There are two types of corticosteroids: glucocorticoids that are potent anti-inflammatory mediators, and mineralocorticoids that regulate vasomotor tone. Glucocorticosteroids are 12-carbon molecules derived from cholesterol and are produced by the adrenals in response to adrenocorticotropin hormone (ACTH). They are produced continuously (20 mg/day) and are influenced by circadian rhythm. During inflammatory processes, inflammatory cytokines such as interleukin-1 (IL-1), tumor necrosis factor (TNF), and IL-6 favor the release of corticotropin releasing factor (CRF) by the hypothalamus. Then, CRF enhances the production of ACTH by the pituitary gland, resulting in an enhanced production of corticosteroids. Accordingly, an i.p. injection of IL-1 into mice induces increased plasma ACTH levels and a peak of corticosterone 2 h after injection (1).
In the 1980s, several clinical studies were performed with glucocorticoids in patients with sepsis. Glucocorticoids were given at high doses for a very brief period of time (4–24 h), with the aim of repressing the exacerbated inflammatory response that was believed to be a key event in the pathophysiology of sepsis. These trials failed (2). More recently, the use of glucocorticoids for sepsis has been revisited based on the putative role of adreno-insufficiency (3–5) and peripheral glucocorticoid resistance (6,7) frequently observed in sepsis. In the present review, we summarize the present understanding of the basic mechanisms of action of glucocorticoids on the inflammatory and cardiovascular responses, and the current evidence for the usefulness of corticosteroids for treating septic shock.
Cells from most tissues are responsive to glucocorticosteroids, which diffuse through the cell membrane. The glucocorticoid receptor (GR) is complexed with heat shock protein (HSP) 56, HSP70, and HSP90 found within the cytoplasm (8). The receptor contain three domains: one binds corticosteroids, one binds to DNA, also involved in dimerization, and one activates the promoters within the genes (Fig. 1). As a result of alternative splicing of the GR pre-mRNA, there are two isoforms of GR, termed GRα and GRβ. GRβ does not bind glucocorticoids and behaves as a dominant inhibitor of GRα activity, possibly through formation of antagonistic GRα/GRβ heterodimers (9).
After interaction of the receptor with corticosteroids, HSP are freed from the receptor, and the receptor and corticosteroids form a dimer. This complex enters within the nucleus and interacts with specific binding sequences known as glucocorticoid responsive elements (GRE). Some GRE down-regulate the transcription of other genes (e.g., most cytokines, adhesion molecules, lipooxygenase), preventing the transcription initiated by various transcriptional factors such as AP1, NF-AT (10), and NF-κB (11,12). GR dimers also prevent AP-1 from interacting with its binding site within the promoters. In vitro inhibition of NF-κB activation has been regularly reported in different types of cells (13,14), although an enhanced expression of the p65 component of NF-κB has been reported in response to corticosteroids (15). In addition, the induction of the inhibitor of NF-κB (IκB) by corticosteroids (16) further inhibits the NF-κB-dependent gene transcription. The amount of cytoplasmic receptor can be upregulated by TNF (17) or down-regulated by IL-1 (18).
In contrast, other GRE sites favor the transcription of certain genes and can act together with other promoters such as NF-IL6, enhancing the production of acute phase proteins. Lipocortin-1 belongs to the products of genes with a positive GRE site. Lipocortin-1 is a member of the annexin family, which binds calcium and phospholipids. Lipocortin-1 binds to a receptor on macrophages and neutrophils and inhibits eicosanoid and superoxide anion formation (19). Lipocortin inhibits neutrophil migration (20) and lymphocyte proliferation (21). Thymosin β4 sulfoxide is another factor generated by monocytes in response to glucocorticoids (22). This factor inhibits neutrophil chemotaxis and is an inhibitor of edema formation.
