Individualized resuscitation strategy for septic shock formalized by finite mixture modeling and dynamic treatment regimen.

BACKGROUND: Septic shock comprises a heterogeneous population, and individualized resuscitation strategy is of vital importance. The study aimed to identify subclasses of septic shock with non-supervised learning algorithms, so as to tailor resuscitation strategy for each class. METHODS: Patients with septic shock in 25 tertiary care teaching hospitals in China from January 2016 to December 2017 were enrolled in the study. Clinical and laboratory variables were collected on days 0, 1, 2, 3 and 7 after ICU admission. Subclasses of septic shock were identified by both finite mixture modeling and K-means clustering. Individualized fluid volume and norepinephrine dose were estimated using dynamic treatment regime (DTR) model to optimize the final mortality outcome. DTR models were validated in the eICU Collaborative Research Database (eICU-CRD) dataset. RESULTS: A total of 1437 patients with a mortality rate of 29% were included for analysis. The finite mixture modeling and K-means clustering robustly identified five classes of septic shock. Class 1 (baseline class) accounted for the majority of patients over all days; class 2 (critical class) had the highest severity of illness; class 3 (renal dysfunction) was characterized by renal dysfunction; class 4 (respiratory failure class) was characterized by respiratory failure; and class 5 (mild class) was characterized by the lowest mortality rate (21%). The optimal fluid infusion followed the resuscitation/de-resuscitation phases with initial large volume infusion and late restricted volume infusion. While class 1 transitioned to de-resuscitation phase on day 3, class 3 transitioned on day 1. Classes 1 and 3 might benefit from early use of norepinephrine, and class 2 can benefit from delayed use of norepinephrine while waiting for adequate fluid infusion. CONCLUSIONS: Septic shock comprises a heterogeneous population that can be robustly classified into five phenotypes. These classes can be easily identified with routine clinical variables and can help to tailor resuscitation strategy in the context of precise medicine.

Sepsis Subclasses: A Framework for Development and Interpretation.

Sepsis is defined as a dysregulated host response to infection that leads to life-threatening acute organ dysfunction. It afflicts approximately 50 million people worldwide annually and is often deadly, even when evidence-based guidelines are applied promptly. Many randomized trials tested therapies for sepsis over the past 2 decades, but most have not proven beneficial. This may be because sepsis is a heterogeneous syndrome, characterized by a vast set of clinical and biologic features. Combinations of these features, however, may identify previously unrecognized groups, or "subclasses" with different risks of outcome and response to a given treatment. As efforts to identify sepsis subclasses become more common, many unanswered questions and challenges arise. These include: 1) the semantic underpinning of sepsis subclasses, 2) the conceptual goal of subclasses, 3) considerations about study design, data sources, and statistical methods, 4) the role of emerging data types, and 5) how to determine whether subclasses represent "truth." We discuss these challenges and present a framework for the broader study of sepsis subclasses. This framework is intended to aid in the understanding and interpretation of sepsis subclasses, provide a mechanism for explaining subclasses generated by different methodologic approaches, and guide clinicians in how to consider subclasses in bedside care.

Comparison of Sepsis Definitions as Automated Criteria.

OBJECTIVES: Assess the impact of heterogeneity among established sepsis criteria (Sepsis-1, Sepsis-3, Centers for Disease Control and Prevention Adult Sepsis Event, and Centers for Medicare and Medicaid severe sepsis core measure 1) through the comparison of corresponding sepsis cohorts. DESIGN: Retrospective analysis of data extracted from electronic health record. SETTING: Single, tertiary-care center in St. Louis, MO. PATIENTS: Adult, nonsurgical inpatients admitted between January 1, 2012, and January 6, 2018. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In the electronic health record data, 286,759 encounters met inclusion criteria across the study period. Application of established sepsis criteria yielded cohorts varying in prevalence: Centers for Disease Control and Prevention Adult Sepsis Event (4.4%), Centers for Medicare and Medicaid severe sepsis core measure 1 (4.8%), International Classification of Disease code (7.2%), Sepsis-3 (7.5%), and Sepsis-1 (11.3%). Between the two modern established criteria, Sepsis-3 (n = 21,550) and Centers for Disease Control and Prevention Adult Sepsis Event (n = 12,494), the size of the overlap was 7,763. The sepsis cohorts also varied in time from admission to sepsis onset (hr): Sepsis-1 (2.9), Sepsis-3 (4.1), Centers for Disease Control and Prevention Adult Sepsis Event (4.6), and Centers for Medicare and Medicaid severe sepsis core measure 1 (7.6); sepsis discharge International Classification of Disease code rate: Sepsis-1 (37.4%), Sepsis-3 (40.1%), Centers for Medicare and Medicaid severe sepsis core measure 1 (48.5%), and Centers for Disease Control and Prevention Adult Sepsis Event (54.5%); and inhospital mortality rate: Sepsis-1 (13.6%), Sepsis-3 (18.8%), International Classification of Disease code (20.4%), Centers for Medicare and Medicaid severe sepsis core measure 1 (22.5%), and Centers for Disease Control and Prevention Adult Sepsis Event (24.1%). CONCLUSIONS: The application of commonly used sepsis definitions on a single population produced sepsis cohorts with low agreement, significantly different baseline demographics, and clinical outcomes.

