microbiological data were recorded in all patients with a diagnosis of septic shock and severe sepsis during the study period. For all patients the PIRO classification system was applied by one of four authors using paramethers measured at admission. Results: Atotal of 42 patients were included with a mean age of 11 months (range 3.25-58.3) of which 52 percent were male. Overall mortality was 19 percent and variables associated with mortality for each category were: (P) Chronic illness (OR: 7 IC95 percent 0.95-51) and Immunodeficiency (OR: 6.2; IC95 percent 1.1-35.2); (R) leucopema (OR 9; IC95 percent: 1.96-41.72); (O) more thanthree dysfunctional organs (OR: 6.1; IC95 percent: 1.22-31). None of the (I) variables were associated with mortality. Conclusions: The PIRO classification system identified factors associated with a fatal outcome in our population. The test is relatively simple to apply but cross-sectional studies are required to define variables associated with death that should then be prospectivelly validated.

Introducción: La compresión de la sepsis como un proceso dinámico, resultado de la interacción entre hospedero y agente infeccioso, ha llevado al sistema de estratificación "PIRO" (P) Predisposición, (I) Injuria/ Infección, (R) Respuesta y (O) disfunción de Órganos, clasificación orientada a predecir la muerte en pacientes con sepsis, a ganar adeptos. Sin embargo, faltan estudios clínicos que lo validen. Objetivo: Evaluar la certeza de la clasificación "PIRO" en sepsis grave y shock séptico para predecir mortalidad. Pacientes y Método: Estudio retrospectivo efectuado en una UCI pediátrica de 13 camas durante 24 meses (enero 2006 a diciembre 2007). Uno de los cuatro autores registró las características demográficas, clínicas y microbiológicas de la totalidad de pacientes ingresados con diagnóstico de sepsis grave y shock séptico, agrupándolos según sobrevida. Fueron clasificadas estas variables según sistema PIRO Se evaluó la asociación de estas variables con la mortalidad. Resultados: 42 pacientes, edad 11 meses (3,2-58) y mortalidad 19 por ciento. Las variables asociadas a mortalidad fueron: (P) antecedente de patología crónica (OR: 7; IC95 por ciento 0,95-51) e inmunodeficiencia (6,2; 1,1-35,2); (R) leucopenia (9; 1,96-41,72); (O) disfunción de 3 o más órganos (6,1; 1,22-31). Ninguna de las variables (I) se asoció a mortalidad. Conclusiones: El sistema "PIRO" es un modelo en desarrollo para una clasificación individual, de fácil aplicación. Permite reconocer factores asociados a un resultado fatal, en la presente casuística dado por inmunodeficiencia, leucopenia y fallo de tres o más sistemas. Es importante realizar estudios transversales para definir una etapificación PIRO consensuada y luego validarla prospectivamente.

Serum neutrophil gelatinase-associated lipocalin (NGAL) as a marker of acute kidney injury in critically ill children with septic shock.

OBJECTIVE: To validate serum neutrophil gelatinase-associated lipocalin (NGAL) as an early biomarker for acute kidney injury in critically ill children with septic shock. DESIGN: Observational cohort study. SETTING: Fifteen North American pediatric intensive care units (PICUs). PATIENTS: A total of 143 critically ill children with systemic inflammatory response syndrome (SIRS) or septic shock and 25 healthy controls. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Serum NGAL was measured during the first 24 hrs of admission to the PICU. Acute kidney injury was defined as a blood urea nitrogen concentration >100 mg/dL, serum creatinine >2 mg/dL in the absence of preexisting renal disease, or the need for dialysis. There was a significant difference in serum NGAL between healthy children (median 80 ng/mL, interquartile ratio [IQR] 55.5-85.5 ng/mL), critically ill children with SIRS (median 107.5 ng/mL, IQR 89-178.5 ng/mL), and critically ill children with septic shock (median 302 ng/mL, IQR 151-570 ng/mL; p < .001). Acute kidney injury developed in 22 of 143 (15.4%) critically ill children. Serum NGAL was significantly increased in critically ill children with acute kidney injury (median 355 ng/mL, IQR 166-1322 ng/mL) compared with those without acute kidney injury (median 186 ng/mL, IQR 98-365 ng/mL; p = .009). CONCLUSIONS: Serum NGAL is a highly sensitive but nonspecific predictor of acute kidney injury in critically ill children with septic shock. Further validation of serum NGAL as a biomarker of acute kidney injury in this population is warranted.

