The use of steroids in the treatment of severe sepsis and septic shock

Sepsis and septic shock remain major causes of mortality and morbidity worldwide. Previously, high dose corticosteroids were used to dampen the inflammatory response but studies and meta-analyses showed this to be of no benefit and possibly detrimental. Subsequently, low dose corticosteroids were used in the treatment of sepsis and septic shock with the hypothesis that these conditions are associated with relative adrenal insufficiency. Although some studies showed promising results larger studies and meta-analyses have failed to reproduce these effects and the use of corticosteroids in the treatment of sepsis and septic shock remains controversial. We review the current literature and guidelines regarding low dose corticosteroid use in the management of sepsis and septic shock.     

The endocrine system during sepsis

Endocrinopathy during sepsis can manifest as hyperglycemia and insulin resistance or as insufficient production of either adrenal corticosteroids or vasopressin. The results of a recent large clinical trial have demonstrated that tight glycemic control with insulin can confer survival benefit to selected intensive care unit patients. Relative impairment of adrenocortical reserve has been suggested to be an important contributor to the pathogenesis of shock in sepsis. Replacement doses of glucocorticoids and mineralocorticoids have been associated with improved survival in the subset of patients with blunted results on adrenocorticotropin hormone stimulation tests. Posterior pituitary production of vasopressin is diminished in septic shock while sensitivity to its vasopressor effects is enhanced. Clinical trials are underway to determine whether administration of vasopressin can improve outcomes in patients with septic shock. Whether the euthyroid sick syndrome represents an adaptive or a maladaptive response to severe illness remains unclear.     

New approaches to the treatment of sepsis

The clinical spectrum of sepsis, severe sepsis, and septic shock is responsible for a growing number of deaths and excessive health care expenditures. Until recently, despite multiple clinical trials, no intervention provided a beneficial outcome in septic patients. Within the last 2 years, studies that involved drotrecogin alfa (activated), corticosteroid therapy, and early goal-directed therapy showed efficacy in those with severe sepsis and septic shock. These results have provided optimism for reducing sepsis-related mortality.     

Adjunctive therapies in severe sepsis and septic shock: Current place of steroids

For more than five decades, the use of corticosteroids as an adjunctive therapy to treat severe sepsis and septic shock has incited consistent debate. Negative results of the Corticosteroid Therapy of Septic Shock (CORTICUS) study evoked a revision of Surviving Sepsis Campaign guidelines suggesting a more restricted use of low-dose hydrocortisone only in patients with severe septic shock. Hemodynamic improvement by low-dose steroids was evident and independent from adrenal insufficiency, but did not improve survival. The roles of cortisol measurement and adrenal function tests for treatment decisions have been questioned. An international task force introduced the concept of critical illness-related corticosteroid insufficiency, which challenges the predominant role of adrenal dysfunction and underscores sustained inflammation due to tissue steroid resistance. Whether moderate steroid doses induce superinfections and muscle weakness is unclear. This article reviews recent publications, actual recommendations, ongoing discussions, and future perspectives.     

Kortikosteroide bei schwerer Sepsis und septischem Schock

The benefit of adjunctive application of low dose corticosteroids in patients with severe sepsis and septic shock is discussed controversially. This summary provides information about the role of the central stress hormone cortisol and contrasts the concept of relative adrenal insufficiency in septic shock with the concept of corticosteroid insufficiency in severe systemic inflammation. Current data and newest meta-analyses are critically evaluated; possible side effects of this therapy are discussed. Finally, evidence-based recommendations for the application of low-dose hydrocortisone in patients with severe septic shock are provided.     

Adrenal insufficiency in liver disease - what is the evidence?

Recently, treatment with corticosteroids in the setting of septic shock and adrenal insufficiency has been shown to decrease mortality. In septic patients, a blunted response to adrenal stimulation identifies patients with a poorer prognosis who may benefit from corticosteroid supplementation. This condition has been termed relative adrenal insufficiency (RAI). Given the similarities between septic shock and liver failure, a number of groups have now studied the incidence of RAI in various forms of liver disease. Although different definitions of RAI exist, the current literature suggests that RAI is common, being seen in 33% of acute liver failure patients and up to 65% of patients with chronic liver disease and sepsis. The finding that RAI can exist in the absence of sepsis and may be as high as 92% of patients undergoing liver transplantation using a steroid free protocol has led one group to propose the term hepatoadrenal syndrome. The purpose of this review is to summarise the existing evidence for adrenal insufficiency in liver disease, to examine the possibility that adrenal dysfunction in liver disease may have a separate pathogenesis to that observed in sepsis and to provide insight into the potential areas for further research into this condition.     

