Adrenal insufficiency in patients with cirrhosis, severe sepsis and septic shock

Patients with cirrhosis are susceptible to bacterial infection, which can result in circulatory dysfunction, renal failure, hepatic encephalopathy, and a decreased survival rate. Severe sepsis is frequently associated with adrenal insufficiency, which may lead to hemodynamic instability and a poor prognosis. We evaluated adrenal function using short corticotropin stimulation test (SST) in 101 critically ill patients with cirrhosis and severe sepsis. Adrenal insufficiency occurred in 51.48% of patients. The patients with adrenal insufficiency had a higher hospital mortality rate when compared with those with normal adrenal function (80.76% vs. 36.7%, P < .001). The cumulative rates of survival at 90 days were 15.3% and 63.2% for the adrenal insufficiency and normal adrenal function groups, respectively (P < .0001). The hospital survivors had a higher cortisol response to corticotropin (16.2 +/- 8.0 vs. 8.5 +/- 5.9 microg/dL, P < .001). The cortisol response to corticotropin was inversely correlated with various disease severity, Model for End-Stage Liver Disease, and Child-Pugh scores. Acute physiology, age, chronic health evaluation III score, and cortisol increment were independent factors to predict hospital mortality. Mean arterial pressure on the day of SST was lower in patients with adrenal insufficiency (60 +/- 14 vs. 74.5 +/- 13 mm Hg, P < .001), and a higher proportion of these patients required vasopressors (73% vs. 24.48%, P < .001). Mean arterial pressure, serum bilirubin, vasopressor dependency, and bacteremia were independent factors that predicted adrenal insufficiency. In conclusion, adrenal insufficiency is common in critically ill patients with cirrhosis and severe sepsis. It is related to functional liver reserve and disease severity and is associated with hemodynamic instability, renal dysfunction, and increased mortality.     

Reducing mortality in severe sepsis and septic shock

Severe sepsis is one of the most common reasons for critically ill patients to be admitted to an intensive care unit (ICU) and has very high associated morbidity and mortality. The Surviving Sepsis Campaign was initiated with the hope that mortality might be reduced by standardizing care informed by data from an increasing number of clinical trials. Important methods for reducing mortality identified by recent studies include aggressive fluid resuscitation, early goal-directed therapy (EGDT), early administration of antibiotics, and the administration of activated protein C to eligible patients.     

Systemic steroids in severe sepsis and septic shock

Despite more than 5 decades of study and debate, the role of corticosteroid treatment in patients with severe sepsis and septic shock remains controversial. Data support a beneficial effect on systemic blood pressure in patients with septic shock. However, the ability of corticosteroid therapy to improve mortality in patients with severe sepsis and septic shock remains controversial, with contradictory results from recent large multicenter clinical trials. Although it appears clear that high-dose corticosteroid treatment provides no benefit and possibly harm in septic patients, the experimental design flaws and biases of recent low-dose (physiologic) steroid treatment trials limit their ability to provide adequate answers to the important questions of which septic patients should be treated, how much steroid to give, and the optimum duration of treatment. Unfortunately, the answer to these important questions is not readily evident based on the current evidence or the application of metaanalysis to the available clinical data. This concise evidence-based review highlights the strengths and weaknesses of the current data to inform the practicing clinician as to which patients are likely to derive significant benefit from corticosteroid treatment, while we await more definitive guidance from future multicenter, prospective, randomized, controlled trials designed to better answer these important therapeutic questions.     

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.     

Statins in prevention and treatment of severe sepsis and septic shock

Severe sepsis is an infection-induced inflammatory syndrome that can lead to multi-organ dysfunction and continues to be a major cause of morbidity and mortality worldwide. Because numerous cascades are triggered during sepsis, selective blocking of inflammatory mediators may be insufficient to arrest this process, and recent therapeutic approaches have proven controversial. Statins are the most commonly prescribed agents for hypercholesterolaemia and dominate the area of cardiovascular risk reduction. Moreover, these drugs have a variety of actions that are independent of their lipid lowering effect. Such anti-inflammatory, antioxidant, immunomodulatory, and antiapoptotic features have been collectively referred to as pleiotropic effects. By virtue of their pleiotropic effects, statins have also emerged as potentially useful in various critical care areas such as bacteraemia, the early phases of sepsis and septic shock, as well as the management of serious infections. This review outlines current evidence on the use of statins for preventing and treating sepsis.     

