Outcomes of severe sepsis and septic shock patients after stratification by initial lactate value

BACKGROUND: In the setting of severe sepsis and septic shock, mortality increases when lactate levels are ≥ 4 mmol/L. However, the consequences of lower lactate levels in this population are not well understood. The study aimed to determine the in-hospital mortality associated with severe sepsis and septic shock when initial lactate levels are < 4 mmol/L.METHODS: This is a retrospective cohort study of septic patients admitted over a 40-month period. Totally 338 patients were divided into three groups based on initial lactate values. Group 1 had lactate levels < 2 mmol/L; group 2: 2-4 mmol/L; and group 3: ≥ 4 mmol/L. The primary outcome was in-hospital mortality.RESULTS: There were 111 patients in group 1, 96 patients in group 2, and 131 in group 3. The mortality rates were 21.6%, 35.4%, and 51.9% respectively. Univariate analysis revealed the mortality differences to be statistically significant. Multivariate logistic regression demonstrated higher odds of death with higher lactate tier group, however the findings did not reach statistical significance.CONCLUSION: This study found that only assignment to group 3, initial lactic acid level of ≥ 4 mmol/L, was independently associated with increased mortality after correcting for underlying severity of illness and organ dysfunction. However, rising lactate levels in the other two groups were associated with increased severity of illness and were inversely proportional to prognosis.     

脓毒症休克的诊治在精准医学时代下的发展及临床应用

脓毒症休克病情凶险,致死率高。精准医学作为新型医学概念,其医疗模式影响了众多肿瘤及慢性病患者,也为脓毒症的精确诊治带来曙光。同时临床操作技术、基因检测、分子生物学的发展为脓毒症的精准诊治提供了数据和信息,通过对脓毒症患者不同病理生理状态、生物标志物、病原学、基因组学的分析与鉴定来进行个性化精准诊治。本文就精准医学在脓毒症休克诊治中取得的进展进行综述,并对这种新医疗模式的未来进行展望。     

相对肾上腺功能不全与脓毒性休克

相对肾上腺功能不全是脓毒症的常见并发症,易发于脓毒症休克患者.下丘脑-垂体-肾上腺轴、医源性因素、血皮质醇结合球蛋白水平、糖皮质激素抵抗等与相对肾上腺功能不全的发病密切相关.关于脓毒性休克合并相对肾上腺功能不全,临床尚缺乏明确的诊断标准.目前,糖皮质激素被推荐用于对液体复苏及血管收缩药物反应不佳的危重患者.血皮质醇水平可作为评价脓毒性休克合并相对肾上腺功能不全患者预后的指标.     

血管升压素在脓毒性休克中的研究进展

血管升压素是维持心血管功能稳定的重要内源性物质。但脓毒性休克时,其在体内却相对不足,给予外源性血管升压素可引起显著的血管升压效应。目前,脓毒性休克时机体血管升压素缺乏以及机体对其敏感性增高的具体机制尚不清楚。目前研究认为,血管升压素受体改变、收缩和舒张血管因素、自主神经系统和下丘脑-垂体-肾上腺轴均参与了血管升压素高敏感性机制的调节。     