Corticosteroid therapy in patients with severe sepsis and septic shock

Corticosteroids have been considered for decades for the treatment of severe sepsis and septic shock, based on their pivotal role in the stress response and their hemodynamic and antiinflammatory effects. Whereas short-term therapy with high doses of corticosteroids (up to 42 g hydrocortisone equivalent for 1-2 days) has been ineffective or potentially harmful, prolonged therapy with lower doses (200-300 mg hydrocortisone for 5-7 days or longer) in septic shock has recently revealed beneficial effects in several randomized, controlled trials. Assuming relative adrenal insufficiency (RAI) and peripheral cortisol resistance, treatment with low-dose hydrocortisone improved shock reversal, reduced inflammation, and improved outcome. Shock reversal and reduction of mortality were more effective in patients with RAI, and most significant in patients with severe shock. Diagnosis of RAI with corticotropin tests in septic shock, however, is highly dependent on cut-off values and definition of RAI. Thus, it is not clear yet which patients benefit most from low-dose hydrocortisone and if treatment should be restricted to patients with RAI. In addition the role of fludrocortisone is uncertain. Nevertheless, based on current data, low-dose hydrocortisone therapy should definitely be considered in vasopressor-dependent septic shock. This review will address some critical points.     

Update on adrenal insufficiency in patients with liver cirrhosis

Liver cirrhosis is a major cause of mortality worldwide,often with severe sepsis as the terminal event.Over the last two decades,several studies have reported that in septic patients the adrenal glands respond inappropriately to stimulation,and that the treatment with corticosteroids decreases mortality in such patients.Both cirrhosis and septic shock share many hemodynamic abnormalities such as hyperdynamic circulatory failure,decreased peripheral vascular resistance,increased cardiac output,hypo-responsiveness to vasopressors,increased levels of proinflammatory cytokines [interleukine(IL)-1,IL-6,tumor necrosis factor-alpha] and it has,consequently,been reported that adrenal insufficiency(AI) is common in critically ill cirrhotic patients.AI may also be present in patients with stable cirrhosis without sepsis and in those undergoing liver transplantation.The term hepato-adrenal syndrome defines AI in patients with advanced liver disease with sepsis and/or other complications,and it suggests that it could be a feature of liver disease per se,with a dif-ferent pathogenesis from that of septic shock.Relative AI is the term given to inadequate cortisol response to stress.More recently,another term is used,namely "critical illness related corticosteroid insufficiency" to define "an inadequate cellular corticosteroid activity for the severity of the patient’s illness".The mechanisms of AI in liver cirrhosis are not completely understood,although decreased levels of high-density lipoprotein cholesterol and high levels of proinflammatory cytokines and circulatory endotoxin have been suggested.The prevalence of AI in cirrhotic patients varies widely according to the stage of the liver disease(compensated or decompensated,with or without sepsis),the diagnostic criteria defining AI and the methodology used.The effects of corticosteroid therapy on cirrhotic patients with septic shock and AI are controversial.This review aims to summarize the existing published information regarding AI in patients with liver cirrhosis.     

How I manage haematology patients with septic shock

Patients with a variety of haematological conditions are at risk of infection and its most serious complication: septic shock. Mortality for septic shock remains high and especially so in patients with haematological malignancy and following bone marrow transplantation. However, advances in the treatment of severe sepsis have improved mortality rates even though evidence for the management of severe sepsis in haematology patients is limited. Wherever possible this review will concentrate on evidence directly applicable to haematology patients but inevitably will have to extrapolate evidence from other patient groups. The Surviving Sepsis Guidelines 2008 provide information on best practice in the management of patients with severe sepsis and septic shock and are broadly applicable though not specific to haematology patients. This review summarizes a practical approach to the management of severe sepsis in haematology patients and highlights areas of research which may bring new treatments in the future. The review is limited to the management and initial resuscitation of septic shock in adult haematology patients and will not address the detailed intensive care management of these patients or the management of severe sepsis in children.     