INHIBITION OF PROINFLAMMATORY CYTOKINE PRODUCTION
Most productions of cytokines are inhibited by glucocorticosteroids. This is observed with T lymphocyte-derived cytokines such as IL-2, γ-interferon (IFN-γ) (23,24), IL-5 (25), IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF) (26), whereas contradictory results have been reported for IL-4 (27,28). Glucocorticosteroids act on many different types of cells such as monocytes/macrophages, dendritic cells, neutrophils, fibroblasts, epithelial cells, endothelial cells, or smooth muscle cells, preventing the production of IL-1 (29), TNF (30), IL-6 (31), G-CSF (24), IL-12 (32), IFN-γ (33), IL-8 (34), and many other different chemokines (e.g., MIP-1α, MCP-1, RANTES) (24,35,36). Indeed, glucocorticosteroids not only inhibit the main neutrophil chemoattractant (i.e., IL-8), but they also limit the responsiveness of neutrophils to chemoattractant signals (37). Glucocorticosteroids have also the potency to inhibit the production of growth factor such as vascular endothelial growth factor (VEGF), which promotes neovascularization and increases vascular permeability (38).
However, in some experimental designs, glucocorticoids have been reported to be inefficient in preventing the production of M-CSF by fibroblasts (39), of G-CSF by epithelial cells (40), and of leukemia inhibitory factor (LIF) in vivo (41).
REGULATION OF ANTI-INFLAMMATORY CYTOKINES
Several cytokines are mainly anti-inflammatory in their capacity to prevent the production of the proinflammatory cytokines, to limit some of their properties, and to induce the IL-1 receptor antagonist (IL-1ra)
Corticosteroids increase IL-1ra mRNA expression in Schwann cells (42), enhance IL-1ra activity from epidermal cells (43), and amplify IL-1ra release by IL-1 or IL-6-treated hepatocytes (44). Indeed, together with IL-1 and TNF, glucocorticoids increase the synthesis of acute phase proteins by hepatocytes (45). However, surprisingly, glucocorticoids inhibit the release of IL-1ra by unstimulated or endotoxin, IL-1-, IL-4-, or IL-10-treated human monocytes (46,47). A similar inhibition was reported with human airway epithelial cells, associated with an accumulation of intracellular IL-1ra within the cells (48). In human volunteers, hydrocortisone injection shortly before an endotoxin (lipopolysaccharide, LPS) injection did not modify the level of circulating IL-1ra (49). Injected in rat, dexamethasone induced a weak reduction of spleen IL-1ra mRNA (50).
IL-10 is one of the major anti-inflammatory cytokines. In most models, glucocorticoids have been shown to enhance IL-10 levels. This was the case in vivo in humans and in mice in response to LPS (51,52). This was confirmed in the clinical settings of asthma (24) and surgery with cardiopulmonary bypass (53). In vitro experimental results are more controversial, perhaps because of species, cell type, or experimental design differences (32,52). Different cell reactivity to glucocorticoids was also reported when transforming growth factor-β (TGFβ) production was analyzed (54).
INHIBITION OF INFLAMMATORY MEDIATORS
Glucocorticosteroids not only prevent the production of proinflammatory cytokines but also that of numerous other inflammatory mediators. The inhibition of eicosanoids reflects the capacity of glucocorticoids to inhibit the synthesis of cyclooxygenase-2 by many cell types such as smooth muscle cells (55), airway (56), and kidney epithelial cells (57). Glucocorticosteroids also accelerate leukotriene C4 (LTC4) catabolism by inducing activity of a LTC4-degrading enzyme (58), and prevent the release of platelet activating factor (PAF) (59). Glucocorticosteroids also limit the generation of free radicals such as nitric oxide (NO) or superoxide anion. The inhibitory effect on the generation of NO reflects the inhibition of the inducible NO synthase (iNOS) production by macrophages (60), neutrophils (61), endothelial cells (62), and in lungs, liver, or aorta (63). As well, many cells, including macrophages, neutrophils, and eosinophils, display a limited superoxide anion production in the presence of glucocorticoids (64).