严重脓毒症与脓毒性休克的若干治疗进展

严重脓毒症（severe sepsis）与脓毒性休克（septic shock）是内外科危重患者常见的并发症,全球每年有数百万人发病,且呈不断增长趋势,死亡率超过25％。面对严重脓毒症与脓毒性休克的挑战,2002年10月欧洲危重病医学会（ESICM）、美国危重病医学会（SC—CM）和国际脓毒症论坛（ISF）在西班牙巴塞罗那共同发起了拯救脓毒症的全球性行动倡议一拯救脓毒症战役（surviving sepsis campaign,SSC）,     

Blood glucose control in patients with severe sepsis and septic shock

The main pathophysiological feature of sepsis is the uncontrollable activation of both pro- and anti-inflammatory responses arising from the overwhelming production of mediators such as pro- and anti-inflammatory cytokines. Such an uncontrollable inflammatory response would cause many kinds of metabolic derangements. One such metabolic derangement is hyperglycemia. Accordingly, control of hyperglycemia in sepsis is considered to be a very effective therapeutic approach. However, despite the initial enthusiasm, recent studies reported that tight glycemic control with intensive insulin therapy failed to show a beneficial effect on mortality of patients with severe sepsis and septic shock. One of the main reasons for this disappointing result is the incidence of harmful hypoglycemia during intensive insulin therapy. Therefore, avoidance of hypoglycemia during intensive insulin therapy may be a key issue in effective tight glycemic control. It is generally accepted that glycemic control aimed at a blood glucose level of 80-100 mg/dL, as initially proposed by van den Berghe, seems to be too tight and that such a level of tight glycemic control puts septic patients at increased risk of hypoglycemia. Therefore, now many researchers suggest less strict glycemic control with a target blood glucose level of 140-180 mg/dL. Also specific targeting of glycemic control in diabetic patients should be considered. Since there is a significant correlation between success rate of glycemic control and the degree of hypercytokinemia in septic patients, some countermeasures to hypercytokinemia may be an important aspect of successful glycemic control. Thus, in future, use of an artificial pancreas to avoid hypoglycemia during insulin therapy, special consideration of septic diabetic patients, and control of hypercytokinemia should be considered for more effective glycemic control in patients with severe sepsis and septic shock.     

Filgrastim in patients with pneumonia and severe sepsis or septic shock

STUDY OBJECTIVES: Evaluate the safety of filgrastim (recombinant methionyl human granulocyte colony-stimulating factor) administration, combined with standard therapy, in patients with pneumonia and either septic shock or severe sepsis who were receiving mechanical ventilation. DESIGN: Multicenter, double-blind, randomized, placebo-controlled study. SETTING: ICU, multicenter. PATIENTS: Eighteen patients with pneumonia and hypotension, or in the absence of shock, two or more end-organ dysfunctions, were enrolled and treated. Baseline acute physiology and chronic health evaluation II scores and median age for the filgrastim (n = 12) and placebo (n = 6) groups were 25.0 and 49.5 years and 31.5 and 56.5 years, respectively. INTERVENTION: Filgrastim (300 microg) or placebo was administered IV daily for up to 5 days. Measurements and results: Study end points included safety; biological response, including endogenous cytokine levels, endotoxin levels, and neutrophil counts; and mortality. Cytokine and endotoxin levels were highly variable in both groups. By day 29, 3 of 12 filgrastim-treated patients and 4 of 6 placebo-treated patients had died. There were no differences in types and occurrences of adverse events, including ARDS, or in outcome between the two groups. Three of four placebo-treated patients had persistent bacterial growth on bronchoscopy repeated after 48 h compared with 2 of 10 filgrastim-treated patients. CONCLUSION: Filgrastim appeared to be well tolerated in this population of patients with pneumonia and severe sepsis or septic shock. Larger studies to determine the benefit of filgrastim in patients with pneumonia and sepsis or organ dysfunction are warranted.     

