Virginie Maxime

Corticosteroid treatment and intensive insulin therapy for septic shock in adults: a randomized controlled trial.

CONTEXT Corticosteroid therapy induces potentially detrimental hyperglycemia in septic shock. In addition, the benefit of adding fludrocortisone in this setting is unclear. OBJECTIVES To test the efficacy of intensive insulin therapy in patients whose septic shock was treated with hydrocortisone and to assess, as a secondary objective, the benefit of fludrocortisone. DESIGN, SETTING, AND PATIENTS A multicenter, 2 x 2 factorial, randomized trial, involving 509 adults with septic shock who presented with multiple organ dysfunction, as defined by a Sequential Organ Failure Assessment score of 8 or more, and who had received hydrocortisone treatment was conducted from January 2006 to January 2009 in 11 intensive care units in France. INTERVENTIONS Patients were randomly assigned to 1 of 4 groups: continuous intravenous insulin infusion with hydrocortisone alone, continuous intravenous insulin infusion with hydrocortisone plus fludrocortisone, conventional insulin therapy with hydrocortisone alone, or conventional insulin therapy with intravenous hydrocortisone plus fludrocortisone. Hydrocortisone was administered in a 50-mg bolus every 6 hours, and fludrocortisone was administered orally in 50-microg tablets once a day, each for 7 days. MAIN OUTCOME MEASURE In-hospital mortality. RESULTS Of the 255 patients treated with intensive insulin, 117 (45.9%), and 109 of 254 (42.9%) treated with conventional insulin therapy died (relative risk [RR], 1.07; 95% confidence interval [CI], 0.88-1.30; P = .50). Patients treated with intensive insulin experienced significantly more episodes of severe hypoglycemia (<40 mg/dL) than those in the conventional-treatment group, with a difference in mean number of episodes per patient of 0.15 (95% CI, 0.02-0.28; P = .003). At hospital discharge, 105 of 245 patients treated with fludrocortisone (42.9%) died and 121 of 264 (45.8%) in the control group died (RR, 0.94; 95% CI, 0.77-1.14; P = .50). CONCLUSIONS Compared with conventional insulin therapy, intensive insulin therapy did not improve in-hospital mortality among patients who were treated with hydrocortisone for septic shock. The addition of oral fludrocortisone did not result in a statistically significant improvement in in-hospital mortality. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00320099.

Science review: Mechanisms of impaired adrenal function in sepsis and molecular actions of glucocorticoids

This review describes current knowledge on the mechanisms that underlie glucocorticoid insufficiency in sepsis and the molecular action of glucocorticoids. In patients with severe sepsis, numerous factors predispose to glucocorticoid insufficiency, including drugs, coagulation disorders and inflammatory mediators. These factors may compromise the hypothalamic–pituitary axis (i.e. secondary adrenal insufficiency) or the adrenal glands (i.e. primary adrenal failure), or may impair glucocorticoid access to target cells (i.e. peripheral tissue resistance). Irreversible anatomical damages to the hypothalamus, pituitary, or adrenal glands rarely occur. Conversely, transient functional impairment in hormone synthesis may be a common complication of severe sepsis. Glucocorticoids interact with a specific cytosolic glucocorticoid receptor, which undergoes conformational changes, sheds heat shock proteins and translocates to the nucleus. Glucocorticoids may also interact with membrane binding sites at the surface of the cells. The molecular action of glucocorticoids results in genomic and nongenomic effects. Direct and indirect transcriptional and post-transcriptional effects related to the cytosolic glucocorticoid receptor account for the genomic effects. Nongenomic effects are probably subsequent to cytosolic interaction between the glucocorticoid receptor and proteins, or to interaction between glucocorticoids and specific membrane binding sites.

Clinical review: Corticotherapy in sepsis

The use of glucocorticoids (corticotherapy) in severe sepsis is one of the main controversial issues in critical care medicine. These agents were commonly used to treat sepsis until the end of the 1980s, when several randomized trials casted serious doubt on any benefit from high-dose glucocorticoids. Later, important progress in our understanding of the role played by the hypothalamic–pituitary–adrenal axis in the response to sepsis, and of the mechanisms of action of glucocorticoids led us to reconsider their use in septic shock. The present review summarizes the basics of the physiological response of the hypothalamic–pituitary–adrenal axis to stress, including regulation of glucocorticoid synthesis, the cellular mechanisms of action of glucocorticoids, and how they influence metabolism, cardiovascular homeostasis and the immune system. The concepts of adrenal insufficiency and peripheral glucocorticoid resistance are developed, and the main experimental and clinical data that support the use of low-dose glucocorticoids in septic shock are discussed. Finally, we propose a decision tree for diagnosis of adrenal insufficiency and institution of cortisol replacement therapy.

Metabolism modulators in sepsis: the abnormal pituitary response.