2000年至2020年脓毒症心肌病领域的研究进展：基于知识可视化分析

目的基于知识可视化分析,探讨2000年至2020年脓毒症心肌病（SCM）领域的研究进展。 方法收集2000年1月1日至2020年12月20日中国知网（CNKI）及科学网（WOS）数据库收录的SCM研究领域相关文献。应用Excel软件对数据进行整理并绘制文献增长柱状图;应用CiteSpace 5.0 R1软件对国家、研究机构、作者信息进行提取及整理并生成相关共现网络,分析该领域主要研究力量分布及合作关系,对关键词及相关引文进行分析并绘制共被引文献网络,分析该领域前沿及热点信息。 结果共收集中文文献774篇,英文文献1883篇,中文文献只进行研究机构、发文量、作者的统计描述,所有英文文献均纳入可视化分析。在发文量方面,2000年至2020年SCM研究领域相关国内外文献数量均呈迅速增长,英文文献数量多于中文文献。英文文献分析显示,全球发文量排名前3位的国家依次为美国（618篇）、中国（441篇）、德国（140篇）。从研究机构上看以武汉大学29篇位列WOS首位,德克萨斯大学与哈佛大学分别位列第2、3位;国内发文最多的研究机构为上海中医药大学（21篇）。作者共现网络分析显示在全球形成了四大科研团体,其中以Horton JW、Neviere R、Li CF和Thiemermann C对该领域贡献最大,其中中国学者在该领域研究势头强劲。关键词共现分析显示,研究热点主要围绕脓毒症患者的心功能及预后方面,而通过突增关键词分析可以看出国内文献更多地关注药物对SCM的治疗效果,而国外文献则更多地倾向对SCM的发病机制与管理方面的研究。共被引文献网络分析显示,未来对SCM的研究也应将从临床-机制-管理这几个方面着手,这也与突增关键词分析结果相吻合。 结论通过知识可视化分析可以直观显示,SCM领域主要研究力量大多集中于美国、欧洲等发达国家,但中国学者势头强劲。未来研究趋势倾向于SCM的机制及治疗管理方面。     

Variation in the care of septic shock: the impact of patient and hospital characteristics

Purpose

The aim of this study was to examine treatments of septic shock in a sample of US hospitals and to assess whether patient and hospital characteristics are associated with use of sepsis therapies.

Materials and Methods

We studied 192 hospitals that treated 50 or more adults with septic shock between 2004 and 2006. We examined hospital-level variation in commonly used therapies including mechanical ventilation, activated protein C (APC), hydrocortisone, central venous pressure (CVP) monitoring, albumin/colloid, and pulmonary artery catheters. We calculated interquartile range to assess the hospital-level variation in treatment. We developed hierarchical mixed-effects logistic regression models to examine the association between patient and hospital characteristics and selected treatments.

Results

A total of 22?702 patients met the inclusion criteria. When compared with patients younger than 45 years, patients 75 years or older were as likely to receive mechanical ventilation but less likely to receive APC (odds ratio [OR], 0.35 [95% confidence interval, 0.27-0.45]), hydrocortisone (OR, 0.65 [0.56-0.75]), or CVP monitoring (OR, 0.73 [0.63-0.84]). Compared with whites, black patients were more likely to be mechanically ventilated (OR, 1.15 [1.05-1.25]) but less likely to receive hydrocortisone (OR, 0.86 [0.78-0.95]) or APC (0.70 [0.58-0.86]).

Conclusion

Treatment of septic shock varies across hospitals. In contrast to mechanical ventilation, treatments with weaker supporting evidence showed greater variation, especially among black and older patients.     

Long-term costs and cost-effectiveness of adjunctive corticosteroids for patients with septic shock in New Zealand

ObjectiveThe aim of the study was to determine whether adjunctive hydrocortisone reduced healthcare expenditure and was cost-effective compared with placebo in New Zealand patients in the Adjunctive Glucocorticoid Therapy in Patients with Septic Shock (ADRENAL) trial.DesignThis is a health economic analysis using data linkage to New Zealand Ministry of Health databases to determine resource use, costs, and cost-effectiveness for a 24-month period.SettingThe study was conducted in New Zealand.Participants and interventionPatients with septic shock were randomised to receive a 7-day continuous infusion of 200 mg of hydrocortisone or placebo in the ADRENAL trial.Main outcome measuresHealthcare expenditure was associated with all hospital admissions, emergency department presentations, outpatient visits, and pharmacy expenditure. Effectiveness outcomes included mortality at 6 months and 24 months and quality of life at 6 months. Cost-effectiveness outcomes were assessed with reference to quality-adjusted life years gained at 6 months and life years gained at 24 months.ResultsOf 3800 patients in the ADRENAL trial, 419 (11.0%) were eligible, and 405 (96.7% of those eligible) were included. The mean total costs per patient over 24 months were $143,627 ± 100,890 and $143,772 ± 97,117 for the hydrocortisone and placebo groups, respectively (p = 0.99). Intensive care unit costs for the index admission were $50,492 and $62,288 per patient for the hydrocortisone and placebo groups, respectively (p = 0.09). The mean number of quality-adjusted life years gained at 6 months and mean number of life years gained at 24 months was not significantly different by treatment group, and the probability of hydrocortisone being cost-effective was 55% at 24 months.ConclusionsIn New Zealand, adjunctive hydrocortisone did not reduce total healthcare expenditure or improve outcomes compared with placebo in patients with septic shock.     

