A Controlled Clinical Trial of High-Dose Methylprednisolone in the Treatment of Severe Sepsis and Septic Shock
The use of high-dose corticosteroids in the treatment of severe sepsis and septic shock remains controversial. Our study was designed as a prospective, randomized, double-blind, placebo-controlled trial of high-dose methylprednisolone sodium succinate for severe sepsis and septic shock. Diagnosis was based on the clinical suspicion of infection plus the presence of fever or hypothermia (rectal temperature greater than 38.3 degrees C [101 degrees F] or less than 35.6 degrees C [96 degrees F]), tachypnea (greater than 20 breaths per minute), tachycardia (greater than 90 beats per minute), and the presence of one of the following indications of organ dysfunction: a change in mental status, hypoxemia, elevated lactate levels, or oliguria. Three hundred eighty-two patients were enrolled. Treatment--either methylprednisolone sodium succinate (30 mg per kilogram of body weight) or placebo--was given in four infusions, starting within two hours of diagnosis. No significant differences were found in the prevention of shock, the reversal of shock, or overall mortality. In the subgroup of patients with elevated serum creatinine levels (greater than 2 mg per deciliter) at enrollment, mortality at 14 days was significantly increased among those receiving methylprednisolone (46 of 78 [59 percent] vs. 17 of 58 [29 percent] among those receiving placebo; P less than 0.01). Among patients treated with methylprednisolone, significantly more deaths were related to secondary infection. We conclude that the use of high-dose corticosteroids provides no benefit in the treatment of severe sepsis and septic shock.
Available from: Philipp Schuetz
- "In high-dose glucocorticoid studies, which used as high as 1 to 3 g hydrocortisone per day, short-term complications, such as co- and re-infections, led to excess mortality [47,48]. In so-called low- or physiological-dose glucocorticoid studies with 100 to 300 mg hydrocortisone-equivalent per day, the main adverse effects included hyperglycemia  and rebound pneumonia . "
[Show abstract] [Hide abstract]
Community-acquired pneumonia (CAP) is the third-leading infectious cause of death worldwide. The standard treatment of CAP has not changed for the past fifty years and its mortality and morbidity remain high despite adequate antimicrobial treatment. Systemic corticosteroids have anti-inflammatory effects and are therefore discussed as adjunct treatment for CAP. Available studies show controversial results, and the question about benefits and harms of adjunct corticosteroid therapy has not been conclusively resolved, particularly in the non-critical care setting.
This randomized multicenter study compares a treatment with 7 days of prednisone 50 mg with placebo in adult patients hospitalized with CAP independent of severity. Patients are screened and enrolled within the first 36 hours of presentation after written informed consent is obtained. The primary endpoint will be time to clinical stability, which is assessed every 12 hours during hospitalization. Secondary endpoints will be, among others, all-cause mortality within 30 and 180 days, ICU stay, duration of antibiotic treatment, disease activity scores, side effects and complications, value of adrenal function testing and prognostic hormonal and inflammatory biomarkers to predict outcome and treatment response to corticosteroids. Eight hundred included patients will provide an 85% power for the intention-to-treat analysis of the primary endpoint.
This largest to date double-blind placebo-controlled multicenter trial investigates the effect of adjunct glucocorticoids in 800 patients with CAP requiring hospitalization. It aims to give conclusive answers about benefits and risks of corticosteroid treatment in CAP. The inclusion of less severe CAP patients will be expected to lead to a relatively low mortality rate and survival benefit might not be shown. However, our study has adequate power for the clinically relevant endpoint of clinical stability. Due to discontinuing glucocorticoids without tapering after seven days, we limit duration of glucocorticoid exposition, which may reduce possible side effects.