Why Activated Protein C Was Not Successful in Severe Sepsis and Septic Shock: Are We Still Tilting at Windmills?

Drotrecogin alpha activated (DAA), trade name Xigris, is a recombinant human protein C that has been the subject of controversy since 2001, when it became the first biologic agent approved for the treatment of severe sepsis and septic shock. The PROWESS trial showed a 6.1 % absolute reduction in 28-day mortality, although these findings were not replicated in later trials, ultimately leading to the withdrawal of DAA in 2011. Observational trials, however, have consistently shown a mortality benefit with the use of DAA, leading to the following questions: Did DAA truly fail and, if so, why? While these questions may never be definitively answered on the basis of available evidence, several factors may explain the conflicting results. In clinical practice, DAA may have been preferentially given to subjects more likely to survive. Contemporary treatments, including early antibiotic administration and volume resuscitation, may have mitigated the inflammatory processes leading to disordered coagulation and microvascular thrombosis and, thus, reduced or abolished the therapeutic opportunity for DAA. Later randomized clinical trials of DAA focused on the clinical phenotype of refractory shock, largely due to a strong efficacy signal in this subset from PROWESS; however, this clinical phenotype may not be tightly linked, at least after contemporary early resuscitation strategies, to the mechanistic phenotype of dysregulated coagulation that may have been a better target for DAA. Future trials of biologic therapies in severe sepsis and septic shock should use a combination of clinical phenotype and biomarkers to identify responsive populations that may benefit from such therapies.     

Glucose control in sepsis

Hyperglycemia is common during the course of critical illness and is associated with adverse clinical outcomes. Randomized controlled trials and large observational trials of insulin therapy titrated to achieve glucose values approximating the normal range (80 to 110 mg/dL) demonstrate improved morbidity and mortality in heterogeneous populations and have led to recommendations for improved glucose control. Patients who have septic shock, however, appear to be at higher risk for hypoglycemia, and a recent randomized trial focusing exclusively on patients who had severe sepsis did not show benefit. The recent Surviving Sepsis consensus statement recommends insulin therapy using validated protocols to lower glucose (less than 150 mg/dL) pending the results of adequately powered trials to determine if normalization (less than 110 mg/dL) of glucose is needed to optimize outcomes in patients who have severe sepsis.     

Hemofiltration in sepsis and septic shock: Where do we stand?

Since continuous hemofiltration was first described by Peter Kramer as a new form of renal replacement therapy, it has undergone many changes, making it a widely accepted treatment modality for acute renal failure in critically ill patients. Concomitantly, new insights into the pathogenesis of severe sepsis and septic shock have led to a recent form of immunomodulating therapy for septic shock. A number of clinical trials investigating the effects of anti-endotoxin or anti-cytokine interventions did not consistently show an improvement in survival in patients with sepsis or septic schock. Another possibility of immunotherapy is the removal of various pro-inflammatory substances including endotoxin, cytokines, oxygen free radicals, and arachidonic acid metabolites by hemofiltration. In animal models of acute septic shock, hemofiltration has shown beneficial hemodynamic effects and even an increased short term survival. In clinical studies, although not prospective and randomized, continuous hemofiltration sometimes showed a increased patient survival rate, which was possibly due to the removal of pro-inflammatory substances. Therefore, continuous hemofiltration seems promising as an adjunctive treatment modality in severe sepsis and septic shock. However, more experimental and clinical research should be performed in order to establish the optimal hemofiltration modalities in terms of membrane, ultrafiltration rate, buffer solution, and timing of the intervention. Received: 3 October 1997 Accepted: 2 December 1997     

A systematic review of antithrombin concentrate use in patients with disseminated intravascular coagulation of severe sepsis.

