IMPORTANCE: Definitions of sepsis and septic shock were last revised in 2001. Considerable advances have since been made into the pathobiology (changes in organ function, morphology, cell biology, biochemistry, immunology, and circulation), management, and epidemiology of sepsis, suggesting the need for reexamination. OBJECTIVE: To evaluate and, as needed, update definitions for sepsis and septic shock. PROCESS: A task force (n = 19) with expertise in sepsis pathobiology, clinical trials, and epidemiology was convened by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. Definitions and clinical criteria were generated through meetings, Delphi processes, analysis of electronic health record databases, and voting, followed by circulation to international professional societies, requesting peer review and endorsement (by 31 societies listed in the Acknowledgment). KEY FINDINGS FROM EVIDENCE SYNTHESIS: Limitations of previous definitions included an excessive focus on inflammation, the misleading model that sepsis follows a continuum through severe sepsis to shock, and inadequate specificity and sensitivity of the systemic inflammatory response syndrome (SIRS) criteria. Multiple definitions and terminologies are currently in use for sepsis, septic shock, and organ dysfunction, leading to discrepancies in reported incidence and observed mortality. The task force concluded the term severe sepsis was redundant. RECOMMENDATIONS: Sepsis should be defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. For clinical operationalization, organ dysfunction can be represented by an increase in the Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score of 2 points or more, which is associated with an in-hospital mortality greater than 10%. Septic shock should be defined as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone. Patients with septic shock can be clinically identified by a vasopressor requirement to maintain a mean arterial pressure of 65 mm Hg or greater and serum lactate level greater than 2 mmol/L (>18 mg/dL) in the absence of hypovolemia. This combination is associated with hospital mortality rates greater than 40%. In out-of-hospital, emergency department, or general hospital ward settings, adult patients with suspected infection can be rapidly identified as being more likely to have poor outcomes typical of sepsis if they have at least 2 of the following clinical criteria that together constitute a new bedside clinical score termed quickSOFA (qSOFA): respiratory rate of 22/min or greater, altered mentation, or systolic blood pressure of 100 mm Hg or less. CONCLUSIONS AND RELEVANCE: These updated definitions and clinical criteria should replace previous definitions, offer greater consistency for epidemiologic studies and clinical trials, and facilitate earlier recognition and more timely management of patients with sepsis or at risk of developing sepsis.

IMPORTANCE: Septic shock currently refers to a state of acute circulatory failure associated with infection. Emerging biological insights and reported variation in epidemiology challenge the validity of this definition. OBJECTIVE: To develop a new definition and clinical criteria for identifying septic shock in adults. DESIGN, SETTING, AND PARTICIPANTS: The Society of Critical Care Medicine and the European Society of Intensive Care Medicine convened a task force (19 participants) to revise current sepsis/septic shock definitions. Three sets of studies were conducted: (1) a systematic review and meta-analysis of observational studies in adults published between January 1, 1992, and December 25, 2015, to determine clinical criteria currently reported to identify septic shock and inform the Delphi process; (2) a Delphi study among the task force comprising 3 surveys and discussions of results from the systematic review, surveys, and cohort studies to achieve consensus on a new septic shock definition and clinical criteria; and (3) cohort studies to test variables identified by the Delphi process using Surviving Sepsis Campaign (SSC) (2005-2010; n = 28,150), University of Pittsburgh Medical Center (UPMC) (2010-2012; n = 1,309,025), and Kaiser Permanente Northern California (KPNC) (2009-2013; n = 1,847,165) electronic health record (EHR) data sets. MAIN OUTCOMES AND MEASURES: Evidence for and agreement on septic shock definitions and criteria. RESULTS: The systematic review identified 44 studies reporting septic shock outcomes (total of 166,479 patients) from a total of 92 sepsis epidemiology studies reporting different cutoffs and combinations for blood pressure (BP), fluid resuscitation, vasopressors, serum lactate level, and base deficit to identify septic shock. The septic shock-associated crude mortality was 46.5% (95% CI, 42.7%-50.3%), with significant between-study statistical heterogeneity (I2 = 99.5%; tau2 = 182.5; P < .001). The Delphi process identified hypotension, serum lactate level, and vasopressor therapy as variables to test using cohort studies. Based on these 3 variables alone or in combination, 6 patient groups were generated. Examination of the SSC database demonstrated that the patient group requiring vasopressors to maintain mean BP 65 mm Hg or greater and having a serum lactate level greater than 2 mmol/L (18 mg/dL) after fluid resuscitation had a significantly higher mortality (42.3% [95% CI, 41.2%-43.3%]) in risk-adjusted comparisons with the other 5 groups derived using either serum lactate level greater than 2 mmol/L alone or combinations of hypotension, vasopressors, and serum lactate level 2 mmol/L or lower. These findings were validated in the UPMC and KPNC data sets. CONCLUSIONS AND RELEVANCE: Based on a consensus process using results from a systematic review, surveys, and cohort studies, septic shock is defined as a subset of sepsis in which underlying circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than sepsis alone. Adult patients with septic shock can be identified using the clinical criteria of hypotension requiring vasopressor therapy to maintain mean BP 65 mm Hg or greater and having a serum lactate level greater than 2 mmol/L after adequate fluid resuscitation.