7 September 2009 on ClinicalTrials.gov: NCT00973154.
Available from: Annelise Goecke
- "However this therapeutic strategy has had several dramatic shifts with time. The early approach of high dose GCs for sepsis therapy was abandoned when the potential benefits initially reported [9-11] could not be replicated, and higher mortality associated with secondary infections was suggested [12,13]. A renewed interest in GC therapy in sepsis, at what has been termed a physiological dose, was seen after reports of improved response to vasopressor drugs and decreased mortality in selected groups of patients who had an inadequate response to adrenocorticotropin hormone (ACTH) (defined as an increase in total plasma cortisol <9 μg/dL) [14,15]. "
[Show abstract] [Hide abstract]
A protective role for glucocorticoid therapy in animal models of sepsis was shown many decades ago. In human sepsis, there is new interest in glucocorticoid therapy at a physiological dose after reports of improved response to vasopressor drugs and decreased mortality in a selected group of patients. However, other reports have not confirmed these results. Cellular glucocorticoid resistance could explain a possible cause of that. To evaluate this hypothesis, we evaluated the expression of glucocorticoid receptor beta, the dominant negative isoform of glucocorticoid receptor, in peripheral mononuclear cells of septic patients and the effect of serum septic patients over glucocorticoid receptor expression and glucocorticoid sensitivity in immune cells culture.
A prospective cohort study and an in vitro experimental study with matched controls were developed. Nine patients with septic shock and nine healthy controls were prospectively enrolled. Mononuclear cells and serum samples were obtained from the patients with sepsis on admission to the Intensive Care Unit and on the day of discharge from hospital, and from healthy volunteers matched by age and sex with the patients. Glucocorticoid receptor alpha and beta expression from patients and from immune cell lines cultured in the presence of serum from septic patients were studied by western blot. Glucocorticoid sensitivity was studied in control mononuclear cells cultured in the presence of serum from normal or septic patients. A statistical analysis was performed using a Mann-Whitney test for non-parametric data and analysis of variance for multiple comparison; P < 0.05 was considered significant.
The patients' glucocorticoid receptor beta expression was significantly higher on admission than on discharge, whereas the alpha receptor was not significantly different. In vitro, septic serum induced increased expression of both receptors in T and B cells in culture, with a greater effect on receptor beta than the control serum. Septic serum induced glucocorticoid resistance in control mononuclear cells.
There is a transient increased expression of glucocorticoid receptor beta in mononuclear cells from septic patients. Serum from septic patients induces cell glucocorticoid resistance in vitro. Our findings support a possible cell glucocorticoid resistance in sepsis.
Available from: PubMed Central
- "Although I have just disparaged large-scale randomized controlled trials, they have nevertheless been the main drivers of change, particularly as the negative findings relating to current practice often went against the seemingly logical rationale that informed the study design. Yet does this mean that high-dose corticosteroids are not always bad , that transfusion to a high hemoglobin target may be appropriate in certain cases, that activated protein C is life-saving in the right patient, and that heavy sedation may sometimes be indicated? We have to reconcile evidence-based medicine that is applicable to populations, with the optimal treatment for an individual patient at a particular point of time in their acute illness. "
[Show abstract] [Hide abstract]
ABSTRACT: The greatest advances in critical care over the past two decades have been achieved through doing less to the patient. We have learnt through salutary experience that our burgeoning Master-of-the-Universe capabilities and the oh-so-obvious stratagems instilled in us from youth were often ineffective or even deleterious. This re-education process, however, is far from complete. We are now rightly agonizing over the need for better characterization of pathophysiology, earlier identification of disease processes and a more directed approach to therapeutic intervention. We need to delineate the point at which intrinsic and protective adaptation ends and true harmful pathology begins, and how our iatrogenic meddling either helps or hinders. We need to improve trial design in the heterogeneous populations we treat, and to move away from syndromic fixations that, while offering convenience, have generally proved counterproductive. Importantly, we need to discover a far more holistic approach to patient care, evolving from the prevailing overmedicalized, number-crunching perspective towards a true multidisciplinary effort that embraces psychological as well as physiological well-being, with appropriate pharmacological minimization or supplementation. Complacency, with an unfair apportion of blame on the patient for not getting better, is the biggest threat to continued improvement.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.