MODULATION OF CELL MARKERS
Glucocorticosteroids down-regulate the expression of a few surface markers such as the endotoxin receptor (CD14) on monocytes/macrophages (65) and adhesion molecules ELAM-1 and ICAM-1 on endothelial cells (66). This last phenomenon is linked to the capacity of glucocorticoids to prevent adhesion of circulating neutrophils to the endothelium, thus limiting their margination toward the inflammatory foci. The capacity of glucocorticoids to reduce LFA-1 and CD2 expression on lymphocytes also inhibits their adherence to endothelium (67). The action of glucocorticoids on class II major histocompatibility complex (MHC) depends on the nature of the cells or on species (29). In humans, an enhanced expression was reported on monocytes (68) and eosinophils (69). Synergistically, with nontypeable Haemophilus influenzae, glucocorticoids enhance Toll-like receptor 2 (TLR2) mRNA in epithelial cells (14).
The induction of tissue factor onto monocytes and endothelial cells by IL-1, TNF, or LPS is a key event that links inflammation and coagulation. There is no evidence that glucocorticoids inhibit the expression of tissue factor on endothelial cells (70). Dexamethasone even enhances tissue factor expression on IL-1- and TNF-activated monocytes, whereas controversial results were reported for LPS-activated monocytes (70,71).
Glucocorticosteroids enhance the expression of various cytokines receptors. This is the case for IL-1R on neutrophils (72), B lymphocytes, and fibroblasts (73), for IL-6R on T lymphocytes (74), epithelial cells (75), and hepatocytes (76), for IL-2R on T lymphocytes (74), for TNFR p55 on airway epithelial cells (77), and for TNFR p75 on monocytes (78). Enhanced expression of soluble TNF receptor has been associated with these properties.
MODULATION OF APOPTOSIS
The injection of corticoids induces a reduction of thymus and spleen weight (79). Indeed, glucocorticoids enhance the occurrence of apoptosis of thymocytes (80), mature T lymphocytes (81), eosinophils (82), epithelial cells (83), and precursors of dermal/interstitial dendritic cells (84), but delay apoptosis of neutrophils (82). High constitutive expression of GRβ by human neutrophils may provide a mechanism by which these cells escape glucocorticoid-induced cell death (85). Moreover, IL-8, which further enhances neutrophil survival, further enhances the expression of this receptor. Finally, glucocorticoids favor phagocytosis of apoptotic neutrophils (86). In an elegant model, Ayala et al. (87) demonstrated the involvement of corticosteroids in the induction of apoptosis of thymocytes that was observed 4 to 24 h after the onset of sepsis in a cecal ligation and puncture model.
REGULATION OF GLUCOCORTICOID PRODUCTION BY MACROPHAGE MIGRATION INHIBITORY FACTOR (MIF)
MIF was one of the earliest cytokine ever described (in 1966). Rediscovered as a product of the pituitary gland, MIF potentiates lethal endotoxin-induced shock (88) and severity of peritonitis (89) in mice. Calandra et al. (90) demonstrated that both in vivo and in vitro glucocorticoids induced MIF production. Within a negative feedback loop, MIF prevents inhibitory effects of corticoids on proinflammatory cytokine production by LPS-activated human monocytes. MIF production is down-regulated by IL-10 (91). Another inhibitory mechanism has been reported with human α-defensins that inhibit the production of glucocorticoids by competing for the binding of ACTH to its receptor (92). Figure 2 summarizes several inhibitory activities of glucocorticoids and regulatory loops.
PARAMETERS THAT AFFECT THE EFFICIENCY OF GLUCOCORTICOIDS
Despite their well established anti-inflammatory properties, various parameters can interfere with glucocorticoids and limit their properties. These parameters include the nature of the activating signals, the nature of the cells or the cellular compartment, and the sequence of signaling. Below are a few examples that illustrate the influence of these parameters.
Nature of the activating signal
Although dexamethasone inhibits IL-8 production by LPS-activated monocytes, this is not the case when these cells have been activated with phorbol myristate acetate (93). The efficiency of hydrocortisone to inhibit IL-6 production by human monocytes is not the same when the cells are activated with IL-1, LPS, or both (94). Similarly, tissue factor expression onto the surface of monocytes can be repressed by dexamethasone when cells are activated with LPS, whereas an enhanced expression was observed when cells were activated with IL-1 (71). In vivo models also reveal discrepancies in the capacities of endogenous glucocorticoids to lower the levels of circulating TNF: in a porcine model, metyrapone that successfully blocked endogenous cortisol synthesis in response to an endotoxin infusion did not markedly influence plasma level of TNF (95). In contrast, in a cecal ligation and puncture-induced sepsis in rats, adrenalectomy increased circulating TNF (96).