OBJECTIVE: To provide an update to

PURPOSE: To assess the effect of low dose corticosteroids on outcomes in adults with septic shock. METHODS: We systematically reviewed randomised clinical trials (RCTs) comparing low-dose corticosteroids to placebo in adults with septic shock. Trial selection, data abstraction and risk of bias assessment were performed in duplicate. The primary outcome was short-term mortality. Secondary and tertiary outcomes included longer-term mortality, adverse events, quality of life, and duration of shock, mechanical ventilation and ICU stay. RESULTS: There were 22 RCTs, including 7297 participants, providing data on short-term mortality. In two low risk of bias trials, the relative risk (RR) of short-term mortality with corticosteroid versus placebo was 0.98 [95% confidence interval (CI) 0.89-1.08, p = 0.71]. Sensitivity analysis including all trials was similar (RR 0.96; 95% CI 0.91-1.02, p = 0.21) as was analysis of longer-term mortality (RR 0.96; 95% CI 0.90-1.02, p = 0.18). In low risk of bias trials, the risk of experiencing any adverse event was higher with corticosteroids; however, there was substantial heterogeneity (RR 1.66; 95% CI 1.03-2.70, p = 0.04, I(2) = 78%). No trials reported quality of life outcomes. Duration of shock [mean difference (MD) -1.52 days; 95% CI -1.71 to -1.32, p < 0.0001], duration of mechanical ventilation (MD -1.38 days; 95% CI -1.96 to -0.80, p < 0.0001), and ICU stay (MD -0.75 days; 95% CI -1.34 to -0.17, p = 0.01) were shorter with corticosteroids versus placebo. CONCLUSIONS: In adults with septic shock treated with low dose corticosteroids, short- and longer-term mortality are unaffected, adverse events increase, but duration of shock, mechanical ventilation and ICU stay are reduced. PROSPERO registration no. CRD42017084037.

OBJECTIVE: This systematic review and meta-analysis addresses the efficacy and safety of corticosteroids in critically ill patients with sepsis. DATA SOURCES: We updated a comprehensive search of MEDLINE, EMBASE, CENTRAL, and LILACS, and unpublished sources for randomized controlled trials that compared any corticosteroid to placebo or no corticosteroid in critically ill children and adults with sepsis. STUDY SELECTION: Reviewers conducted duplicate screening of citations, data abstraction, and, using a modified Cochrane risk of bias tool, individual study risk of bias assessment. DATA EXTRACTION: A parallel guideline committee provided input on the design and interpretation of the systematic review, including the selection of outcomes important to patients. We assessed overall certainty in evidence using Grading of Recommendations Assessment, Development and Evaluation methodology and performed all analyses using random-effect models. For subgroup analyses, we performed metaregression and considered p value less than 0.05 as significant. DATA SYNTHESIS: Forty-two randomized controlled trials including 10,194 patients proved eligible. Based on low certainty, corticosteroids may achieve a small reduction or no reduction in the relative risk of dying in the short-term (28-31 d) (relative risk, 0.93; 95% CI, 0.84-1.03; 1.8% absolute risk reduction; 95% CI, 4.1% reduction to 0.8% increase), and possibly achieve a small effect on long-term mortality (60 d to 1 yr) based on moderate certainty (relative risk, 0.94; 95% CI, 0.89-1.00; 2.2% absolute risk reduction; 95% CI, 4.1% reduction to no effect). Corticosteroids probably result in small reductions in length of stay in ICU (mean difference, -0.73 d; 95% CI, -1.78 to 0.31) and hospital (mean difference, -0.73 d; 95% CI, -2.06 to 0.60) (moderate certainty). Corticosteroids result in higher rates of shock reversal at day 7 (relative risk, 1.26; 95% CI, 1.12-1.42) and lower Sequential Organ Failure Assessment scores at day 7 (mean difference, -1.39; 95% CI, -1.88 to -0.89) (high certainty). Corticosteroids likely increase the risk of hypernatremia (relative risk, 1.64; 95% CI, 1.32-2.03) and hyperglycemia (relative risk, 1.16; 95% CI, 1.08-1.24) (moderate certainty), may increase the risk of neuromuscular weakness (relative risk, 1.21; 95% CI, 1.01-1.52) (low certainty), and appear to have no other adverse effects (low or very low certainty). Subgroup analysis did not demonstrate a credible subgroup effect on any of the outcomes of interest (p > 0.05 for all). CONCLUSIONS: In critically ill patients with sepsis, corticosteroids possibly result in a small reduction in mortality while also possibly increasing the risk of neuromuscular weakness.

