Bolus or continuous hydrocortisone – that is the question

Constantly evolving treatment guidelines based on a growing body of randomized controlled trials are helping us to improve outcomes in sepsis. However, it must be borne in mind that proven benefit from individual sepsis treatments does not guarantee synergistic beneficial effects when new treatments are added to sepsis management. Indeed, unexpected harmful interactions are also possible. A good example of this is the conflict between intensive insulin therapy and 'low dose' hydrocortisone in septic shock. The goal of tight glycaemic control is made more complicated by steroid-induced hyperglycaemia. In their recent study, Loisa and coworkers demonstrate a measure that reduces the risk for this interaction. They found continuous infusion of hydrocortisone to be associated with fewer hyperglycaemic episodes and reduced staff workload compared with bolus application.     

Bolus or continuous hydrocortisone--that is the question

Constantly evolving treatment guidelines based on a growing body of randomized controlled trials are helping us to improve outcomes in sepsis. However, it must be borne in mind that proven benefit from individual sepsis treatments does not guarantee synergistic beneficial effects when new treatments are added to sepsis management. Indeed, unexpected harmful interactions are also possible. A good example of this is the conflict between intensive insulin therapy and 'low dose' hydrocortisone in septic shock. The goal of tight glycaemic control is made more complicated by steroid-induced hyperglycaemia. In their recent study, Loisa and coworkers demonstrate a measure that reduces the risk for this interaction. They found continuous infusion of hydrocortisone to be associated with fewer hyperglycaemic episodes and reduced staff workload compared with bolus application.     

Glucocorticoids in the treatment of severe sepsis and septic shock

PURPOSE OF REVIEW: Septic shock remains one of the leading causes of death in intensive care units. In recent years, there is general use of low to moderate doses of corticosteroids in the treatment of septic shock. However, there are wide variations in the practical modality of this treatment, mainly with regard to patients' selection, treatment's dose, timing, route of administration, duration, and weaning. This review provides opinion-based guidelines for the use of corticosteroids in severe sepsis and septic shock. RECENT FINDINGS: A summary of the latest understanding of the mechanisms of action of corticosteroids and the most recent observations in the clinical and biologic responses to corticosteroids in severe sepsis and septic shock is presented. SUMMARY: In septic shock, intravenous hydrocortisone should be started immediately after a 250 microg corticotropin test, at a dose of 200-300 mg per day. When adrenal insufficiency is confirmed, treatment should be continued at full doses for 7 days. Otherwise, hydrocortisone should be stopped. It is worth considering adding enteral fludrocortisone at a dose of 50 microg per day for 7 days. In severe sepsis, despite growing evidence to support the use of a moderate dose of corticosteroids, the efficacy and safety of this treatment needs to be assessed in a large-scale study.     

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.     

Low-dose hydrocortisone during severe sepsis: effects on microalbuminuria

OBJECTIVE: The aim of this study was to investigate the effect of low-dose hydrocortisone on glomerular permeability measured by the microalbuminuria to creatinine ratio (MACR) and on other markers of sepsis in severe septic patients. DESIGN: Randomized prospective study. SETTING: University intensive care unit. PATIENTS: The study involved 40 patients with severe sepsis randomized into the hydrocortisone group (n = 20) and the standard therapy group (n = 20). INTERVENTIONS: The hydrocortisone group received standard therapy plus a continuous infusion of hydrocortisone for 6 days, whereas the standard therapy group received only standard therapy. MEASUREMENTS AND MAIN RESULTS: MACR, serum C-reactive protein, and procalcitonin concentrations were recorded every day from the day before the steroid therapy (T(0)) until the 6 days after (T(1), T(2), T(3), T(4), T(5), and T(6)). Concentrations in the hydrocortisone group and the standard therapy group were compared using Mann-Whitney test at each time. We also compared with Wilcoxon signed rank test the values determined in each group at T(0) with those at each subsequent time. Median MACR decreased from T(0) to T(6) in both patient groups; however, values were significantly lower in the hydrocortisone group from T(3) through to T(6). Median serum C-reactive protein also decreased from T(0) in both patient groups, with significantly lower values in the hydrocortisone group from T(3) through to T(6). There were no significant differences in procalcitonin between groups compared with baseline values or at any individual time point. CONCLUSIONS: Low-dose hydrocortisone seems to reduce MACR and serum C-reactive protein but not procalcitonin in patients with severe sepsis. Further studies are needed to confirm these results and to understand the underlying molecular mechanisms.     