Nature of the cells and of the compartment
Glucocorticoids inhibit the production of IL-6 from IL-1-activated endothelial cells and fibroblasts (30), whereas this was not the case when astrocytes were studied (97). Dexamethasone was shown to be more efficient in inhibiting TNF production by LPS-activated monocytes than the TNF production by LPS-activated alveolar macrophages (98). Hydrocortisone was capable of inhibiting IL-1 production in response to LPS + IFN-γ when acting on freshly isolated human monocytes, whereas this was not the case when tested with aged monocytes (99). Furthermore, cells derived from compartments associated with pathologies can behave differently than cells derived from healthy donors. Accordingly, dexamethasone was inefficient to prevent basal or LPS-stimulated IL-8 production by alveolar macrophages from chronic obstructive pulmonary disease patients (100). As well, dexamethasone was unable to inhibit basal or LPS-stimulated IL-8 production by neutrophils derived from sputum of patients with cystic fibrosis, whereas it did with blood-derived neutrophils (101).
Nature of the regulated cytokine
The amounts of dexamethasone required to inhibit cytokines produced by LPS-activated human monocytes are not the same for IL-1 and TNF (IC50 = 0.2–0.4 μM), IL-8 (IC50 = 50 μM), and IL-6 (IC50 > 100 μM) (102). When myoblasts were studied, it was reported that dexamethasone inhibits LPS-induced IL-6 mRNA but not TNF mRNA (103).
Route of delivery
The route of delivery of both the inflammatory agent and the administrated glucocorticoids may influence the results observed. When dexamethasone was injected i.v. in mice 1 h before an i.v. injection of LPS, whole body imaging using the expression of luciferase under the control of NF-κB revealed a reduction of NF-κB activation (104). In contrast, dexamethasone given i.p. before an inhalation of LPS enhanced NF-κB activation in the lungs as assessed by bioluminescence (13).
During physiological processes, cells receive different signals that occur in a chronological order. As a consequence, inhibitory signals delivered by glucocorticoids may or may not occur. Thus, pretreatment with dexamethasone or simultaneous addition with LPS lead to an inhibition of IL-8 production by monocytes or alveolar macrophages, whereas, if the glucocorticoids are delivered 1 or 2 h after LPS activation, inhibition is not observed (34). Numerous studies have established that pretreatment with IFN-γ reduces the inhibitory properties of glucocorticoids (64,105). A pretreatment with TNF may favor or limit the inhibitory activity of glucocorticoids, depending on the studied model (17,106). Indeed, the number of intracellular glucocorticoids receptors may be enhanced by cytokine pretreatment (e.g., IL-10) or reduced (e.g., TNF) (106). Similarly, LPS pretreatment was reported to enhance the number of glucocorticoid receptors (107).
In vivo, timing of administration dramatically influences the results observed. For example, if dexamethasone is injected from 1 to 7 days before an injection of LPS, TNF levels in plasma are enhanced as compared with the injection of LPS in the absence of glucocorticoid pretreatment (108,109). In human volunteers, injection of LPS 12 to 144 h after the end of a cortisol infusion was associated with an enhanced plasma levels of TNF and IL-6 as compared with the absence of cortisol pretreatment (110). This enhanced proinflammatory cytokine response may have played a role in the failure of the studies of glucocorticoid administration to protect in human sepsis: indeed, these treatments never exceeded 24 h in a disease that lasts for days with a long persistence of triggering signals.