OBJECTIVE: To investigate the effectiveness and safety of corticosteroids therapy in adult critical ill patients with septic shock. METHODS: The PUBMED, EMBASE, Web of Science, Cochrane Library databases were systematically searched from the inception dates to March 24, 2018. To identify randomized controlled trials that evaluating the role of corticosteroids therapy in adult critical ill patients with septic shock. The primary outcome was 28-day mortality. The second outcomes included 90-day mortality, intensive care unit (ICU) mortality, in-hospital mortality, length of stay in ICU, length of stay in hospital, reversal of shock, and superinfection. RESULTS: A total of 18 randomized controlled trials involving 8,128 adult critical ill patients with septic shock fulfilled the inclusion criteria. The outcomes of this meta-analysis showed that corticosteroids therapy did not significantly reduce the 28-day mortality [RR = 0.94; 95% CI, 0.84-1.05; Z = 1.07 (P = 0.285)]. However, corticosteroids therapy was associated with a significantly shorter length of stay in ICU [WMD = -1.55; 95% CI, -2.19 to -0.91; Z = 4.74 (P = 0.000)]. 90-day mortality, ICU mortality, in-hospital mortality, length of stay in hospital, reversal of shock, and superinfection had no significant difference between the corticosteroids therapy and placebo therapy (P > 0.05). Similar results were obtained in subgroups of trials stratified according to the dose of corticosteroids (high dose or low does). CONCLUSIONS: Based on the results of this meta-analysis, corticosteroids therapy was associated with a significantly shorter length of stay in ICU among adult critical ill patients with septic shock. The mortality was similar between the corticosteroids therapy and placebo.

What Is Known and Objective. To reevaluate the benefits and risks of corticosteroid treatment in adult patients with septic shock. Methods. This study was performed based on PRISMA guidelines. Randomized controlled trials (RCTs) of corticosteroids versus placebo were retrieved from PubMed, MEDLINE, EMBASE, Web of Science, the Cochrane Central RCTs, and ClinicalTrials.gov from January 1980 to April 2018. We also conducted a trial sequential analysis to indicate the possibility of type I or II errors and calculate the information size. Grading of Recommendations, Assessment, Development and Evaluation approach (GRADE) was applying to assess the certainty of evidence at the primary outcome level. Results. Twenty-one RCTs were identified and analyzed. Patients treated with corticosteroid had a 7% reduction in relative risk in 28-day all-cause mortality compared to controls (RR 0.93, 95% CI 0.88 to 0.99). However, there were no significant differences for the intensive care unit (ICU) mortality (RR 0.97, 95% CI 0.86 to 1.09) or in-hospital mortality (RR 1.01, 95% CI 0.92 to 1.11). Corticosteroids shortened the length of ICU stay by 1.04 days (RR -1.04, 95% CI -1.72 to -0.36) and the length of hospital stay by 2.49 days (RR -2.49, 95% CI -4.96 to -0.02). Corticosteroids increased the risk of hyperglycemia (RR 1.11, 95% CI 1.06 to 1.16) but not gastroduodenal bleeding (RR 1.06, 95% CI 0.82 to 1.37) or superinfection (RR 1.04, 95% CI 0.94 to 1.15). However, some date on secondary outcomes were unavailable because they were not measured or not reported in the included studies which may cause a lack of power or selective outcome reporting. The information size was calculated at 10044 patients. Trial sequential analysis showed that the meta-analysis was conclusive and the risk of type 2 error was minimal. What Is New and Conclusion. Corticosteroids are likely to be effective in reducing 28-day mortality and attenuating septic shock without increasing the rate of life-threatening complications. TSA showed that the risk of type II error in this meta-analysis was minimal and the result was conclusive.