The use of corticosteroids in severe sepsis and acute respiratory distress syndrome

During sepsis or acute respiratory distress syndrome, the hypothalamic pituitary adrenal axis is rapidly activated through a systemic pathway, i.e. by circulating pro-inflammatory cytokines and through the vagus nerve. Subsequently, the adrenal glands release cortisol, a hormone which will likely counteract the inflammatory process and restore cardiovascular homeostasis. Both experimental models and studies in humans suggest that inadequate hypothalamic pituitary adrenal axis response to stress accounts, at least partly, for the genesis of shock and organ dysfunction in sepsis and acute respiratory distress syndrome. Relative adrenal insufficiency and peripheral glucocorticoid resistance syndrome are the two main features of the inappropriate hormonal response and provide the grounds for cortisol replacement in these diseases. In practice, a high dose of corticosteroids (i.e. one to four boluses of 30 mg/kg of methylprednisolone, or equivalent) had no effects on survival in severe sepsis or acute respiratory distress syndrome. There are at least seven randomised controlled trials reporting the benefits and risks of low dose corticosteroids (i.e. 200 to 300 mg daily of hydrocortisone or equivalent) given for a prolonged period in severe sepsis or in the late phase of acute respiratory distress syndrome. These trials showed consistently that, in these patients, the use of low dose of corticosteroids alleviated inflammation, restored cardiovascular homeostasis, reduced organ dysfunction, improved survival and was safe. Further studies are ongoing to better identify the target population. In the meantime, cortisol replacement (i.e. 200 to 300 mg daily of hydrocortisone or equivalent) should be considered as standard care for these patients.     

The use of corticosteroids in severe sepsis and acute respiratory distress syndrome

During sepsis or acute respiratory distress syndrome, the hypothalamic pituitary adrenal axis is rapidly activated through a systemic pathway, i.e. by circulating pro-inflammatory cytokines and through the vagus nerve. Subsequently, the adrenal glands release cortisol, a hormone which will likely counteract the inflammatory process and restore cardiovascular homeostasis. Both experimental models and studies in humans suggest that inadequate hypothalamic pituitary adrenal axis response to stress accounts, at least partly, for the genesis of shock and organ dysfunction in sepsis and acute respiratory distress syndrome. Relative adrenal insufficiency and peripheral glucocorticoid resistance syndrome are the two main features of the inappropriate hormonal response and provide the grounds for cortisol replacement in these diseases. In practice, a high dose of corticosteroids (i.e. one to four boluses of 30 mg/kg of methylprednisolone, or equivalent) had no effects on survival in severe sepsis or acute respiratory distress syndrome. There are at least seven randomised controlled trials reporting the benefits and risks of low dose corticosteroids (i.e. 200 to 300 mg daily of hydrocortisone or equivalent) given for a prolonged period in severe sepsis or in the late phase of acute respiratory distress syndrome. These trials showed consistently that, in these patients, the use of low dose of corticosteroids alleviated inflammation, restored cardiovascular homeostasis, reduced organ dysfunction, improved survival and was safe. Further studies are ongoing to better identify the target population. In the meantime, cortisol replacement (i.e. 200 to 300 mg daily of hydrocortisone or equivalent) should be considered as standard care for these patients.     