CARDIOVASCULAR EFFECTS OF CORTICOSTEROIDS
Corticosteroids exert important actions of the various elements of the cardiovascular system, including the capillaries, the arterioles, and the myocardium. In the absence of corticosteroids, capillary permeability increases, vasomotor tone decreases, and cardiac size and cardiac output decrease. In contrast, excess of mineralocorticoids, such as primary aldosteronism, induces hypertension. Although it was suggested that corticosteroids induced hypertension through the increase in water and salt content of the arteriolar walls (111), other studies suggest that the vascular effects of corticosteroids probably result from a glucocorticoid activity rather than from a mineralocorticoid activity (112). In addition, topical glucocorticoids without demonstrable mineralocorticoid activity constrict the dermal vessels, provoking blanching (113). The mechanisms of this vasoconstriction remain poorly understood. In normal volunteers, cortisol administration was associated with unchanged or even suppressed sympathetic activity, suggesting that cortisol-induced hypertension is not mediated through increased sympathetic tone (114). However, there is growing evidence that corticosteroids may upregulate the sympathetic nervous system and the renin-angiotensin system (Table 1). For example, in dogs and cats, cortisol and aldosterone increase vasoconstrictor response to epinephrine (115). In Wistar rats, the corticosteroid antagonist RU 486 induced a pronounced reduction in mean blood pressure (−20 mmHg at peak effect) without altering cardiac output, suggesting a decrease in vascular resistance (112). This study also showed that corticosteroids regulate vascular responses to norepinephrine and angiotensin II, but not to vasopressin. In vitro studies on vascular smooth muscles cells suggested that cortisol stimulated the phosphoinositide signaling system in smooth muscle cells of the rat aorta (116). In this study, a 15-min stimulation with physiological concentrations of cortisol (0.02–5.0 μg/mL) induced a dose-dependent increase of the inositol trisphosphate concentrations (+500% at peak effect) and also induced a translocation of the calcium- and lipid-dependent protein kinase C activity from the cytosolic to the membranous compartment. In contrast, the inositol trisphosphate response was potentiated by epinephrine only after preincubation of cells with cortisol. This cortisol-induced stimulation of the phosphoinositide system could influence intracellular free calcium and thus vascular reactivity and blood pressure. In rats, dexamethasone at doses ranging from 0.2 to 20 mg/kg increased the phenylethanolamine N-methyltransferase (PNMT) activity (up to 230%) in cardiac atria, ventricle, skeletal muscle, and the adrenal glands, and subsequently enhanced epinephrine synthesis (117). Other mechanisms underlying corticosteroid-induced potentiation of catecholamine actions include inhibition of catecholamine reuptake in neuromuscular junctions and a decrease in catechol-O-methyltransferase and mono-amine oxydase (118), increased binding capacity and affinity of β-adrenergic receptors in arterial smooth muscles cells (119), receptor G coupling, and catecholamine-induced cAMP synthesis (120). Corticosteroids also increase angiotensin II type I receptors in vascular smooth muscles (121) and significantly enhance central pressor effects of exogenous angiotensin II (122).
Effects on vessels reactivity to vasoconstrictors
Numerous studies in various animal models, in healthy volunteers challenged with LPS, and in patients consistently show that corticosteroids enhance vessel responsiveness to various vasoactive agents. In anesthetized rats, intravenous injection of LPS induces a sustained decrease in blood pressure and impaired aortic rings contractility to norepinephrine (123). These effects were associated with an increase in iNOS activity, and were partly prevented by pretreatment with an NOS inhibitor. When animals were pretreated with serial intraperitoneal injections of sublethal doses of LPS for 4 days, subsequent intravenous injection of a lethal dose of LPS failed to impair blood vessels' sensitivity to norepinephrine, a phenomenon called cardiovascular tolerance to endotoxin. In endotoxin-tolerant animals, iNOS activity was reduced by 63% and plasma corticosterone levels increased by 9-fold from 2 h after LPS injection and remained elevated for 6 to 24 h. Administration of RU 486 restored iNOS activity and subsequent aortic ring hyporesponsiveness to norepinephrine. In naive animals, administration of RU 486 had no effect. In a similar LPS model, pretreatment with dexamethasone prevented endotoxin-induced vascular hyporesponsiveness to norepinephrine (124), probably by inhibiting extracellular release of lipocortin-1 (125). In a rodent model of hypotensive and hypokinetic septic shock, the effects of early or late dexamethasone administration were investigated on hemodynamics, response to catecholamines, and cardiac β-adrenergic signaling (126). As compared with sham-operated rats, the untreated septic rats were hypotensive and had reduced aortic blood flow. However, in vivo, chronotropic response to isoproterenol and not pressor response to epinephrine and phenylephrine was attenuated in animals with sepsis. In animals with sepsis, dexamethasone administration resulted in a complete reversal of hypotension, improvement in aortic blood flow, and reduced plasma lactate and nitrite/nitrate concentrations as compared with untreated animals with sepsis. The number of myocardial β-adrenergic receptors and in vivo isoproterenol-stimulated myocardial cAMP content were similar in sham animals and animals with sepsis. Late and not early administration of dexamethasone significantly decreased the receptor's affinity. Thus, one may argue that in this model of sepsis, the favorable cardiovascular effects of dexamethasone were not mediated through resensitization of adrenergic receptors.