Importance: Although corticosteroids are widely used for adults with sepsis, both the overall benefit and potential risks remain unclear. Objective: To conduct a systematic review and meta-analysis of the efficacy and safety of corticosteroids in patients with sepsis. Data Sources and Study Selection: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched from inception until March 20, 2018, and updated on August 10, 2018. The terms corticosteroids, sepsis, septic shock, hydrocortisone, controlled trials, and randomized controlled trial were searched alone or in combination. Randomized clinical trials (RCTs) were included that compared administration of corticosteroids with placebo or standard supportive care in adults with sepsis. Data Extraction and Synthesis: Meta-analyses were conducted using a random-effects model to calculate risk ratios (RRs) and mean differences (MDs) with corresponding 95% CIs. Two independent reviewers completed citation screening, data abstraction, and risk assessment. Main Outcomes and Measures: Twenty-eight-day mortality. Results: This meta-analysis included 37 RCTs (N = 9564 patients). Eleven trials were rated as low risk of bias. Corticosteroid use was associated with reduced 28-day mortality (RR, 0.90; 95% CI, 0.82-0.98; I2 = 27%) and intensive care unit (ICU) mortality (RR, 0.85; 95% CI, 0.77-0.94; I2 = 0%) and in-hospital mortality (RR, 0.88; 95% CI, 0.79-0.99; I2 = 38%). Corticosteroids were significantly associated with increased shock reversal at day 7 (MD, 1.95; 95% CI, 0.80-3.11) and vasopressor-free days (MD, 1.95; 95% CI, 0.80-3.11) and with ICU length of stay (MD, -1.16; 95% CI, -2.12 to -0.20), the sequential organ failure assessment score at day 7 (MD, -1.38; 95% CI, -1.87 to -0.89), and time to resolution of shock (MD, -1.35; 95% CI, -1.78 to -0.91). However, corticosteroid use was associated with increased risk of hyperglycemia (RR, 1.19; 95% CI, 1.08-1.30) and hypernatremia (RR, 1.57; 95% CI, 1.24-1.99). Conclusions and Relevance: The findings suggest that administration of corticosteroids is associated with reduced 28-day mortality compared with placebo use or standard supportive care. More research is needed to associate personalized medicine with the corticosteroid treatment to select suitable patients who are more likely to show a benefit.

Background: With new randomised pieces of evidence and the latest clinical practice guideline from the BMJ emerging in 2018, an updated analysis of best available evidence on the controversial effects of corticosteroids in sepsis is warranted. Objectives: To comprehensively evaluate whether corticosteroids are beneficial in reducing mortality and what cumulative dosage, daily dosage, and duration of corticosteroid treatment would enable adult patients with sepsis to reach the critical point of benefits. Methods: Ovid MEDLINE, Ovid EMbase, Cochrane Library, and LILACS database were searched until March 22, 2019. Results: Thirty RCTs with 8,836 participants were identified. Long course low-dose corticosteroid therapy could improve 28-day mortality (RR = 0.90, 95% CI = 0.84-0.97; high quality), intensive care unit mortality (RR = 0.87; 95% CI = 0.79-0.95; moderate quality), and in-hospital mortality (RR = 0.88, 95% CI = 0.79-0.997; high quality). However, we found no benefits for 90-day, 180-day, and 1-year mortality. Subgroup results of long course corticosteroid treatment in a population with septic shock and vasopressor-dependent septic shock, corticosteroid regimen with hydrocortisone plus fludrocortisone, corticosteroid dosing strategies including bolus dosing and infusion dosing, the strategies of abrupt discontinuation, timing of randomisation /=10, and sample size >/=500 were associated with a marginally reduction in 28-day mortality. Conclusions: This meta-analysis found that the long course low-dose and not short course high-dose corticosteroid treatment could marginally improve short-term 28-day mortality with high quality, especially septic shock and vasopressor-dependent septic shock, and it is recommended that long course (about 7 days) low-dose (about 200-300mg per day) hydrocortisone (or equivalent) with cumulative dose (at least about 1,000mg) may be a viable management option for overall patients with sepsis, and it can be also adapted to patient with septic shock alone. Early hydrocortisone plus fludrocortisone administration, via continuous infusion or bolus dosing, is also particularly important for the prognosis. Abrupt discontinuation of corticosteroids, as opposed to the conventional tapered discontinuation, may be considered as a desirable option in 28-day mortality. The safety profile of long course low-dose corticosteroid treatment, including adverse hyperglycaemia and hypernatraemia events, remains a concern, although these events could be easily treated. Clinical Trial Registration: PROSPERO, identifier CRD 42018092849.