Characteristics and clinical outcomes of culture-negative and culture-positive septic shock: a single-center retrospective cohort study.

BACKGROUND: We evaluated the characteristics and outcomes of culture-negative versus culture-positive septic shock. METHODS: We performed a retrospective observational study of data from a prospective registry from 2014 to 2018. A total of 2,499 adult patients with septic shock were enrolled. The primary outcome was 90-day mortality, and the secondary outcomes were the length of hospital stay, a requirement for mechanical ventilation or renal replacement therapy, and in-hospital mortality. RESULTS: Of 1,718 patients with septic shock, 1,012 (58.9%) patients were culture-positive (blood 803, urine 302, sputum 102, others 204) and the median pathogen detection time was 9.5 h (aerobic 10.2 h and anaerobic 9.0 h). The most common site of culture-positive infection was the hepatobiliary tract (39.5%), while for the culture-negative it was the lower respiratory tract (38.2%). The culture-negative group had a lower mean body temperature (37.3 vs 37.7 ℃), lactate (2.5 vs. 3.2 mmol/L), C-reactive protein (11.1 vs 11.9 mg/dL), and sequential organ failure assessment score (7.0 vs. 8.0) than that of the culture-positive group. However, 90-day mortality between the groups was not significantly different (32.7 vs 32.2%, p = 0.83), and the other clinical outcomes also did not differ significantly. Moreover, a shorter culture detection time was correlated with a higher sequential organ failure assessment score but not with mortality. CONCLUSION: Patients with septic shock are frequently culture-negative, especially in cases where the infection focus is in the lower respiratory tract. Although culture-negative was associated with a degree of organ dysfunction, it was not an independent predictor of death.

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.

A prospective observational study to explore the correlation of peripheral arterial pulse/resistance index, organ function, and inflammation in patients with septic shock.

INTRODUCTION: The evaluation of the functional status of blood vessels, especially the arterial system, plays a very important role in the judgment of the condition of septic shock patients and the guidance of resuscitation programs and the judgment of the therapeutic effect. We aimed to design an observational study protocol to explore the correlation of peripheral arterial pulse/resistance index, organ function and inflammation in patients with septic shock. METHODS AND ANALYSIS: A total of 60 patients with septic shock in the Affiliated Hospital of Southwest Medical University from June 2020 to September 2020 and 20 healthy volunteers will be enrolled. Total of 60 patients with septic shock will be randomly divided into 20 groups by lot method. Group 1: fluid resuscitation; Group 2: fluid resuscitation + norepinephrine; Group 3: fluid resuscitation + norepinephrine + ulinastatin; Group 4: healthy control group. Fluid resuscitation is an early goal-directed fluid resuscitation in which norepinephrine is adjusted by a senior intensive care unit specialist for clinical presentation and ulinastatin is pumped at 20,000 U/h. Index including vascular ultrasound, inflammatory factors, organ function will be collected and analyzed. DISCUSSION: Existing studies on septic shock focus on hemodynamics of the heart, brain, and kidney, while the differences in blood flow between peripheral blood vessels and protective renal vessels may be consistent, and imaging analysis is still lacking. This study protocol aims to explore the correlation of peripheral arterial pulsation index/resistance index, organ function, and inflammation in patients with septic shock. TRIAL REGISTRATION: Chinese Clinical trial registry: ChiCTR2000031565.

Subphenotypes in Patients with Septic Shock Receiving Vitamin C, Hydrocortisone, and Thiamine: A Retrospective Cohort Analysis.

This study aimed to identify septic phenotypes in patients receiving vitamin C, hydrocortisone, and thiamine using temperature and white blood cell count. Data were obtained from septic shock patients who were also treated using a vitamin C protocol in a medical intensive care unit. Patients were divided into groups according to the temperature measurements as well as white blood cell counts within 24 h before starting the vitamin C protocol. In the study, 127 patients included who met the inclusion criteria. In the cohort, four groups were identified: "Temperature ≥37.1 °C, white blood cell count ≥15.0 1000/mm3" (group A; n = 27), "≥37.1 °C, <15.0 1000/mm3" (group B; n = 30), "<37.1 °C, ≥15.0 1000/mm3" (group C; n = 35) and "<37.1 °C, <15.0 1000/mm3" (group D; n = 35). The intensive care unit mortality rates were 15% for group A, 33% for group B, 34% for group C, and 49% for group D (p = 0.051). The temporal improvement in organ dysfunction and vasopressor dose seemed more apparent in group A patients. Our results suggest that different subphenotypes exist among sepsis patients treated using a vitamin C protocol, and clinical outcomes might be better for patients with the hyperinflammatory subphenotype.