In healthy volunteers, local instillation of LPS induced a profound reduction in venous contractile response to norepinephrine (127). This effect was completely prevented with pretreatment by 100 mg orally of hydrocortisone. In this experiment, 1 h after LPS instillation, Emax (the maximal constrictor effect, expressed as percentage of control values) was 52% in controls and 70% in treated subjects. The administration of the NOS inhibitor L-NMMA or of aspirin (a cyclo-oxygenase blocking agent) did not alter the effects of LPS. In another experiment, hydrocortisone was given intravenously to 23 healthy subjects, simultaneously, immediately before, or 6, 12, or 144 h after an intravenous LPS challenge (110). Hydrocortisone given immediately before or simultaneously with the LPS challenge prevented the fall in blood pressure, and the increase in heart rate and in circulating epinephrine levels. In parallel, hydrocortisone inhibited the production of TNFα.
In septic shock, the relationship between corticosteroid insufficiency and pressor response to norepinephrine was investigated in nine patients (128). Corticosteroid insufficiency was defined by an increment in plasma cortisol levels of less than 9 μg/dL (250 nmol/L) after an acute corticotropin test (intravenous bolus of 250 μg of tetracosactrin). By definition, five patients with sepsis had corticosteroid insufficiency. These patients had a profound decrease in pressor response to an incremental dose of norepinephrine when compared with patients with presumed normal endogenous cortisol production (P = 0.028). The difference between the two groups for mean arterial pressure was 7 mmHg when norepinephrine was infused at a concentration of 0.05 μg/kg/min and was 20 mmHg when the norepinephrine infusion rate was 1.5 μg/kg/min. In addition, the maximal increase in mean arterial pressure during norepinephrine infusion correlated positively to the maximal increment in plasma cortisol levels after corticotropin (r = 0.783, P = 0.013). One hour after a single intravenous bolus of 50 mg of hydrocortisone, in patients with adrenal insufficiency, mean arterial pressure response to norepinephrine was significantly improved. For example, hydrocortisone increased mean arterial pressure by 10 mmHg when the norepinephrine infusion rate was 0.075 μg/kg/min and by 30 mmHg when the norepinephrine infusion rate was 1.5 μg/kg/min. Subsequently, after hydrocortisone administration, patients with corticosteroid insufficiency had similar pressor response to norepinephrine than patients with normal cortisol production. Another study investigated the effects of a single intravenous bolus of 50 mg of hydrocortisone on phenylephrine-mean arterial response curves in 12 patients with septic shock and 12 healthy volunteers (129). At baseline, hydrocortisone similarly increased mean arterial pressure and decreased heart rate in septic shock and healthy volunteers. Incremental doses of phenylephrine induced greater increases in mean arterial pressure in healthy volunteers than in volunteers with septic shock, an effect that was enhanced by hydrocortisone administration. The difference in mean arterial response to phenylephrine between septic shock and healthy volunteers increased in a dose-dependent manner. Hydrocortisone induced a greater increase in Emax for phenylephrine in volunteers with septic shock than in controls (+97% vs. +26%, P = 0.028), did not change ED50 for phenylephrine, and tended to normalize the slope of the dose-effect relationship. Then, in septic shock treated by hydrocortisone, the dose-response curves of mean arterial pressure to phenylephrine were closely similar to the curves obtained in nontreated healthy subjects. In this experiment, the effects of hydrocortisone were correlated neither to circulating catecholamines levels, to plasma renin activity, nor to cyclic GMP levels.