CONTEXT AND OBJECTIVE: Sepsis and septic shock are very common conditions among critically ill patients that lead to multiple organ dysfunction syndrome (MODS) and death. Our purpose was to investigate the efficacy of early administration of dexamethasone for patients with septic shock, with the aim of halting the progression towards MODS and death. DESIGN AND SETTING: Prospective, randomized, double-blind, single-center study, developed in a surgical intensive care unit at Hospital das Clinicas, Faculdade de Medicina da Universidade de Sao Paulo. METHODS: The study involved 29 patients with septic shock. All eligible patients were prospectively randomized to receive either a dose of 0.2 mg/kg of dexamethasone (group D) or placebo (group P), given three times at intervals of 36 hours. The patients were monitored over a seven-day period by means of the sequential organ failure assessment score. RESULTS: Patients treated with dexamethasone did not require vasopressor therapy for as much time over the seven-day period as did the placebo group (p = 0.043). Seven-day mortality was 67% in group P (10 out of 15) and 21% in group D (3 out of 14) (relative risk = 0.31, 95% confidence interval 0.11 to 0.88). Dexamethasone enhanced the effects of vasopressor drugs. CONCLUSIONS: Early treatment with dexamethasone reduced the seven-day mortality among septic shock patients and showed a trend towards reduction of 28-day mortality.

OBJECTIVES: To investigate the effect of low-dose hydrocortisone on time to shock reversal, the cytokine profile, and its relation to adrenal function in patients with early septic shock. DESIGN: Prospective, randomized, double-blind, single-center study. SETTING: Medical intensive care unit of a university hospital. PATIENTS: Forty-one consecutive patients with early hyperdynamic septic shock. INTERVENTIONS: After inclusion and a short adrenocorticotropic hormone test, all patients were randomized to receive either low-dose hydrocortisone (50-mg bolus followed by a continuous infusion of 0.18 mg/kg body of weight/hr) or matching placebo. After shock reversal, the dose was reduced to 0.06 mg/kg/hr and afterward slowly tapered. Severity of illness was estimated using Acute Physiology and Chronic Health Evaluation II score and Sequential Organ Failure Assessment score. MEASUREMENTS AND MAIN RESULTS: Time to cessation of vasopressor support (primary end point) was significantly shorter in hydrocortisone-treated patients compared with placebo (53 hrs vs. 120 hrs, p < .02). This effect was more profound in patients with impaired adrenal reserve. Irrespective of endogenous steroid production, cytokine production was reduced in the treatment group with lower plasma levels of interleukin-6 and a diminished ex vivo lipopolysaccharide-stimulated interleukin-1 and interleukin-6 production. Interleukin-10 levels were unaltered. Adverse events were not more frequent in the treatment group. CONCLUSIONS: Treatment with low-dose hydrocortisone accelerates shock reversal in early hyperdynamic septic shock. This was accompanied by reduced production of proinflammatory cytokines, suggesting both hemodynamic and immunomodulatory effects of steroid treatment. Hemodynamic improvement seemed to be related to endogenous cortisol levels, whereas immune effects appeared to be independent of adrenal reserve.