Objective:Summarize the current knowledge on the role of the hypothalamic pituitary axis in the development of sepsis. Design:Review article. Method:We systematically searched for relevant articles in MEDLINE and Embase (up to December 2006) using the following search terms: sepsis or septic shock or septicemia or endotoxemia and pituitary gland or hypothalamus. We also retrieved relevant references from selected articles. Results:During sepsis, the pituitary gland is activated via blood-borne proinflammatory cytokines and through a complex interaction between the autonomic nervous system and the immune cells. Sepsis elicits a very reproducible pattern of pituitary hormone secretion, with plasma adrenocorticotropin and prolactin increasing within a few minutes following the insult, and with a rapid inhibition of secretion of luteinizing and thyroid-stimulatory hormone but not of follicle-stimulating hormone. Growth hormone secretion also is stimulated. Nitric oxide is a key mediator in the activation of the hypothalamic-pituitary axis and in excess nitric oxide is the main factor accounting for abnormal pituitary response. Low adrenocorticotropin and vasopressin levels are likely the most deleterious consequences of the abnormal pituitary response, because they will contribute to shock and progression of inflammation with subsequent multiple organ failure and death. Conclusions:Sepsis is associated with major changes in the hypothalamic-pituitary axis. The manipulation of the pituitary function during sepsis is a major challenge for the next decade.

Masseter tissue oxygen saturation predicts normal central venous oxygen saturation during early goal-directed therapy and predicts mortality in patients with severe sepsis.

Objective: This study aimed to investigate, in patients with severe sepsis, the correlation between central venous oxygen saturation and tissue oxygen saturation at different levels. Design: Prospective observational study. Setting: General intensive care unit at an academic medical center in France. Patients: Thirty-eight patients with underresuscitated severe sepsis and septic shock on intensive care unit admission. Interventions: None. Measurements and Main Results: During early resuscitation according to the 6-hr bundles of the Surviving Sepsis Campaign guidelines, tissue oxygen saturation was recorded every other hour at the level of the thenar, masseter, and deltoid muscles along with central hemodynamics, arterial lactate concentrations, and central venous oxygen saturation. Over the 6-hr resuscitation period, thenar tissue oxygen saturation was consistently higher than masseter tissue oxygen saturation (p = .04) and deltoid tissue oxygen saturation (p = .002), and masseter tissue oxygen saturation was consistently higher than deltoid tissue oxygen saturation (p = .04). Receiver operating characteristic curves analyses showed that masseter tissue oxygen saturation was better predictor of central venous oxygen saturation >70% than thenar tissue oxygen saturation (area under the curve, 0.80; 95% confidence interval 0.71−0.89 vs. 0.67; 95% confidence interval 0.56–0.77; p = .02). The crude 28-day mortality was 36.8%. Receiver operating characteristic curve analysis showed that masseter tissue oxygen saturation (area under the curve 0.87; 0.75−0.98) and deltoid tissue oxygen saturation (area under the curve 0.88; 0.77−0.98) but not thenar tissue oxygen saturation (area under the curve 0.66; 0.46–0.86) or central venous oxygen saturation (area under the curve 0.56; 0.38–0.80) were strong predictors of 28-day mortality. Conclusions: This study suggested that in the early 6-hr resuscitation period, masseter tissue oxygen saturation accurately identified patients with severe sepsis and central venous oxygen saturation >70%. Both masseter tissue oxygen saturation and deltoid tissue oxygen saturation but not central venous oxygen saturation or thenar tissue oxygen saturation are strong predictors of 28-day mortality.

Procalcitonin levels to guide antibiotic therapy in adults with non-microbiologically proven apparent severe sepsis: a randomised controlled trial

Objective Some patients with the phenotype of severe sepsis may have no overt source of infection or identified pathogen. We investigated whether a procalcitonin-based algorithm influenced antibiotic use in patients with non-microbiologically proven apparent severe sepsis. Design This multicentre, randomised, controlled, single-blind trial was performed in two parallel groups. Setting Eight intensive care units in France. Participants Adults with the phenotype of severe sepsis and no overt source of infection, negative microbial cultures from multiple matrices and no antibiotic exposure shortly before intensive care unit admission. Intervention The initiation and duration of antibiotic therapy was based on procalcitonin levels in the experimental arm and on the intensive care unit physicians’ clinical judgement without reference to procalcitonin values in the control arm. Main outcome measure The primary outcome was the proportion of patients on antibiotics on day 5 postrandomisation. Results Over a 3-year period, 62/1250 screened patients were eligible for the study, of whom 31 were randomised to each arm; 4 later withdrew their consent. At day 5, 18/27 (67%) survivors were on antibiotics in the experimental arm, versus 21/26 (81%) controls (p=0.24; relative risk=0.83, 95% CI: 0.60 to 1.14). Only 8/58 patients (13%) had baseline procalcitonin <0.25 µg/l; in these patients, physician complied poorly with the algorithm. Conclusions In intensive care unit patients with the phenotype of severe sepsis or septic shock and without an overt source of infection or a known pathogen, the current study was unable to confirm that a procalcitonin-based algorithm may influence antibiotic exposure. However, the premature termination of the trial may not allow definitive conclusions.