A prolonged (5 days or more) treatment by intravenous hydrocortisone (around 300 mg daily) increases mean systemic arterial pressure and systemic vascular resistance with no significant change in pulmonary hemodynamics and cardiac index. In three phase II (130) and one phase III trials (134) in vasopressor-dependent septic shock, prolonged treatment with a low dose of corticosteroids was associated with a significant reduction in the duration of shock.
Effects on systemic and pulmonary hemodynamics
In patients with septic shock, the effects of corticosteroids on systemic and pulmonary hemodynamics vary according to concomitant vasopressor therapy. In septic shock not treated by vasoconstrictors, intravenous administration of 50 mg of hydrocortisone had little effects on systemic blood pressure (128,129). In one randomized, placebo-controlled, double-blind trial, the hemodynamic effects of 100 mg of hydrocortisone every 8 h for 5 days were investigated in 41 patients with septic shock (130). In this study, mean arterial pressure increased in the hydrocortisone group (+10% at peak effects) and decreased (−7% at peak effects) in the placebo group. Simultaneously, systemic vascular resistance increased in the treated group and decreased in the placebo group. This increase in cardiac afterload by hydrocortisone was not associated with variation in cardiac index. In a second randomized, placebo-controlled, double-blind trial, the hemodynamic effects of a continuous infusion of hydrocortisone (0.18 mg/kg/h) for 6 days were investigated in 40 hyperkinetic patients with septic shock (131). In this study, as compared with placebo, hydrocortisone increased mean arterial pressure from study day 1 (+7 mmHg) to study day 5 (+8 mmHg). Simultaneously, systemic vascular resistance was increased in the hydrocortisone group (+260 and +369 dynes s/cm5 m2 at study days 1 and 5, respectively). This increase in cardiac afterload was associated with a decrease in cardiac index in the hydrocortisone group (−25%) as compared with the placebo group (+6%). Otherwise, hydrocortisone did not change pulmonary hemodynamics. In a third randomized, placebo-controlled trial, the hemodynamic effects of a continuous infusion of hydrocortisone (10 mg/h) were investigated in 40 patients with septic shock (132). As compared with placebo, hydrocortisone significantly improved mean arterial pressure (+14 vs. +1 mmHg at peak effect) and systemic vascular resistance (+237 vs. +10 dynes s/cm5 m2 at peak effect). Subsequently, cardiac index slightly decreased (−11%) in the hydrocortisone group as compared with the placebo group (+9%). Otherwise, hydrocortisone did not change pulmonary hemodynamics.