Association of septic shock definitions and standardized mortality ratio in a contemporary cohort of critically ill patients.

PURPOSE: The newly proposed septic shock definition has provoked a substantial controversy in the emergency and critical care communities. We aim to compare new (SEPSIS-III) versus old (SEPSIS-II) definitions for septic shock in a contemporary cohort of critically ill patients. MATERIAL AND METHODS: Retrospective cohort of consecutive patients, age ≥ 18 years admitted to intensive care units at the Mayo Clinic between January 2009 and October 2015. We compared patients who met old, new, both, or neither definition of sepsis shock. SMR were calculated using APACHE IV predicted mortality. RESULTS: The initial cohort consisted of 16,720 patients who had suspicion of infection, 7463 required vasopressor support. The median (IQR) age was 65(54-75) years and 4167(55.8%) were male. Compared to patients with old definition, the patients with new definition had higher APACHE III score (median IQR); (73 (57-92) vs. 70 (56-89), p < .01); SOFA score; (6 (4-10) vs. 6 (4-9), p < .01), were older (70 (59-79) vs. 64 (54-74) years, p = .03). They also had higher hospital mortality, N (%) 71, (19.7%) vs. 40 (12.6%), p < .01) and a higher SMR (0.66 vs. 0.45, p < .01). CONCLUSIONS: Compared to SEPSIS-II, SEPSIS-III definition of septic shock identifies patients further along disease trajectory with higher likelihood of poor outcome.

Prognostic performance of disease severity scores in patients with septic shock presenting to the emergency department.

BACKGROUND: An accurate disease severity score that can quickly predict the prognosis of patients with sepsis in the emergency department (ED) can aid clinicians in distributing resources appropriately or making decisions for active resuscitation measures. This study aimed to compare the prognostic performance of quick sequential organ failure assessment (qSOFA) with that of other disease severity scores in patients with septic shock presenting to an ED. METHODS: We performed a prospective, observational, registry-based study. The discriminative ability of each disease severity score to predict 28-day mortality was evaluated in the overall cohort (which included patients who fulfilled previously defined criteria for septic shock), the newly defined sepsis subgroup, and the newly defined septic shock subgroup. RESULTS: A total of 991 patients were included. All disease severity scores had poor discriminative ability for 28-day mortality. The sequential organ failure assessment and acute physiology and chronic health evaluation II scores had the highest area under the receiver-operating characteristic curve (AUC) values, which were significantly higher than the AUC values of other disease severity scores in the overall cohort and the sepsis and septic shock subgroups. The discriminative ability of each disease severity score decreased as the mortality rate of each subgroup increased. CONCLUSIONS: All disease severity scores, including qSOFA, did not display good discrimination for 28-day mortality in patients with serious infection and refractory hypotension or hypoperfusion; additionally, none of the included scoring tools in this study could consistently predict 28-day mortality in the newly defined sepsis and septic shock subgroups.

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

Proof of concept study of mass cytometry in septic shock patients reveals novel immune alterations.

Innovative single cell technologies such as mass cytometry (CyTOF) widen possibilities to deeply improve characterisation of immune alterations mechanisms in human diseases. So far, CyTOF has not been used in sepsis - a condition characterized by complex immune disorders. Here, we evaluated feasibility of CyTOF analysis in patients with septic shock. We designed a mass cytometry panel of 25 extracellular markers to study mononuclear cells from 5 septic shock patients and 5 healthy donors. We explored single-cell data with global and specific unsupervised approaches such as heatmaps, SPADE and viSNE. We first validated relevance of our CyTOF results by highlighting established immune hallmarks of sepsis, such as decreased monocyte HLA-DR expression and increased expressions of PD1 and PD-L1 on CD4 T cells and monocytes. We then showed that CyTOF analysis reveals novel aspects of sepsis-induced immune alterations, e.g. B cell shift towards plasma cell differentiation and uniform response of several monocyte markers defining an immune signature in septic patients. This proof of concept study demonstrates CyTOF suitability to analyse immune features of septic patients. Mass cytometry could thus represent a powerful tool to identify novel pathophysiological mechanisms and therapeutic targets for immunotherapy in septic shock patients.

Septic shock-3 vs 2: an analysis of the ALBIOS study.