Reanimación protocolizada del shcok séptico / Protocolized reanimation of septic shock

Severe sepsis and septic shock are pathologies with an increasing incidence in the world. Annually, in the USA 200.000 people die because of severe sepsis, the same number that die because of a myocardial infarction, being this last disease much more common. In Chile, a multicentric study found a 40 percent of prevalence of severe sepsis in critically ill patients, with amortality of 27 percent. In this scenario, it becomes of great importance the appropriate and integral management of this condition, by means of an early diagnosis and the implementation of anaggressive protocolized resuscitation, guided by clear goals. During the first stage of the resuscitation cristalloids and/ or colloids can be used, in order to expand the intravascular space, searching for CVP around 8 to 12 mmHg. In case of hypotension refractory to the administration of fluids, it is recommended to start with increasing doses of norepinephrin untila MAP of 65 - 75 mmHg is achieved. The intensity of the septic shock can be stratified according to the requirements of norepinephrine. It is of great importance to obtain blood cultures of the patients and to start with empiric antibiotic therapy as soon as possible. The initial metabolic goal must be the normalization of the central venous oxygen saturation. The implementation of the resuscitation bundle during the first six hours, since the diagnose of severe sepsis is done, increases the chances of surviving. Protocols of sedation and analgesia, and the use of protective mechanical ventilation is highly recommended. The use of hydrocortisone and human recombinant protein C in selected patients, may have a beneficial result in the outcome.Vasopressin, terlipressin and high-volume hemofiltration can be used as rescue measures for the most severe patients.

Endocan, a new endothelial marker in human sepsis.

OBJECTIVES: a) To evaluate in septic patients the blood levels of endocan, a circulating proteoglycan, which regulates leukocyte function-associated antigen-1/intercellular adhesion molecule-1 interactions in vitro; b) to determine whether endocan could be used as a diagnostic and prognostic marker in sepsis in the intensive care unit; and c) to study kinetics of endocan secretion by endothelial cells in vitro after stimulation by soluble mediators involved in sepsis. DESIGN: Prospective observational study. SETTING: Intensive care unit of the University Hospitals of Lille, France, and Geneva, Switzerland. PATIENTS: All patients admitted to the intensive care unit over a 6-month period with clinical evidence of severe sepsis or septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In vitro, we showed a sustained endocan secretion by endothelial cells after stimulation by lipopolysaccharide and tumor necrosis factor-alpha. Circulating levels of endocan measured in 63 patients admitted to the intensive care unit with sepsis were significantly elevated compared with 20 healthy donors and seven patients with systemic inflammatory response syndrome: 2.71 +/- 4.88 ng/mL vs. 0.77 +/- 0.44 ng/mL vs. 0.68 +/- 1.03 ng/mL (median +/- interquartile range, p < .001). Endocan levels were higher in patients with septic shock (6.11 +/- 12.99 ng/mL, n = 22) than in patients with severe sepsis (1.97 +/- 7.8 ng/mL, n = 12) or sepsis (1.95 +/- 1.63 ng/mL, n = 29). Measurement of endocan at intensive care unit admission revealed higher levels in nonsurvivors (n = 12) than in patients still alive 10 days later (n = 51, 6.98 +/- 13.8 vs. 2.45 +/- 4.09, p < .01). CONCLUSIONS: These results suggest that in septic patients, endocan blood level is related to the severity of illness and the outcome of the patient and may represent a novel endothelial cell dysfunction marker.

Decreased levels of dehydroepiandrosterone sulphate in severe critical illness: a sign of exhausted adrenal reserve?