The objective was to estimate the effect of antithrombin therapy on mortality in disseminated intravascular coagulation (DIC) of severe sepsis and septic shock. Randomized clinical trials (RCT) on patients with DIC and severe sepsis or septic shock assigned to intravenous antithrombin or placebo were searched. Eligible studies reported death as the outcome measure. Of 35 RCT, 32 trials were excluded because patients were not randomized to antithrombin versus placebo, or no separate data on patients with DIC were given. In three RCT, 364 patients with severe sepsis or septic shock and DIC were randomized. The disease severity, definition of DIC, dose and duration of treatment varied among the trials. In two of the three RCT, data were from subgroup analyses (patients not stratified by DIC). The combined odds ratio for short-term all-cause mortality in those who received antithrombin was 0.649 (95% confidence interval, 0.422-0.998). Data on bleeding complications in patients treated with antithrombin were reported only in one of the RCT and were not considered suitable for systematic safety estimation. In sepsis patients with DIC, administration of antithrombin concentrate may increase overall survival. Current available evidence, however, is not suited to sufficiently inform clinical practice.     

Current role of activated protein C therapy for severe sepsis and septic shock

Drotrecogin alfa (activated) (DrotAA) has been approved for therapy of severe sepsis and septic shock for 7 years, but controversy persists regarding efficacy and safety. Only a single randomized, controlled trial (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis; PROWESS) has shown evidence of efficacy, and the risk of complications (especially hemorrhage) is recognized. Moreover, subsequent prospective studies (albeit in children and lower-risk adult patient populations) have been nonconfirmatory. Opinion is polarized whether DrotAA is effective and should be used. Safety data are not in dispute (DrotAA therapy increases risk of bleeding complications), but controversy exists regarding efficacy, the ethics of marketing the drug, and the design and conduct of current and future trials designed to resolve efficacy questions. DrotAA is approved therapy in the United States, the European Union, and many other countries, and clinicians should keep the drug in their armamentarium, balancing risk and benefit, for therapy of patients with severe sepsis or septic shock who are at high risk of death until the controversy is resolved by randomized, prospective trials now in progress.     

Immunoglobulins in sepsis and septic shock

Clinical efficacy of polyspecific immunoglobulins or monoclonal antibodies to treat patients with severe sepsis or septic shock is still under debate after several clinical trials. Only a few of them have been able to demonstrate a direct benefit to reduce mortality or this effect appears after meta-analysis. Evidence sustains that polyspecific immunoglobulin G reduces mortality in these patients, being this effect higher for IgM-enriched immunoglobulins. Best indications are postsurgical sepsis or early septic shock patients with high titers of endotoxinemia. The use of intravenous immunoglobulins is also recommended for the treatment of patients with streptococcal toxic shock, as demonstrated by the evidence obtained through case-control studies and one randomized clinical trial with a clear trend toward benefit. Evidence does not sustain a favorable impact on mortality for monoclonal antibodies directed against bacterial lypopolysaccaride, other bacterial antigens or against TNF-alpha. Furthermore, infusion of recombinant IL-1 receptor antagonist or soluble receptors for TNF-alpha that could attenuate the inflammatory response have not demonstrated utility after many clinical trials. These therapeutic tools are characterized by a high acquisition cost and adequate cost-effectiveness analysis has not been yet performed.     

高水平血清诱骗受体3预示脓毒症休克患者病情严重

目的:探讨诱骗受体3(DCR3)对严重脓毒症/脓毒症休克患者病情和预后的预测价值。方法:选取西安市中心医院ICU 2016年9月-2018年9月收治的严重脓毒症患者100例,按照是否发生感染性休克分为严重脓毒症组48例,脓毒症休克组52例,脓毒症休克组根据1个月生存情况又分为存活组36例和死亡组16例。同时选取50例同期健康体检者为对照组。采用酶联免疫法、化学发光法、IMMAGE800特种蛋白仪检测所有入选者治疗前、后不同时间血清DCR3、降钙素原(PCT)、C反应蛋白(CRP)水平。结果:治疗前,与对照组比较,严重脓毒症组和脓毒症休克组患者血清DCR3、PCT和CRP水平显著升高;且脓毒症休克组高于严重脓毒症组(P均0. 05)。治疗后1、3、7 d,与严重脓毒症组比较,脓毒症休克组患者血清DCR3、PCT和CRP水平较高(P均0. 05)。存活组患者治疗后第1、3、7 d血清DCR3、PCT和CRP水平显著低于死亡组(P均0. 05)。结论:与严重脓毒症患者比较,脓毒症休克患者DCR3、PCT、CRP水平显著升高,治疗过程中血清DCR3水平变化敏感,可能指导临床治疗。     