CONTEXT: Septic shock may be associated with relative adrenal insufficiency. Thus, a replacement therapy of low doses of corticosteroids has been proposed to treat septic shock. OBJECTIVE: To assess whether low doses of corticosteroids improve 28-day survival in patients with septic shock and relative adrenal insufficiency. DESIGN AND SETTING: Placebo-controlled, randomized, double-blind, parallel-group trial performed in 19 intensive care units in France from October 9, 1995, to February 23, 1999. PATIENTS: Three hundred adult patients who fulfilled usual criteria for septic shock were enrolled after undergoing a short corticotropin test. INTERVENTION: Patients were randomly assigned to receive either hydrocortisone (50-mg intravenous bolus every 6 hours) and fludrocortisone (50- micro g tablet once daily) (n = 151) or matching placebos (n = 149) for 7 days. MAIN OUTCOME MEASURE: Twenty-eight-day survival distribution in patients with relative adrenal insufficiency (nonresponders to the corticotropin test). RESULTS: One patient from the corticosteroid group was excluded from analyses because of consent withdrawal. There were 229 nonresponders to the corticotropin test (placebo, 115; corticosteroids, 114) and 70 responders to the corticotropin test (placebo, 34; corticosteroids, 36). In nonresponders, there were 73 deaths (63%) in the placebo group and 60 deaths (53%) in the corticosteroid group (hazard ratio, 0.67; 95% confidence interval, 0.47-0.95; P =.02). Vasopressor therapy was withdrawn within 28 days in 46 patients (40%) in the placebo group and in 65 patients (57%) in the corticosteroid group (hazard ratio, 1.91; 95% confidence interval, 1.29-2.84; P =.001). There was no significant difference between groups in responders. Adverse events rates were similar in the 2 groups. CONCLUSION: In our trial, a 7-day treatment with low doses of hydrocortisone and fludrocortisone significantly reduced the risk of death in patients with septic shock and relative adrenal insufficiency without increasing adverse events.

OBJECTIVE: To investigate the effects of stress doses of hydrocortisone on the duration of vasopressor therapy in human septic shock. DESIGN: Prospective, randomized, double-blind, single-center study. SETTING: Twenty-bed multidisciplinary intensive care unit in a 1400-bed university hospital. PATIENTS: Forty consecutive patients who met the ACCP/SCCM criteria for septic shock. An additional criterion for inclusion in the study was vasopressor support and high-output circulatory failure with a cardiac index of >4 L/min/m2 after fluid resuscitation (pulmonary capillary wedge pressure: 12-15 mm Hg) and without the use of positive inotropes such as dobutamine or dopexamine. The primary study end point was the time to cessation of vasopressor support (norepinephrine or epinephrine in any dose, dopamine > or = 6 microg/kg/min). Secondary study end points were the evolution of hemodynamics and the multiple organ dysfunction syndrome (MODS). The severity of illness at recruitment was graded using the Acute Physiology and Chronic Health Evaluation II and the Simplified Acute Physiology Score II scoring systems. MODS was described by the Sepsis-related Organ Failure Assessment score. INTERVENTIONS: All eligible patients were prospectively randomized to receive either stress doses of hydrocortisone or placebo. Hydrocortisone was started with a loading dose of 100 mg given within 30 mins and followed by a continuous infusion of 0.18 mg/ kg/hr. When septic shock had been reversed, the dose of hydrocortisone was reduced to 0.08 mg/kg/hr. This dose was kept constant for 6 days. As soon as the underlying infection had been treated successfully or sodium serum concentrations had increased to >155 mmol/L, the hydrocortisone infusion was tapered in steps of 24 mg/day. Physiologic saline solution was the placebo. MEASUREMENTS AND MAIN RESULTS: Hemodynamic and oxygen-derived variables were measured at previously defined time points over a study period of 5 days. Relevant clinical and laboratory measurements were registered for a study period of 14 days to assess the evolution of organ dysfunction. Baseline data at recruitment did not differ between the two groups. Shock reversal was achieved in 18 of the 20 patients treated with hydrocortisone vs. 16 of the 20 patients treated with placebo. Hydrocortisone significantly reduced the time to cessation of vasopressor support. The median time of vasopressor support was 2 days (1st and 3rd Quartiles, 1 and 6 days) in the hydrocortisone-treated group and 7 days (1st and 3rd Quartiles, 3 and 19 days) in the placebo group (p = .005 Breslow test). There was a trend to earlier resolution of the organ dysfunction syndrome in the hydrocortisone group. CONCLUSIONS: Infusion of stress doses of hydrocortisone reduced the time to cessation of vasopressor therapy in human septic shock. This was associated with a trend to earlier resolution of sepsis-induced organ dysfunctions. Overall shock reversal and mortality were not significantly different between the groups in this low-sized single-center study.