INTRODUCTION: Dehydroepiandrosterone (DHEA) and its sulphate (DHEAS) are pleiotropic adrenal hormones with immunostimulating and antiglucocorticoid effects. The present study was conducted to evaluate the time course of DHEAS levels in critically ill patients and to study their association with the hypothalamic-pituitary-adrenal axis. MATERIALS AND METHOD: This was a prospective observational clinical and laboratory study, including 30 patients with septic shock, eight patients with multiple trauma, and 40 age- and sex-matched control patients. We took serial measurements of blood concentrations of DHEAS, cortisol, tumour necrosis factor-alpha and IL-6, and of adrenocorticotrophic hormone immunoreactivity over 14 days or until discharge/death. RESULTS: On admission, DHEAS was extremely low in septic shock (1.2 +/- 0.8 mol/l) in comparison with multiple trauma patients (2.4 +/- 0.5 micromol/l; P < 0.05) and control patients (4.2 +/- 1.8; P < 0.01). DHEAS had a significant (P < 0.01) negative correlation with age, IL-6 and Acute Physiology and Chronic Health Evaluation II scores in both patient groups. Only during the acute phase did DHEAS negatively correlate with dopamine. Nonsurvivors of septic shock (n = 11) had lower DHEAS levels (0.4 +/- 0.3 micromol/l) than did survivors (1.7 +/- 1.1 micromol/l; P < 0.01). The time course of DHEAS exhibited a persistent depletion during follow up, whereas cortisol levels were increased at all time points. CONCLUSION: We identified extremely low DHEAS levels in septic shock and, to a lesser degree, in multiple trauma patients as compared with those of age- and sex-matched control patients. There appeared to be a dissociation between DHEAS (decreased) and cortisol (increased) levels, which changed only slightly over time. Nonsurvivors of sepsis and patients with relative adrenal insufficiency had the lowest DHEAS values, suggesting that DHEAS might be a prognostic marker and a sign of exhausted adrenal reserve in critical illness.

Association between mitochondrial dysfunction and severity and outcome of septic shock.

BACKGROUND: Sepsis-induced multiple organ failure is the major cause of mortality and morbidity in critically ill patients. However, the precise mechanisms by which this dysfunction is caused remain to be elucidated. We and others have shown raised tissue oxygen tensions in septic animals and human beings, suggesting reduced ability of the organs to use oxygen. Because ATP production by mitochondrial oxidative phosphorylation accounts for more than 90% of total oxygen consumption, we postulated that mitochondrial dysfunction results in organ failure, possibly due to nitric oxide, which is known to inhibit mitochondrial respiration in vitro and is produced in excess in sepsis. METHODS: We did skeletal muscle biopsies on 28 critically ill septic patients within 24 h of admission to intensive care, and on nine control patients undergoing elective hip surgery. The biopsy samples were analysed for respiratory-chain activity (complexes I-IV), ATP concentration, reduced glutathione (an intracellular antioxidant) concentration, and nitrite/nitrate concentrations (a marker of nitric oxide production). FINDINGS: Skeletal muscle ATP concentrations were significantly lower in the 12 patients with sepsis who subsequently died than in the 16 septic patients who survived (p=0.0003) and in controls (p=0.05). Complex I activity had a significant inverse correlation with norepinephrine requirements (a proxy for shock severity, p=0.0003) and nitrite/nitrate concentrations (p=0.0004), and a significant positive correlation with concentrations of reduced glutathione (p=0.006) and ATP (p=0.03). INTERPRETATION: In septic patients, we found an association between nitric oxide overproduction, antioxidant depletion, mitochondrial dysfunction, and decreased ATP concentrations that relate to organ failure and eventual outcome. These data implicate bioenergetic failure as an important pathophysiological mechanism underlying multiorgan dysfunction.

A pilot study of coupled plasma filtration with adsorption in septic shock.

OBJECTIVE: To test the hypothesis that nonselective plasma adsorption by a hydrophobic resin (coupled plasmafiltration and adsorption) could improve hemodynamics and restore leukocyte responsiveness in patients with septic shock. DESIGN: Prospective, pilot, crossover clinical trial. SETTING: General intensive care unit in a teaching hospital. SUBJECTS: Ten patients with hyperdynamic septic shock. INTERVENTIONS: Patients were randomly allocated to 10 hrs of either coupled plasma filtration adsorption plus hemodialysis (treatment A) or continuous venovenous hemodiafiltration (treatment B) in random order. We measured the change in mean arterial pressure, norepinephrine requirements, and leukocyte tumor necrosis factor-alpha (TNF-alpha) production (both spontaneous and lipopolysaccharide-stimulated) after 10 hrs of each treatment. We also tested TNF-alpha production from normal human adherent monocytes incubated with patients' plasma obtained before and after the resin, both with or without incubation with an anti-interleukin-10 monoclonal antibody. RESULTS: Mean arterial pressure increased after 10 hr by 11.8 mm Hg with treatment A and by 5.5 mm Hg with treatment B (p =.001). There was an average decrease of norepinephrine requirement of 0.08 microg/kg/min with treatment A and 0.0049 microg/kg/min with treatment B (p =.003). All patients but one survived. Spontaneous and lipopolysaccharide-induced TNF-alpha production from patients' whole blood increased over time with treatment A. This increase was more marked in blood drawn after the device (plasmafiltrate-sorbent plus hemodialyzer) (p =.009). Preresin plasma suppressed lipopolysaccharide-stimulated production of TNF-alpha by 1 x 10(6)cultured adherent monocytes from healthy donors. This suppressive effect was significantly reduced after passage of plasma through the resin (p =.019) and after incubation with anti-interleukin-10 monoclonal antibodies (p =.028). CONCLUSIONS: In patients with septic shock, coupled plasmafiltration-adsorption combined with hemodialysis was associated with improved hemodynamics compared with continuous venovenous hemodiafiltration. This result might be related to its ability to restore leukocyte responsiveness to lipopolysaccharide. These findings suggest a potential role for blood purification in the treatment of septic shock.