Sepsis and the heart

Sepsis is generally viewed as a disease aggravated by an inappropriate immune response encountered in the afflicted individual. As an important organ system frequently compromised by sepsis and always affected by septic shock, the cardiovascular system and its dysfunction during sepsis have been studied in clinical and basic research for more than 5 decades. Although a number of mediators and pathways have been shown to be associated with myocardial depression in sepsis, the precise cause remains unclear to date. There is currently no evidence supporting global ischemia as an underlying cause of myocardial dysfunction in sepsis; however, in septic patients with coexistent and possibly undiagnosed coronary artery disease, regional myocardial ischemia or infarction secondary to coronary artery disease may certainly occur. A circulating myocardial depressant factor in septic shock has long been proposed, and potential candidates for a myocardial depressant factor include cytokines, prostanoids, and nitric oxide, among others. Endothelial activation and induction of the coagulatory system also contribute to the pathophysiology in sepsis. Prompt and adequate antibiotic therapy accompanied by surgical removal of the infectious focus, if indicated and feasible, is the mainstay and also the only strictly causal line of therapy. In the presence of severe sepsis and septic shock, supportive treatment in addition to causal therapy is mandatory. The purpose of this review is to delineate some characteristics of septic myocardial dysfunction, to assess the most commonly cited and reported underlying mechanisms of cardiac dysfunction in sepsis, and to briefly outline current therapeutic strategies and possible future approaches.     

Intravenous polyclonal IgM-enriched immunoglobulin therapy in sepsis: a review of clinical efficacy in relation to microbiological aetiology and severity of sepsis

The efficacy of intravenous polyclonal immunoglobulin (IVIG) as adjunct therapy in sepsis has long been debated. Clinical trials have yielded contradicting results, in part due to the varying study design and varying microbiological aetiologies. In most trials, the study drug has been IVIG containing polyclonal IgG. However, in recent reports, the efficacy of IgM-enriched IVIG as adjunct therapy in sepsis has been highlighted. Here we review studies on IgM-enriched IVIG therapy in sepsis and we discuss the clinical efficacy in relation to microbiological aetiology and severity of sepsis. The results suggest that patients most likely to benefit from IgM-enriched IVIG therapy are those with Gram-negative septic shock.     

Corticosteroids for the treatment of septic shock.

Despite the substantial amount of data supporting the use of glucocorticoids in experimental models in septic shock, patients with severe sepsis and signs of deteriorating hemodynamic status or organ function do not benefit from glucocorticoid administration as given under the conditions of two well-done prospective, controlled trials. In fact, some glucocorticoid-treated patient subgroups showed increased mortality. Thus, the conclusion must be drawn that, despite potential theoretical and experimental value, glucocorticoids should not be used in the septic patient.     

Polyclonal intravenous immunoglobulin for the prophylaxis and treatment of infection in critically ill adults.

Infection is a major cause of morbidity and mortality in critically ill patients. Despite advances in technology, its mortality rate has changed minimally over the past two decades, and new therapies are needed. Polyclonal intravenous immunoglobulin (IVIG) has been investigated both as a preventive and a treatment modality for sepsis and septic shock in critically ill adult patients. Prophylaxis with IVIG has been shown to reduce significantly the incidence of infection, particularly pneumonia, in selected postsurgical intensive care patients. However, it does not reduce mortality. The risk-benefit and cost effectiveness of this therapeutic intervention have not been determined, and its routine use is therefore not recommended. Treatment with IVIG has been shown in a number of small trials and a meta-analysis to reduce dramatically sepsis and septic shock mortality. However, a large, unpublished randomized trial has apparently shown no mortality benefit with this therapy. Despite limited evidence, IVIG has become the standard of care for the management of group A streptococcal toxic shock syndrome. At present, clinical equipoise exists for the use of IVIG in the treatment of sepsis and septic shock, and further study is needed.