We conducted a prospective, randomized, double-blind study to determine whether high-dose methylprednisolone could prevent parenchymal lung injury, including the adult respiratory distress syndrome (ARDS), or improve mortality when administered early in septic shock. All patients already hospitalized in or newly admitted to the medical and surgical intensive care units at San Francisco General Hospital between September 1, 1983 and August 29, 1986 were eligible for admission to the study if they had either (1) an increase in temperature of 1.5 degrees C and a decrease in systolic blood pressure of 20 mm Hg or more from baseline values (in already hospitalized patients), or (2) a temperature greater than 38.5 degrees C or less than 35.5 degrees C and a systolic blood pressure of less than 90 mm Hg (in newly admitted patients). Patients meeting these criteria were excluded if they (1) had severe immunodeficiency, (2) were less than 18 or greater than 76 yr of age, (3) had multilobar roentgenographic infiltrates, or (4) were already receiving corticosteroids. Eighty-seven patients enrolled in the study received either methylprednisolone, 30 mg/kg per dose, or mannitol placebo for a total of 4 doses every 6 h, following the presumptive diagnosis of septic shock. Of these patients, 75 ultimately were determined on the basis of culture results to have actually had septic shock at the time of entry. Thirteen of the patients who received methylprednisolone developed ARDS, compared to 14 patients who received placebo. Lesser degrees of parenchymal lung injury did not differ between the 2 groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Glucocorticoids have been used as adjunctive therapy in patients with sepsis and septic shock for more than four decades. The rationale for the use of glucocorticoids is that this class of drugs downregulates the proinflammatory response and limits the anti-inflammatory response while preserving innate immunity. Between 1976 and 2017, 22 randomised placebo-controlled trials have been published evaluating the benefit of glucocorticoids in patients with community-acquired pneumonia, sepsis, and septic shock. These studies produced conflicting results. In 2018, two large randomised controlled trials (RCTs) were published evaluating the role of hydrocortisone in patients with septic shock. The Activated Protein C and Corticosteroids for Human Septic Shock (APROCCHSS) trial reported a reduction in 90-day mortality whereas the Adjunctive Corticosteroid Treatment in Critically Ill Patients with Septic Shock (ADRENAL) trial reported no mortality benefit. This Viewpoint critically appraises these two RCTs and evaluates the use of glucocorticoids in the treatment of sepsis and septic shock in the modern era.

Anesthesiologists are increasingly confronting the difficult problem of caring for patients with sepsis in the operating room and in the intensive care unit. Sepsis occurs in more than 750,000 patients in the United States annually and is responsible for more than 210,000 deaths. Approximately 40% of all intensive care unit patients have sepsis on admission to the intensive care unit or experience sepsis during their stay in the intensive care unit. There have been significant advances in the understanding of the pathophysiology of the disorder and its treatment. Although deaths attributable to sepsis remain stubbornly high, new treatment algorithms have led to a reduction in overall mortality. Thus, it is important for anesthesiologists and critical care practitioners to be aware of these new therapeutic regimens. The goal of this review is to include practical points on important advances in the treatment of sepsis and provide a vision of future immunotherapeutic approaches.

Sepsis is a common condition that is associated with unacceptably high mortality and, for many of those who survive, long-term morbidity. Increased awareness of the condition resulting from ongoing campaigns and the evidence arising from research in the past 10 years have increased understanding of this problem among clinicians and lay people, and have led to improved outcomes. The World Health Assembly and WHO made sepsis a global health priority in 2017 and have adopted a resolution to improve the prevention, diagnosis, and management of sepsis. In 2016, a new definition of sepsis (Sepsis-3) was developed. Sepsis is now defined as infection with organ dysfunction. This definition codifies organ dysfunction using the Sequential Organ Failure Assessment score. Ongoing research aims to improve definition of patient populations to allow for individualised management strategies matched to a patient's molecular and biochemical profile. The search continues for improved diagnostic techniques that can facilitate this aim, and for a pharmacological agent that can improve outcomes by modifying the disease process. While waiting for this goal to be achieved, improved basic care driven by education and quality-improvement programmes offers the best hope of increasing favourable outcomes.