Risk of death does not alter the efficacy of hydrocortisone therapy in a mouse E. coli pneumonia model

BACKGROUND: Risk of death may influence the efficacy of anti-inflammatory agents in sepsis. "Physiologic" dose corticosteroids, while improving survival in earlier trials with higher control mortality rates (>50%), were not beneficial in the recent CORTICUS trial with lower control mortality (31%). We investigated whether risk of death altered the effects of hydrocortisone in a mouse pneumonia model. METHODS: Mice (n=637) challenged with high, medium or low intratracheal E. coli doses were randomized to receive one of three hydrocortisone doses (5, 25 or 125 mg/kg) or normal saline (NS) only (control) for 4 days. All animals were treated with similar volumes of ceftriaxone and NS support following E. coli and were observed for 168 h. RESULTS: Decreasing E. coli doses reduced control mortality rates (from 94 to 12%). In similar patterns (not significant) each hydrocortisone dose increased the odds ratio (OR) of survival (95% confidence interval) with each E. coli dose (ORs ranging from 1.2 [0.4, 3.7] to 6.1 [0.6, 61.0]). The effect of hydrocortisone on the OR was not related to control mortality rate (r=-0.13, p=0.29) and overall was highly significant (2.04 [1.37, 3.03], p=0.0004). In randomly selected animals 48 h after the highest E. coli dose, compared with the control, hydrocortisone (125 mg/kg) significantly decreased IL-6, INFgamma, and nitric oxide levels. CONCLUSIONS: In this mouse model the beneficial effects of hydrocortisone were independent of risk of death. These findings suggest that factors other than risk of death may underlie the differing effects of corticosteroids in recent sepsis trials.     

Review article: Sepsis in the emergency department – Part 3: Treatment

Although comprehensive guidelines for treatment of sepsis exist, current research continues to refine and revise several aspects of management. Imperatives for rapid administration of broad‐spectrum antibiotics for all patients with sepsis may not be supported by contemporary data. Many patients may be better served by a more judicious approach allowing consideration of investigation results and evidence‐based guidelines. Conventional fluid therapy has been challenged with early evidence supporting balanced, restricted fluid and early vasopressor use. Albumin, vasopressin and hydrocortisone have each been shown to support blood pressure and reduce catecholamine requirements but without effect on mortality, and as such should be considered for ED patients with septic shock on a case‐by‐case basis. Measurement of quality care in sepsis should incorporate quality of blood cultures and guideline‐appropriateness of antibiotics, as well as timeliness of therapy. Local audit is an essential and effective means to improve practice. Multicentre consolidation of data through agreed minimum sepsis data sets would provide baseline quality data, required for the design and evaluation of interventions.     

Hemodynamic aspects of multiple organ failure

Multiple organ failure (MOF) secondary to sepsis is associated with a high mortality. A large body of evidence suggests that the disturbed relationship between oxygen supply and oxygen uptake plays an important role in the pathogenesis of MOF. The relationship between oxygen-supply dependency and MOF and the practical implications of the relationship are reviewed. It is concluded that, apart from the all-important eradication of the source of the sepsis, optimizing oxygen transport is the best method of preventing the development of MOF. Since the effects of hemodynamic and ventilatory treatments on oxygen uptake are often unpredictable, the impact of the treatments on oxygen uptake should be evaluated directly.     

Evolving concepts in sepsis definitions

Developing effective therapies for any disease process relies on the ability to clearly define the population of patients who will benefit from that intervention. Advances in our understanding of sepsis pathogenesis have made it clear that the global definition or concept of sepsis as a single, homogeneous disease process is inadequate. The idea that all patients who have severe sepsis will respond positively to any single therapeutic intervention is probably too simple, although some interventions may target more general pathways and be globally beneficial. For example, drotrecogin alfa (activated) was shown to be effective at reducing mortality in a clinical trial with a heterogeneous patient population,(28) although even here positive results were restricted to patients who had severe sepsis, highlighting the importance of being able to better characterize patients. Our approach to sepsis and its definition has evolved as we increasingly recognize the complex nature of the process and the importance of targeting treatments according to individual patients' characteristics. Clinical variables are too sensitive and nonspecific and improved biologic and biochemical tools need to be incorporated into current definitions to provide precise and accurate methods of diagnosis. Systems, such as PIRO, that can characterize patients according to their likely prognosis and response to a specific therapy need to be further developed so that treatments can be appropriately directed for individual patients.     