Patterns of corticosteroid-binding globulin and the free cortisol index during septic shock and multitrauma.

OBJECTIVE: To study the time course of corticosteroid binding-globulin (CBG) level and the free cortisol index (FCI) in comparison with total cortisol and ACTH concentrations during acute and prolonged critical illness. DESIGN: Prospective observational clinical study. SETTING: Twenty-bed medical/surgical intensive care unit. PATIENTS AND PARTICIPANTS: Thirty patients with septic shock, eight patients with multitrauma, and forty healthy control subjects. MEASUREMENTS AND RESULTS: During 14 days or until discharge/death, we serially measured serum concentrations of CBG, cortisol, TNF-alpha, IL-6, plasma ACTH immunoreactivity, and the FCI (=cortisol/CBG x 100). We also recorded haemodynamic parameters, APACHE II, ISS, SOFA scores, shock duration, inotrope use, and ICU mortality. In both groups we found markedly decreased CBG levels in the early phase (septic shock: 17.5+/-5.9, and trauma: 16.1+/-2.3 mg/l) in comparison with controls (37.3+/-5.3 mg/l). The FCI was high in this early phase (septic shock: 7.2+/-2.7; trauma: 6.5+/-1.3; controls: 1.25+/-0.76). During follow-up, CBG levels significantly increased, reaching normal levels from day 7 on. The FCI showed an opposite biphasic pattern, with near-normalising FCI values during the second phase. Regression analysis showed a negative correlation between CBG and IL-6 levels (rs=-0.63; P<0.05), but no relation between CBG concentrations and disease severity, shock duration or death was found. CONCLUSIONS: We found extremely low CBG levels in early stage septic shock and multitrauma. These dramatic changes are reflected in a concomitant higher FCI, indicating a higher free cortisol level. A second phase displays increasing and normalising CBG levels, independent from clinical parameters. We believe that CBG plays an active role in the glucocorticoid response to severe stress and in the regulation of cortisol availability to target tissues.

Plasma granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor levels in critical illness including sepsis and septic shock: relation to disease severity, multiple organ dysfunction, and mortality.

OBJECTIVE: To define the circulating levels of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) during critical illness and to determine their relationship to the severity of illness as measured by the Acute Physiology and Chronic Health Evaluation (APACHE) II score, the development of multiple organ dysfunction, or mortality. DESIGN: Prospective cohort study. SETTING: University hospital intensive care unit. PATIENTS: A total of 82 critically ill adult patients in four clinically defined groups, namely septic shock (n = 29), sepsis without shock (n = 17), shock without sepsis (n = 22), and nonseptic, nonshock controls (n = 14). INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: During day 1 of septic shock, peak plasma levels of G-CSF, interleukin (IL)-6, and leukemia inhibitory factor (LIF), but not GM-CSF, were greater than in sepsis or shock alone (p < .001), and were correlated among themselves (rs = 0.44-0.77; p < .02) and with the APACHE II score (rs = 0.25-0.40; p = .03 to .18). G-CSF, IL-6, and UF, and sepsis, shock, septic shock, and APACHE II scores were strongly associated with organ dysfunction or 5-day mortality by univariate analysis. However, multiple logistic regression analysis showed that only septic shock remained significantly associated with organ dysfunction and only APACHE II scores and shock with 5-day mortality. Similarly, peak G-CSF, IL-6, and LIF were poorly predictive of 30-day mortality. CONCLUSIONS: Plasma levels of G-CSF, IL-6, and LIF are greatly elevated in critical illness, including septic shock, and are correlated with one another and with the severity of illness. However, they are not independently predictive of mortality, or the development of multiple organ dysfunction. GM-CSF was rarely elevated, suggesting different roles for G-CSF and GM-CSF in human septic shock.