Implementation of the Surviving Sepsis Campaign guidelines for severe sepsis and septic shock: We could go faster

Purpose

The aim of this study is to evaluate the feasibility of applying sepsis bundles in the intensive care unit (ICU) and their effect on outcomes.

Methods

In this prospective, observational study in a 31-bed capacity department of intensive care, we measured the time taken to perform sepsis bundle interventions in 69 consecutive patients with severe sepsis or septic shock.

Results

Compliance with the 6-hour bundle was obtained in 44 (72%) of 61 patients; these patients had a lower mortality rate (16% vs 41%, P = .04) and shorter ICU stay (median [range], 5 [3-10] vs 9 [6-19] days, P = .01) than other patients. Compliance with the 24-hour bundle was obtained in 30 (67%) of 44 eligible patients. The mortality rate and duration of ICU stay were not significantly lower in the 24-hour compliant as compared with the noncompliant group (23% vs 33% and 6 [4-11] vs 9 [6-25] days, respectively; P value is not significant). Patients who complied with the 24-hour sepsis bundle after only 12 hours had a lower mortality rate (10% vs 39%, P = .036) and shorter stay (6 [4-10] vs 9 [6-25] days, P = .055) than those who were compliant after 24 hours.

Conclusions

Correct application of the sepsis bundles was associated with reduced mortality and length of ICU stay. Earlier implementation of the 24-hour management bundle could result in better outcomes.     

Hemodynamic variables related to outcome in septic shock

Objective To assess the impact of hemodynamic variables on the outcome of critically ill patients in septic shock and to identify the optimal threshold values related to outcome with special reference to continuously monitored mean arterial pressure (MAP) and mixed venous oxygen saturation (SvO₂).Design and setting Retrospective cohort study in a university hospital intensive care unit (ICU).Patients All consecutive 111 patients with septic shock treated in our ICU between 1 Jan. 1999 and 30 Jan. 2002.Measurements and results The data on the hemodynamic and respiratory monitoring and circulation-related laboratory tests over the first 48 h of treatment in the ICU were collected from the clinical data management system. Data from 6 h and 48 h were analyzed separately. The 30-day mortality rate was 33% (36 of 111). Univariate analysis and forward stepwise logistic regression analysis were performed using the 30-day mortality as the primary endpoint. Mean MAP and lactate on arrival during 6 h, while mean MAP, the area of SvO₂ under 70%, and mean CVP during 48 h were independently associated with mortality. MAP level of 65 mmHg and SvO₂ of 70% had the highest areas under receiver characteristics curves.Conclusions MAP, SvO₂, CVP, and initial lactate were independently associated with mortality in septic shock, with threshold values supporting those published in recent guidelines.     

Sepsis and septic shock

Mortality from septic shock is considerable despite the advantages of cardiovascular support and antibiotic therapy. Understanding the pathophysiology of sepsis enables clinicians to institute rational intervention directed towards the pathophysiological mechanisms. This article reviews definitions of sepsis and offers a brief overview of ist pathophysiology. Current knowledge on the pathophysiological mechanism of cytokines and modulation of systemic cytokine levels during sepsis and septic shock is discussed. The important role of cytokines in sepsis and septic shock may require more detailed investigations of the cytokine pathophysiological network.     