Hemodynamic aspects of multiple organ failure

Multiple organ failure (MOF) secondary to sepsis is associated with a high mortality. A large body of evidence suggests that the disturbed relationship between oxygen supply and oxygen uptake plays an important role in the pathogenesis of MOF. The relationship between oxygen-supply dependency and MOF and the practical implications of the relationship are reviewed. It is concluded that, apart from the all-important eradication of the source of the sepsis, optimizing oxygen transport is the best method of preventing the development of MOF. Since the effects of hemodynamic and ventilatory treatments on oxygen uptake are often unpredictable, the impact of the treatments on oxygen uptake should be evaluated directly.     

Identification of sepsis subtypes in critically ill adults using gene expression profiling

Introduction

Sepsis is a syndromic illness that has traditionally been defined by a set of broad, highly sensitive clinical parameters. As a result, numerous distinct pathophysiologic states may meet diagnostic criteria for sepsis, leading to syndrome heterogeneity. The existence of biologically distinct sepsis subtypes may in part explain the lack of actionable evidence from clinical trials of sepsis therapies. We used microarray-based gene expression data from adult patients with sepsis in order to identify molecularly distinct sepsis subtypes.

Methods

We used partitioning around medoids (PAM) and hierarchical clustering of gene expression profiles from neutrophils taken from a cohort of septic patients in order to identify distinct subtypes. Using the medoids learned from this cohort, we then clustered a second independent cohort of septic patients, and used the resulting class labels to evaluate differences in clinical parameters, as well as the expression of relevant pharmacogenes.

Results

We identified two sepsis subtypes based on gene expression patterns. Subtype 1 was characterized by increased expression of genes involved in inflammatory and Toll receptor mediated signaling pathways, as well as a higher prevalence of severe sepsis. There were differences between subtypes in the expression of pharmacogenes related to hydrocortisone, vasopressin, norepinephrine, and drotrecogin alpha.

Conclusions

Sepsis subtypes can be identified based on different gene expression patterns. These patterns may generate hypotheses about the underlying pathophysiology of sepsis and suggest new ways of classifying septic patients both in clinical practice, and in the design of clinical trials.     

Adjunctive therapy with vitamin c and thiamine in patients treated with steroids for refractory septic shock: A propensity matched before-after,case-control study

PurposeTriple therapy with steroids, vitamin C and thiamine has been recently proposed as a safe and beneficial in patients with sepsis. In 2017, we added the use of intravenous vitamin C and thiamine in septic shock patients receiving low dose hydrocortisone because poorly responsive to vasopressors. Aim of this study is to verify whether triple therapy rather than steroids alone can improve outcome in patients with refractory shock.Materials and methodsIn this before-after retrospective analysis, we compared septic shock patients admitted to our intensive care unit (ICU) who received triple therapy from June 2017 to November 2019 to septic shock patients who received only hydrocortisone from January 2015 to June 2017. Patients of the two study periods were matched 1:1 using a propensity score model.ResultsA final cohort of 56 patients treated with triple therapy were matched to 56 patients treated only with steroids. Triple therapy reduced the length of mechanical ventilation (p = 0,01) and showed a trend in lowering the 30-day and hospital mortality compared to therapy with only hydrocortisone.ConclusionsAlthough with significant limitations, our experience indicated that triple therapy seems to provide an improvement of clinical outcomes in patients with refractory septic shock.     