The diagnosis and management of severe sepsis and septic shock.

Shock due to or associated with sepsis may present a clinical picture quite different from that usually seen in hypovolemic or cardiogenic shock. Any trend which suggests increasing sepsis should be treated aggressively as if shock were present. The earlier such therapy is begun, the better the results tend to be. Perhaps the greatest errors in the therapy of severe sepsis and septic shock are (1) delayed control of the primary septic process, (2) giving too little fluid in the early phases of therapy (and too much later), and (3) delaying ventilator assistance if the patient's ventilation or blood gases are deteriorating.     

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.     

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.     

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.     

Brain natriuretic peptide increases in septic patients without severe sepsis or shock

BACKGROUND: B-type natriuretic peptide (BNP) production increases in critically ill septic patients. We assessed the hypothesis that BNP is elevated in patients with community-acquired infections without severe sepsis or septic shock. METHODS: We studied 54 patients [20 males, median age 39 (interquartile range 23, 71)] without heart disease, persistent arrhythmias, or renal failure. BNP was measured in all patients at hospital admission and at pre-discharge and in a control group of 52 individuals. Myoglobin levels were also measured in septic patients. RESULTS: The infection was microbial in 40 patients, viral in 11, and of undefined etiology in 3. A systemic inflammatory response was evident in 38 patients on the initial evaluation. BNP on admission was higher in patients than in controls [25 (10, 82) pg/ml vs. 13 (5, 30) pg/ml, p=0.01] and it decreased to 16 (5, 47) pg/ml pre-discharge (p=0.0002). Multiple logistic regression identified the presence of microbial infection as the only independent predictor of an elevated BNP value on admission [adjusted odds ratio 9.8 (1.02-93.8), p=0.04]. In patients with microbial infection, location of infection in the lower respiratory tract and the presence of diabetes mellitus were independent predictors of the magnitude of BNP increase. Myoglobin was also increased on hospital admission 80 (37, 231) ng/ml and decreased pre-discharge to 59 (38, 94) ng/ml, p=0.004. Myoglobin level changes from admission to discharge were more prominent with increasing age and in females. CONCLUSION: BNP levels are elevated in the acute phase of community-acquired microbial infections without severe sepsis or septic shock.     

Cardiovascular dysfunction in sepsis and septic shock

Opinion statement The optimal therapy for the treatment of sepsis and septic shock remains controversial. Many protocols are followed, using different strategies for initial resuscitation, cardiovascular monitoring, hemodynamic intervention, and eradication of infection. Overall, an aggressive approach to the management of cardiovascular dysfunction in septic shock is warranted. Initially, large volume fluid resuscitation is instituted. Our first choice of resuscitation fluid is 0.9% normal saline. Invasive hemodynamic monitoring using a flotation pulmonary artery catheter as well as invasive arterial blood pressure monitoring is a necessity in the hemodynamic management of septic shock. If the patient remains hypotensive (mean arterial pressure < 65 mm Hg) after adequate volume resuscitation has been established (pulmonary capillary wedge pressure 12 to 15 mm Hg), then vasopressor agents must be instituted. Our first choice is usually dopamine. In patients who remain hypotensive after maximal doses of dopamine are reached, norepinephrine is added. If these agents generate excessive tachycardia or if tachyarrhythmias develop, phenylephrine can be substituted or added. Inotropic agents are useful if the patient demonstrates hypotension with a low cardiac output state. Dobutamine is the agent of choice. We initiate broad-spectrum empiric antibiotics at presentation, modifying the exact regimen based on 1) site of infection; 2) prevailing organisms and antibiotic resistance patterns in the patient’s environment; and 3) other specific risk factors (immunosuppression, chronic disease, exposure and vaccination history, invasive medical devices). When appropriate, aggressive surgical debridement is pursued. Currently, there are no clinical data to support the use of antagonists for sepsis mediators, although various clinical trials remain underway. Steroids are contraindicated except for adrenal replacement therapy.