The pathophysiology of septic shock

Septic shock remains a significant challenge for clinicians. Recent advances in cellular and molecular biology have significantly improved our understanding of its pathogenetic mechanisms. These improvements in understanding should translate to better care and improved outcomes for these patients.     

Role of vasopressin in the management of septic shock

Vasopressin is a potent vasopressor for improving organ perfusion during septic shock. The rationale for the use of vasopressin is its relative deficiency of plasma levels and hypersensitivity to its vasopressor effects during septic shock. Growing evidence suggests that low-dose (<0.04 U/min) vasopressin is safe and effective for the treatment of vasodilatory shock. Although it is being used more frequently, there are no randomized clinical trials comparing vasopressin as a first-line agent to commonly used vasopressors. However, vasopressin causes arterial smooth muscle cell contraction through a non-catecholamine receptor pathway, thus it represents an attractive adjunct to the management of septic shock, especially when catecholamines are ineffective.This work was supported by the American Heart Association, HL-66211, and the Evanston Northwestern Healthcare Research Institute.     

Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock

Objective To develop management guidelines for severe sepsis and septic shock that would be of practical use for the bedside clinician, under the auspices of the Surviving Sepsis Campaign, an international effort to increase awareness and improve outcome in severe sepsis.Design The process included a modified Delphi method, a consensus conference, several subsequent smaller meetings of subgroups and key individuals, teleconferences, and electronic-based discussion among subgroups and among the entire committee. The modified Delphi methodology used for grading recommendations built upon a 2001 publication sponsored by the International Sepsis Forum. We undertook a systematic review of the literature graded along 5 levels to create recommendation grades from A–E, with A being the highest grade. Pediatric considerations were provided to contrast adult and pediatric management.Participants Participants included 44 critical care and infectious disease experts representing 11 international organizations.Results A total of 46 recommendations plus pediatric management considerations.Conclusions Evidence-based recommendations can be made regarding many aspects of the acute management of sepsis and septic shock that will hopefully translate into improved outcomes for the critically ill patient. The impact of these guidelines will be formally tested and guidelines updated annually, and even more rapidly when some important new knowledge becomes available.Electronic Supplementary Material Supplementary material is available in the online version of this articel at This article is published jointly with Critical Care MedicineChairs: R. Phillip Dellinger, MD*; Henry Masur, MD; Jean M. Carlet, MD; Herwig Gerlach, MD, PhD**. Committee members: Richard J. Beale, MD**; Marc Bonten, MD; Christian Brun-Buisson, MD; Thierry Calandra, MD; Joseph A. Carcillo, MD; Jonathan Cohen, MD**; Catherine Cordonnier, MD; E. Patchen Dellinger, MD; Jean-Francois Dhainaut, MD, PhD; Roger G. Finch, MD; Simon Finfer, MD; Francois A. Fourrier, MD; Juan Gea-Banacloche MD; Maurene A. Harvey, RN, MPH**; Jan A. Hazelzet, MD; Steven M. Hollenberg, MD; James H. Jorgensen, PhD; Didier Keh, MD; Mitchell M. Levy*, MD; Ronald V. Maier, MD; Dennis G. Maki, MD; John J. Marini, MD; John C. Marshall, MD; Steven M. Opal, MD; Tiffany M. Osborn, MD; Margaret M. Parker, MD**; Joseph E. Parrillo, MD; Graham Ramsay, MD*; Andrew Rhodes, MD; Jonathan E. Sevransky, MD; Charles L. Sprung, MD, JD**; Antoni Torres, MD; Jeffery S. Vender, MD; Jean-Louis Vincent, MD, PhD**; Janice L. Zimmerman, MD. Associate members: E. David Bennett, MD; Pierre-Yves Bochud, MD; Alain Cariou, MD; Glenn S. Murphy, MD; Martin Nitsun, MD; Joseph W. Szokol, MD; Stephen Trzeciak, MD; Christophe Vinsonneau, MD. *Executive Committee, Surviving Sepsis Campaign. **Steering Committee, Surviving Sepsis Campaign.Sponsoring organizations: American Association of Critical-Care Nurses; American College of Chest Physicians; American College of Emergency Physicians; American Thoracic Society; Australian and New Zealand Intensive Care Society; European Society of Clinical Microbiology and Infectious Diseases; European Society of Intensive Care Medicine; European Respiratory Society; International Sepsis Forum; Society of Critical Care Medicine; Surgical Infection Society.The Surviving Sepsis Campaign is administered jointly by the European Society of Intensive Care Medicine, International Sepsis Forum, and the Society of Critical Care Medicine, and is supported in part by unrestricted educational grants from Baxter Bioscience, Edwards Lifesciences, and Eli Lilly and Company (majority sponsor).The authors and the publisher have exercised great care to ensure that drug dosages, formulas, and other information presented in this book are accurate and in accord with the professional standards in effect at the time of publication. Readers are, however, advised to always check the manufacturers product information sheet that is packaged with the respective products to be fully informed of changes in recommended dosages, contraindications, and the like before prescribing or administering any drug.     