Effects on shock duration
The favorable effects of corticosteroids on vessel responsiveness to vasopressor agents is depicted at bedside by a shortening of the time on vasoconstrictor drugs. Five randomized, placebo-controlled, double-blind trials have investigated the effects of a prolonged (more than 3 days) treatment with moderate doses of hydrocortisone (200–300 mg per day) on shock duration and vasopressor withdrawal in septic shock (22–26) (Table 2). In one study, as compared with placebo, within 1 day, hydrocortisone significantly reduced the amount of catecholamine needed to maintain adequate systemic hemodynamics (−40% form baseline versus +43%) (130). At study day 7, the rate of shock reversal was 68% in the hydrocortisone group and 21% in the placebo group. The median time to cessation of vasopressor therapy was 4 days in the treated group and 13 days in the placebo group. In a second study, at study day 7, the rate of shock reversal was 85% in the hydrocortisone group and 60% in the placebo group. The median time to vasopressor therapy withdrawal was 2 days in the treated group and 7 days in the placebo group (131). In a third study, as compared with placebo, hydrocortisone increased the rate of shock reversal at study day 3 (70% vs. 33%) and decreased the median time to cessation of vasopressor therapy (3 vs. 5 days) (133). In a fourth study, at study day 3, the rate of shock reversal was 70% in the hydrocortisone group and 30% in the placebo group (132). Finally, in the fifth study, a phase III randomized placebo-controlled, double blind trial of 300 patients with septic shock, hydrocortisone combined with fludrocortisone significantly reduced the time on vasopressor in nonresponders to corticotropin (increment in plasma cortisol levels of less than 9 μg/dL in response to ACTH stimulation) with a median time to vasopressor therapy withdrawal of 7 vs. 10 days (log rank P = 0.009). The rate of shock reversal at study day 7 was 50% vs. 70% (134). These effects were not seen in patients with septic shock who had a cortisol increment or more than 9 μg/dL in response to corticotropin (median time to vasopressor therapy withdrawal: 9 vs. 7 days, log rank P = 0.49, and rate of shock reversal at day 7: 43% vs. 60%).
EFFECTS OF CORTICOSTEROIDS ON SURVIVAL
High doses of corticosteroids, i.e., 30 mg/kg of methylprednisolone (or equivalent) once to four times had no effect on survival in severe sepsis or septic shock (2). By contrast, in septic shock, low doses ranging from 200 to 300 mg daily of corticosteroids given for a prolonged period of time (more than 5 days) have been shown to improve outcome in several controlled clinical trials. In 18 critically ill patients, as compared with standard treatment alone, 100 mg twice daily of hydrocortisone dramatically improved intensive care unit survival rate (90% vs. 12.5%) (135). In another study of 41 patients with septic shock, as compared with placebo, a 100-mg bolus of hydrocortisone every 8 h for 5 days improved the 28-day survival rate (68% vs. 37%) (130). Similar findings have been reported in another study (133). Finally, a phase III, multicenter, placebo-controlled, randomized, double-blind study has evaluated the efficacy and safety of a combination of hydrocortisone (50 mg intravenous bolus four times per day) and fludrocortisone (50 μg orally once a day) given for 7 days in 300 patients with septic shock (134). In this trial, patients with corticosteroid insufficiency (nonresponders to the corticotropin test) were more likely to draw benefit from cortisol replacement, i.e., 1 month survival rates 37% vs. 47% (log rank P = 0.02), ICU survival rates 30% vs. 42% (log rank P = 0.01), and hospital survival rates 28% vs. 39% (log rank P = 0.02). Patients who were responding normally to corticotropin test (cortisol increment of more than 9 μg/dL after 250 μg of corticotropin) had no benefit from corticosteroid therapy (1 month mortality rates: 61% vs. 53%, log rank P = 0.81). An ongoing phase III, randomized, placebo-controlled, double-blind trial is aimed at confirming the benefit from cortisol replacement in less sick patients in Europe and at clarifying treatment effects in patients who have presumably normal adrenal function (CORTICUS trial).
In aggregate, these studies suggest that, in vasopressor-dependent septic shock, a low dose of corticosteroids attenuates inflammation, restores vessels reactivity to vasopressor agents, shortens the time on vasopressor agent, and improves survival. A strategy that would maximize benefit while minimizing potential toxicity or unnecessary drugs would be the use of low-dose corticosteroids in patients with septic shock. Preferably, intravenous hydrocortisone at a daily dose of 200 to 300 mg should be given in combination with oral fludrocortisone at a daily dose of 50 μg. Corticosteroids should be given for 1 week from onset of shock defined by the need of vasopressors. Corticosteroid administration should be preceded by an acute ACTH test. Then, when the results of the test are available (preferably within 2 to 24 h) treatment should be continued only in patients with corticosteroid insufficiency defined by a random cortisol of 15 μg/dL or less, a peak cortisol of 20 μg/dL or less, or a cortisol increment of 9 μg/dL or less.
The authors thank Shaw Warren for critical review of the manuscript.
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