BACKGROUND: A reanalysis of the ALBIOS trial suggested that patients with septic shock - defined by vasopressor-dependent hypotension in the presence of severe sepsis (Shock-2) - had a survival benefit when treated with albumin. The new septic shock definition (Shock-3) added the criterion of a lactate threshold of 2 mmol/L. We investigated how the populations defined according to Shock-2 and Shock-3 differed and whether the albumin benefit would be confirmed. METHODS: This is a retrospective analysis of the ALBIOS study, a randomized controlled study conducted between 2008 and 2012 in 100 intensive care units in Italy comparing the administration of 20% albumin and crystalloids versus crystalloids alone in patients with severe sepsis or septic shock. We analyzed data from 1741 patients from ALBIOS with serum lactate measurement available at baseline. We compared group size, physiological variables and 90-day mortality between patients defined by Shock-2 and Shock-3 and between the albumin and crystalloid treatment groups. RESULTS: We compared the Shock-2 and the Shock-3 definitions and the albumin and crystalloid treatment groups in terms of group size and physiological, laboratory and outcome variables. The Shock-3 definition reduced the population with shock by 34%. The Shock-3 group had higher lactate (p < 0.001), greater resuscitation-fluid requirement (p = 0.014), higher Simplified Acute Physiology Score II (p < 0.001) and Sepsis-related Organ Failure Assessment scores (p = 0.022), lower platelet count (p = 0.002) and higher 90-day mortality (46.7% vs 51.9%; p = 0.031). Albumin decreased mortality in Shock-2 patients compared to crystalloids (43.5% vs 49.9%; 12.6% relative risk reduction; p = 0.04). In patients defined by Shock-3 a similar benefit was observed for albumin with a 11.3% relative risk reduction (48.7% vs 54.9%; 11.3% relative risk reduction; p = 0.22). CONCLUSIONS: The Sepsis-3 definition reduced the size of the population with shock and showed a similar effect size in the benefits of albumin. The Shock-3 criteria will markedly slow patients' recruitment rates, in view of testing albumin in septic shock. TRIAL REGISTRATION: ClinicalTrials.gov, number NCT00707122 . Registered on 30 June 2008.

Refractory septic shock: our pragmatic approach.

Despite timely intervention, there exists a small subgroup of patients with septic shock who develop progressive multi-organ failure. Seemingly refractory to conventional therapy, they exhibit a very high mortality. Such patients are often poorly represented in large clinical trials. Consequently, good evidence for effective treatment strategies is lacking. In this article, we describe a pragmatic, multi-faceted approach to managing patients with refractory septic shock based on our experience of toxin-mediated sepsis in a specialist referral centre. Many components of this strategy are inexpensive and widely accessible, and so may offer an opportunity to improve outcomes in these critically ill patients.

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.

Six subphenotypes in septic shock: Latent class analysis of the PROWESS Shock study.

PURPOSE: Septic shock is a highly heterogeneous condition which is part of the challenge in its diagnosis and treatment. In this study we aim to identify clinically relevant subphenotypes of septic shock using a novel statistic al approach. METHODS: Baseline patient data from a large global clinical trial of septic shock (n = 1696) was analysed using latent class analysis (LCA). This approach allowed investigators to identify subgroups in a heterogeneous population by estimating a categorical latent variable that detects relatively homogeneous subgroups within a complex phenomenon. RESULTS: LCA identified six different, clinically meaningful subphenotypes of septic shock each with a typical profile: (1) "Uncomplicated Septic Shock, (2) "Pneumonia with adult respiratory distress syndrome (ARDS)", (3) "Postoperative Abdominal", (4) "Severe Septic Shock", (5): "Pneumonia with ARDS and multiple organ dysfunction syndrome (MODS)", (6) "Late Septic Shock". The 6-class solution showed high entropy approaching 1 (i.e., 0.92), indicating there was excellent separation between estimated classes. CONCLUSIONS: LCA appears to be an applicable statistical tool in analysing a heterogenous clinical cohort of septic shock. The results may lead to a better understanding of septic shock complexity and form a basis for considering targeted therapies and selecting patients for future clinical trials.

[New definition of and diagnostic criteria for sepsis - Swedish use of Sepsis-3]. / Nu gäller Sepsis-3 för definitioner och diagnostiska kriterier - De nya internationella begreppen ska användas i svensk sjukvård ­ bland annat ska ¼SIRS« och ¼svår sepsis« skrotas.

A working group representing the Swedish Society for Infectious Diseases, the Swedish Society for Anaesthesiology and Intensive Care, the Swedish Society for Emergency Medicine, and the Swedish Intensive Care Registry have reached consensus on how to adopt the new sepsis definition, Sepsis-3, in Sweden. The recommendation is to implement the new definitions and diagnostic criteria for sepsis and septic shock, but not the use of the new screening tool for sepsis, quick-SOFA, as it needs prospective validation and since it is not clear if quick-SOFA is more useful than the currently used general triage and early warning score systems. The group recommends the use of the sfollowing ICD-10 codes: R65.1 for sepsis and R57.2 for septic shock.