Management of severe sepsis and septic shock

PURPOSE OF REVIEW: Severe sepsis and septic shock are common and deadly conditions for which the epidemiology, pathogenesis, and management continue to evolve. Recent publications (2003 and early 2004) have been systematically reviewed for important new original research and scholarly reviews, with an emphasis on clinical advances in adults. RECENT FINDINGS: Important new epidemiologic studies establish the increasing frequency (nearly 9% per year) and falling mortality rates associated with sepsis. Sepsis definitions were reviewed by a group of experts, and the principal features of the 1991 consensus conference definitions were supported, with a new framework for evaluation of sepsis proposed. New research and thoughtful reviews continue to elucidate the pathogenesis of sepsis, with emphasis on innate immunity and time-based changes in immune status, varying from hyperreactive immunity and inflammation to immune depression with enhanced risk for nosocomial infections. A comprehensive evidence-based approach to the management of severe sepsis is presented in an important document developed by representatives from many critical care and infectious disease societies. Management includes early targeted resuscitation, broad empiric antibiotic coverage and source control, effective shock evaluation and treatment, adjuvant therapy with recombinant human activated protein C and moderate-dose hydrocortisone in selected patients, and comprehensive supportive care. Recently published multicenter clinical trials for novel agents have been disappointing, particularly for a nitric oxide synthase inhibitor that effectively supported blood pressure but increased mortality. SUMMARY: The works reviewed reflect the advances in the care of patients with sepsis.     

Implementation of an evidence-based "standard operating procedure" and outcome in septic shock

OBJECTIVE: To assess the impact of an algorithm defining resuscitation according to early goal-directed therapy, glycemic control, administration of stress doses of hydrocortisone, and use of recombinant human activated protein C (rhAPC) on measures of organ dysfunction and outcome in septic shock. DESIGN: Retrospective cohort study. SETTING: Multidisciplinary ten-bed intensive care unit of a university hospital. PATIENTS: Sixty patients were analyzed: 30 consecutive patients fulfilling criteria for diagnosis of septic shock, treated from September 2002 until December 2003 after implementation of a standard operating procedure (SOP) for severe sepsis and septic shock; and 30 patients with septic shock treated from January until August 2002 in the same unit, who served as controls. MEASUREMENTS AND RESULTS: Data for blood gas analysis, lactate, glucose, serum creatinine, bilirubin, white blood cells, platelets, and C-reactive protein were obtained from patient files on admission or at time of diagnosis of septic shock and at 7:00 a.m. on days 2 and 4; Sequential Organ Failure Assessment scores were calculated and 28-day survival was assessed. With implementation of the SOP, use of dobutamine (12/30 vs. 2/30), insulin (blood glucose <150 mg/dL, day 4: 26/28 vs. 13/25), hydrocortisone (30/30 vs. 13/30), and rhAPC (7/30 vs. 0/30) significantly increased, whereas volume for resuscitation and use of packed red blood cells were unaffected. Mortality was 53% in the historical control group and 27% after implementation of the SOP (p < .05). CONCLUSION: The combined approach of early goal-directed therapy, intensive insulin therapy, hydrocortisone administration, and additional application of rhAPC in selected cases seems to favorably influence outcome. The implementation of a "sepsis bundle" can be facilitated by a standardized protocol while significantly reducing the time until the defined therapeutic measures are realized in daily practice.     

MicroRNA对脓毒症炎症因子的调控

在过去的几十年里关于脓毒症的研究取得了巨大的进展,但是脓毒症休克发生后尽管给予很多治疗,其死亡率仍然保持在50%左右.脓毒症的发生机制极其复杂,近年的研究显示其与调节失控的炎症反应有密切的关系.已经证实MicroRNA可以在转录后水平调节生物蛋白质的表达.近年研究发现MicroRNA可以通过转录后水平下调炎症因子以及炎症因子信号通路的受体来控制失衡的炎症反应,有望成为治疗脓毒症的一条更合适的途径.本文就MicroRNA 在脓毒症炎症因子调节失衡中作用的研究近况做一综述.