An extreme form of the hyperdynamic syndrome in septic shock

We classified 41 patients in septic shock on the basis of cardiac index (CI) after volume expansion with plasma protein solution, in order to obtain adequate filling pressures. Five had decreased CI (<3.5 l/min per m²), 31 had moderately increased CI (3.5–7.0 l/min per m²) and 5 had extreme hyperdynamic shock with CI superior to 7.0 l/min per m². Among the patients with increased CI, those with extreme hyperdynamic state (EHS) had lower total systemic and pulmonary arteriolar resistances (370 vs 658 and 52 vs 119 dynes·s·cm^-5, respectively) and a higher stroke index (67 vs 46 ml/m²), in spite of similar right atrial pressures. In this latter group, blood lactate was higher (6.5 vs 2.1 mmol/l), acidosis was more severe and coagulation disorders more pronounced; all five patients maintained an extremely high CI until death, which supervened after a brief episode of sinus bradycardia. A similar clinical course was rarely observed in the remaining moderately hyperdynamic group, in which mortality rate was significantly lower (35%). Three of five patients with EHS (compared to 2 of 31 in the moderately hyperdynamic group) had liver cirrhosis, the fourth died of fulminant meningococcemia and the fifth had prolonged polymicrobial bacteremia before adequate treatment was begun. Thus, underlying liver disease or particularly severe and uncontrolled infection seems to predispose to EHS. It is concluded that septic shock with extremely high cardiac output and excessively low peripheral resistances represents a distinct subset with more severe metabolic and coagulation disorders, an unusual hemodynamic evolution and a particularly poor prognosis.     

Decrease in circulating dendritic cells predicts fatal outcome in septic shock

Objective Biomarkers allowing accurate early staging of septic shock patients are lacking despite their obvious interest for patient management. Experimental models of septic shock in mouse previously noted a decrease in dendritic cell numbers. The aim of the study was to find a rapid reproducible biological test for an assessment of disease severity. Design Evaluation of peripheral blood dendritic cell counts by flow cytometry using three commercially available kits. Patients and participants Forty-two consecutive septic shock patients were studied prospectively. Measurements and results Early low dendritic cell counts were correlated to disease severity as assessed by Simplified Acute Physiology Score or Sequential Organ Failure Assessment and predicted fatal outcome. The correlation was still present when the results were adjusted for age. Conclusion The monitoring of blood dendritic cell count may provide an early and valuable assessment of the severity of the host response against infection and may influence the therapeutic management of septic shock patients. O. Guisset and M.-S. Dilhuydy contributed equally to this work.     