Hormonal status in protracted critical illness and in-hospital mortality

IntroductionThe aim of this study was to determine the relationship between hormonal status and mortality in patients with protracted critical illness.MethodsWe conducted a prospective observational study in four medical and surgical intensive care units (ICUs). ICU patients who regained consciousness after 7 days of mechanical ventilation were included. Plasma levels of insulin-like growth factor 1 (IGF-1), prolactin, thyroid-stimulating hormone, follicle-stimulating hormone, luteinizing hormone, estradiol, progesterone, testosterone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS) and cortisol were measured on the first day patients were awake and cooperative (day 1). Mean blood glucose from admission to day 1 was calculated.ResultsWe studied 102 patients: 65 men and 37 women (29 of the women were postmenopausal). Twenty-four patients (24%) died in the hospital. The IGF-1 levels were higher and the cortisol levels were lower in survivors. Mean blood glucose was lower in women who survived, and DHEA and DHEAS were higher in men who survived.ConclusionsThese results suggest that, on the basis of sex, some endocrine or metabolic markers measured in the postacute phase of critical illness might have a prognostic value.

Adrenal Insufficiency in Septic Shock

During disease states, the endocrine axes exhibit different levels of activity according to the severity of illness. These various alterations have been widely investigated. Indeed, evidence indicates that the anterior pituitary is dysfunctional in these states, especially when multiple organ dysfunction syndrome is present, impacting both adrenal and thyroid glands, but also secretion of estrogen, growth hormone, insulin-like growth factor-1, and prolactin. In a majority of these cases, substitutive treatment is not obviously beneficial, inappropriate secretions being considered as adaptive responses to stressful events. The hypothalamic-pituitaryadrenal axis appears to play the most important role in the regulation of inflammation during septic shock. Many factors modulate this axis. Some are well known. Others, such as vasopressin and apelin, are newly ascribed. Therapeutic issues in critically ill patients still remain controversial and are ardently debated, especially with regard to the needs and practical use of corticosteroids in septic shock. This article focuses on actual knowledge, mechanisms, definitions, and therapeutic recommendations, as well as on areas of uncertainty relative to adrenal gland insufficiency in septic shock.

Osmoregulation of vasopressin secretion is altered in the postacute phase of septic shock.

Objective:To determine whether septic shock patients have an abnormal reponse to increasing osmolarity. Design:Prospective interventional study. Setting:Intensive care unit at Raymond Poincaré and Etampes Hospitals. Patients:Normonatremic patients at >72 hrs from septic shock onset. Intervention:Osmotic challenge consisting of infusing 500 mL of hypertonic saline solution (with cumulative amount of sodium not exceeding 24 g) over 120 mins. Measurements and Main Results:Plasma arginine vasopressin levels were measured 15 mins before the test and then four times every 30 mins. A slope of the relation between arginine vasopressin and plasma sodium levels of <0.5 pg/mEq defined nonresponders. Among the 33 included patients, 17 (52%) were nonresponders. During osmotic challenge, variations throughout the test in plasma sodium levels, blood pressure, and central venous pressure were comparable between the two groups. Arginine vasopressin increased from 4.8 pg/mL [3.3–6.4 pg/mL] to 14.4 pg/mL [11.2–23.3 pg/mL] in responders but only from 2.8 pg/mL [2.3–4.0 pg/mL] to 4.0 pg/mL [3.1–5.3 pg/mL] in nonresponders (p < .0001). Responders had a higher plasma arginine vasopressin levels at baseline and a more severe hematosis alteration. Nonresponders had more frequently bacteremia and liver dysfunction, been referred from the ward and undergone surgery. Critical illness severity, hemodynamic alteration, hydroelectrolytic disturbances, treatment, and outcome did not differ between the two groups. Conclusion:Osmoregulation is dramatically altered in half of patients with prolonged septic shock.

Hyperglycaemia and apoptosis of microglial cells in human septic shock

IntroductionThe effect of hyperglycaemia on the brain cells of septic shock patients is unknown. The objective of this study was to evaluate the relationship between hyperglycaemia and apoptosis in the brains of septic shock patients.MethodsIn a prospective study of 17 patients who died from septic shock, hippocampal tissue was assessed for neuronal ischaemia, neuronal and microglial apoptosis, neuronal Glucose Transporter (GLUT) 4, endothelial inducible Nitric Oxide Synthase (iNOS), microglial GLUT5 expression, microglial and astrocyte activation. Blood glucose (BG) was recorded five times a day from ICU admission to death. Hyperglycaemia was defined as a BG 200 mg/dL g/l and the area under the BG curve (AUBGC) > 2 g/l was assessed.ResultsMedian BG over ICU stay was 2.2 g/l. Neuronal apoptosis was correlated with endothelial iNOS expression (rho = 0.68, P = 0.04), while microglial apoptosis was associated with AUBGC > 2 g/l (rho = 0.70; P = 0.002). Neuronal and microglial apoptosis correlated with each other (rho = 0.69, P = 0.006), but neither correlated with the duration of septic shock, nor with GLUT4 and 5 expression. Neuronal apoptosis and ischaemia tended to correlate with duration of hypotension.ConclusionsIn patients with septic shock, neuronal apoptosis is rather associated with iNOS expression and microglial apoptosis with hyperglycaemia, possibly because GLUT5 is not downregulated. These data provide a mechanistic basis for understanding the neuroprotective effects of glycemic control.