Article

A Controlled Clinical Trial of High-Dose Methylprednisolone in the Treatment of Severe Sepsis and Septic Shock

New England Journal of Medicine (Impact Factor: 54.42). 10/1987; 317(11):653-8. DOI: 10.1056/NEJM198709103171101
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ABSTRACT 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.

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    • "In the early eighties, conventional treatment (e.g., antibiotics, fluid therapy, inotropic support and mechanical ventilation) was supplemented by 30 mg kg À1 of methylprednisolone administered immediately at the time of diagnosis of septic shock and re-administered after 4 hours if the initial response was not beneficial [8]. A controlled clinical trial showed significantly higher mortality at 14 days in patients receiving high dose methylprednisolone compared to those receiving placebo [9]. "
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    ABSTRACT: Once a septic condition is progressing, administration of steroids in the pro-inflammatory phase of septic shock ought to yield maximal effect on the subsequent, devastating inflammatory response. Recently, a retrospective study showed that early initiation of corticosteroid therapy improved survival in septic shock. We aimed to prospectively evaluate effects of early administrated hydrocortisone therapy on physiologic variables in a porcine model of septic shock. EXPERIMENT: Eight anesthetized pigs were given a continuous infusion of endotoxin during this 6 h prospective, randomized, parallel-grouped placebo-controlled experimental study. At the onset of endotoxemic shock, defined as the moment when the mean pulmonary arterial pressure reached the double baseline value, the pigs were either given a single intravenous dose of hydrocortisone (5 mg kg(-1)) or the corresponding volume of saline. Mean arterial pressure and systemic vascular resistance index were significantly higher (both p<0.05), and heart rate was significantly lower (p<0.05), in the endotoxin+hydrocortisone group as compared to the endotoxin+saline group. Body temperature and blood hemoglobin levels increased significantly in the endotoxin+saline group (both p<0.05). Urinary hydrocortisone increased significantly in both groups (p<0.05). There were no significant differences in the plasma levels of TNF-alpha, IL-6 or nitrite/nitrate between the groups. Early treatment with hydrocortisone ameliorates some endotoxin mediated circulatory derangements, fever response and microvascular outflow. Our results suggest that these effects are not directly mediated by the pro-inflammatory cytokines TNF-alpha or IL-6, nor by NO.
    Steroids 06/2012; 77(11):1101-6. DOI:10.1016/j.steroids.2012.06.001 · 2.72 Impact Factor
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    • "Therefore, strategies aimed at suppressing increases in pro-inflammatory cytokines during endotoxaemia could potentially be beneficial in facilitating the recovery of muscle mass and improving insulin sensitivity and/or carbohydrate oxidation under these conditions. Glucocorticoids have been proposed to be useful in the treatment of systemic inflammatory diseases due to their anti-inflammatory properties (for review see Rhen & Cidlowski, 2005), but the potential benefit of glucocorticoid therapy in the treatment of sepsis is controversial, and may depend on dose (Bone et al. 1987; Briegel et al. 1994; Cronin et al. 1995; Annane, 2001; Keh & Sprung, 2004). Indeed, previous reports have indicated that glucocorticoids are important in regulating muscle protein breakdown during sepsis (Tiao et al. 1996). "
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    ABSTRACT: We recently provided evidence suggesting a role for cytokine-mediated inhibition of Akt/Forkhead box O 1 (FOXO1) signalling in the induction of muscle atrophy and impairment of muscle carbohydrate oxidation during lipopolysaccharide (LPS)-induced endotoxaemia in rats. We hypothesized that a low-dose dexamethasone (Dex; anti-inflammatory agent) infusion during endotoxaemia would prevent the LPS-induced impairment of Akt/FOXO1 signalling, and therefore prevent the muscle atrophy and impairment of carbohydrate oxidation. Chronically instrumented Sprague-Dawley rats received a continuous intravenous infusion of LPS (15 microg kg(-1) h(-1)), Dex (12.5 microg kg(-1) h(-1)), Dex+LPS or saline for 24 h at 0.4 ml h(-1). LPS infusion caused haemodynamic changes consistent with a hyperdynamic circulation and induced increases in muscle tumour necrosis factor-alpha (TNF-alpha; 10-fold, P < 0.001), interleukin-6 (IL-6; 14-fold, P < 0.001) and metallothionein-1A (MT-1A; 187-fold, P < 0.001) mRNA expression. Dex co-administration abolished most of the haemodynamic effects of LPS and reduced the increase in muscle TNF-alpha, IL-6 and MT-1A by 51% (P < 0.01), 85% (P < 0.001) and 58% (P < 0.01), respectively. Dex infusion during endotoxaemia also prevented the LPS-induced 40% reduction in the muscle protein:DNA ratio and decrease in Akt phosphorylation, and partially prevented the reduction in FOXO1 phosphorylation. However, Dex did not prevent the LPS-mediated increase in muscle atrophy F-box (MAFbx) and muscle RING finger 1 (MuRF1) mRNA expression, but did significantly reduce the LPS-mediated increase in cathepsin-L mRNA expression and enzyme activity by 43% (P < 0.001) and 53% (P < 0.05), respectively. Furthermore, Dex suppressed LPS-induced pyruvate dehydrogenase kinase 4 (PDK4) mRNA upregulation by approximately 50% (P < 0.01), and prevented LPS-mediated muscle glycogen breakdown and lactate accumulation. Thus, low-dose Dex infusion during endotoxaemia prevented muscle atrophy and the impairment of carbohydrate oxidation, potentially through suppression of cytokine-mediated Akt/FOXO inhibition, and blunting of cathepsin-L-mediated lysosomal protein breakdown.
    The Journal of Physiology 02/2010; 588(Pt 8):1333-47. DOI:10.1113/jphysiol.2009.183699 · 4.54 Impact Factor
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    • "ately after diagnosis ; up to two doses in 24 h 10 x 38% Not blinded ; two groups with different steroids Sprung et al . ( 1984 ) 59 Methylprednisolone or dexameta - sone / placebo ; initiation immediately after diagnosis ; up to two doses in 24 h 76 x 69% Reversal of shock oc - curred earlier in steroid group ; no difference in hospital mortality Bone et al . ( 1987b ) 382 Methylprednisolone / placebo ; initia - tion up to 2 h after diagnosis 34 x 25% Higher mortality in renal insufficiency group VASSCSG ( 1987 ) 223 Methylprednisolone / placebo ; ad - ministration within 2 h ; initiation up to 2 h after diagnosis 20 x 21% Treatment was initiated within 2 h of shock ; par - ticipation of 10 centres "
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    ABSTRACT: Corticosteroids are widely used to treat a diversity of pathological conditions including allergic, autoimmune and some infectious diseases. These drugs have complex mechanisms of action involving both genomic and non-genomic mechanisms and interfere with different signal transduction pathways in the cell. The use of corticosteroids to treat critically ill patients with acute respiratory distress syndrome and severe infections, such as sepsis and pneumonia, is still a matter of intense debate in the scientific and medical community with evidence both for and against its use in these patients. Here, we review the basic molecular mechanisms important for corticosteroid action as well as current evidence for their use, or not, in septic patients. We also present an analysis of the reasons why this is still such a controversial point in the literature.
    Memórias do Instituto Oswaldo Cruz 08/2009; 104(4):531-48. DOI:10.1590/S0074-02762009000400001 · 1.57 Impact Factor
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