Reversal of refractory septic shock with drotrecogin alpha (activated)

Objective  We previously reported that early continuous veno-venous hemodiafiltration (CVVHDF) enables rapid identification of a subgroup of patients with “refractory” septic shock and a 100% risk of death. The objective of this study was to investigate whether early administration of drotrecogin alpha (activated) (DrotAA) to this selected subgroup of septic patients at extremely high risk of death would significantly improve prognosis. Method  Prospective observational study in a medical intensive-care unit of a University Hospital. Twenty-three patients with refractory septic shock were included. “Refractory” shock was defined as persistent circulatory failure despite adequate circulatory support, associated with persisting lactic acidosis despite early CVVHDF. Response to CVVDHF was assessed after 6 h of this continuous procedure. Patients selected by this strategy received DrotAA infusion for four days. Results  The 28-day mortality rate of the 23 patients was 39%. No difference was observed at inclusion between survivors and nonsurvivors. In patients who finally survived, 12 h of DrotAA infusion was associated with a significant decrease in lactic acidosis and in norepinephrine dose. Conclusion  DrotAA therapy was associated with unexpectedly high 28-day survival in patients with “refractory” septic shock.     

Metabolic theory of septic shock

Septic shock is a life threatening condition that can develop subsequent to infection. Mortality can reach as high as 80% with over 150000 deaths yearly in the United States alone. Septic shock causes progressive failure of vital homeostatic mechanisms culminating in immunosuppression, coagulopathy and microvascular dysfunction which can lead to refractory hypotension, organ failure and death. The hypermetabolic response that accompanies a systemic inflammatory reaction places high demands upon stored nutritional resources. A crucial element that can become depleted early during the progression to septic shock is glutathione. Glutathione is chiefly responsible for supplying reducing equivalents to neutralize hydrogen peroxide, a toxic oxidizing agent that is produced during normal metabolism. Without glutathione, hydrogen peroxide can rise to toxic levels in tissues and blood where it can cause severe oxidative injury to organs and to the microvasculature. Continued exposure can result in microvascular dysfunction, capillary leakage and septic shock. It is the aim of this paper to present evidence that elevated systemic levels of hydrogen peroxide are present in septic shock victims and that it significantly contributes to the development and progression of this frequently lethal condition.     

Precision medicine in sepsis and septic shock: From omics to clinical tools

Sepsis is a heterogeneous disease with variable clinical course and several clinical phenotypes. As it is associated with an increased risk of death, patients with this condition are candidates for receipt of a very well-structured and protocolized treatment. All patients should receive the fundamental pillars of sepsis management, which are infection control, initial resuscitation, and multiorgan support. However, specific subgroups of patients may benefit from a personalized approach with interventions targeted towards specific pathophysiological mechanisms. Herein, we will review the framework for identifying subpopulations of patients with sepsis, septic shock, and multiorgan dysfunction who may benefit from specific therapies. Some of these approaches are still in the early stages of research, while others are already in routine use in clinical practice, but together will help in the effective generation and safe implementation of precision medicine in sepsis.     

Optimizing antimicrobial therapy in sepsis and septic shock

Every patient with sepsis and septic shock must be evaluated thoroughly at presentation before the initiation of antibiotic therapy. However, in most situations, an abridged initial assessment focusing on critical diagnostic and management planning elements is sufficient. Intravenous antibiotics should be administered as early as possible, and always within the first hour of recognizing severe sepsis and septic shock. Broad-spectrum antibiotics must be selected with one or more agents active against likely bacterial or fungal pathogens and with good penetration into the presumed source. Antimicrobial therapy should be reevaluated daily to optimize efficacy, prevent resistance, avoid toxicity, and minimize costs. Consider combination therapy in Pseudomonas infections, and combination empiric therapy in neutropenic patients. Combination therapy should be continued for no more than 3 to 5 days and de-escalation should occur following availability of susceptibilities. The duration of antibiotic therapy typically is limited to 7 to 10 days; longer duration is considered if response is slow, if there is inadequate surgical source control, or in the case of immunologic deficiencies. Antimicrobial therapy should be stopped if infection is not considered the etiologic factor for a shock state.