Special Feature
Corticosteroid Treatment for Septic Shock: New Insights
By Francisco Baigorri, MD, PhD
Activation of the hypothalamic-pituitary-adrenal (HPA) axis is an essential component of the general adaptation to stress and contributes to the maintenance of homeostasis. Cortisol, in particular, has a vital supportive role in the maintenance of vascular tone, endothelial integrity, vascular permeability, and the distribution of total body water within the vascular compartment. It also potentiates the vasoconstrictor actions of cathecolamines.1,2 Moreover, cortisol exerts important metabolic and immune functions in response to infection. It is now widely accepted that the glucocorticoid action counteracts the systemic inflammatory response, thus protecting the host against its own inflammatory defense reactions.3 (See Table 1.)
| Table 1-Some Effects of Corticosteroids That May be Involved in a Beneficial Action in Patients with Septic Shock |
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| • Inhibition of the migration of leucocytes to inflammatory sites | ||||||
| • Inhibition of the adhesion of neutrophils to endothelial cells and their subsequent production of humoral factors |
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| • Inhibition of macrophage and endothelial function | ||||||
| • Increment in blood pressure through blockade of nitric oxide synthesis | ||||||
| • Increment in myocardial contractility | ||||||
| • Stimulation of the function of alpha1-adrenoreceptors and beta- adrenoreceptors, and by increasing the number of these receptors |
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| • Attenuation of down-regulation of adrenergic receptors induced by the use of cathecolamines for long periods |
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| • Increment of gluconeogenesis | ||||||
| • Shift of the oxygen dissociation curve | ||||||
In the last three decades, the anti-inflammatory properties of corticosteroids have encouraged researchers to investigate the potential benefit of pharmacologic doses of these substances in severe infections. However, despite a substantial amount of data supporting the use of glucocorticoids in experimental models of septic shock, the results of randomized, controlled trials in humans have been controversial. Two meta-analyses concluded that glucocorticoids are not beneficial in sepsis and septic shock, and in one of them, that the use of glucocorticoids may be harmful.4,5
In recent years, several authors have hypothesized a syndrome of relative adrenocortical deficiency in septic shock in the presence of normal or even elevated serum cortisol concentrations. Moreover, a few uncontrolled studies indicate that stress doses of hydrocortisone improve hemodynamics in patients with hyperdynamic septic shock unresponsive to conventional therapy.6,7 As a result, there is renewed interest in corticosteroids as therapy for septic shock.8,9 This essay will focus on recent investigations in this field.
Sepsis and Adrenal Function
New insights into glucocorticoid physiology and regulation during septic shock reveal that the functional integrity of both the HPA axis and glucocorticoid receptors in target cells is altered in several ways, and that this may result in an insufficient endogenous glucocorticoid action.3 Consequently, in the setting of sepsis, adrenal function can be difficult to evaluate. Cortisol levels, normally elevated by the stress of sepsis, are occasionally reduced, signifying possible adrenal dysfunction. On the other hand, even elevated cortisol levels do not assure that adrenal reserve is adequate. Paradoxical though it may seem, several studies showed that the higher the plasma cortisol concentrations, the worse the patient’s outcome. Thus, in severe sepsis, the evaluation of the appropriateness of the activation of the HPA axis requires dynamic testing.
The most commonly used test is the short corticotropin test, absolute adrenocortical deficiency being defined by a low basal cortisol concentration that is not increased with the rapid 250 µg corticotropin stimulation test (usually, basal and stimulated cortisol concentrations are < 20 µg/dL). The fact of the matter is that basal plasma cortisol levels are commonly greater than 20 µg/dL in severe sepsis, and the use of the absolute increase in plasma cortisol levels after the injection of corticotropin may be more useful to evaluate adrenal function.1
Annane and colleagues recently investigated the spectrum of serum cortisol levels and the cortisol response to corticotropin stimulation in patients with septic shock.10 In multivariate analysis, Annane et al found that a basal cortisol level greater than 34 µg/dL, and a cortisol response to corticotropin of no more than 9 µg/dL were independent predictors of death. Moreover, they defined three different patterns of activation of the HPA axis in septic shock according to the combination of the value of basal cortisol levels (£ or > 34 µg/dL) and the highest value of the cortisol response to corticotropin (£ or > 9 µg/dL). These patterns were associated with three different outcomes:
• Patients with basal cortisol level below 34 µg/dL and a cortisol response to corticotropin above 9 µg/dL. These patients with a seemingly adequate HPA axis activation had the lowest risk of death (28-day mortality rate of 26%).
• Patients with basal cortisol level above 34 µg/dL but a cortisol response to corticotropin below 9 µg/dL. These patients with occult adrenal insufficiency had the highest risk of death (82%).
• Patients with basal cortisol level below 34 µg/dL and a cortisol response to corticotropin below 9 µg/dL, or a basal cortisol level above 34 µg/dL and a cortisol response to corticotropin above 9 µg/dL. These patients had an intermediate risk of death (67%).
Only 30% of patients studied by Annane et al had an adequate HPA axis activation (pattern 1).10 According to the results of this study, adrenocortical deficiency is undoubtedly a predictor of a worse prognosis. However, it could be either the cause or simply a consequence of the severity of illness with which it is associated.
New Randomized, Clinical Trials of Corticosteroids in Septic Shock
Recently, two small, double-blind studies have been published showing that moderate stress doses of hydrocortisone (200-300 mg daily) improve hemodynamics and reduce the time of vasopressor support.11,12 These trials were different from the previous, negative studies in that hydrocortisone was administered in lower doses, relatively late in the course of sepsis, prolonged for 5-6 days and progressively reduced, and all patients were treated with cathecholamines.
The study of Bollaert and colleagues displayed an encouraging trend toward reduced 28-day mortality (32% in the treatment group vs 63% in the placebo group; P = 0.091).11 Unfortunately, the study was discontinued at the halfway point because of the positive effect on shock reversal. Moreover, this study deserves special consideration because all eligible patients underwent a short corticotropin stimulation test 24 hours before inclusion. Patients with absolute adrenal deficiency (as defined by a plasma cortisol concentration < 18 µg/dL after the corticotropin stimulation test) were excluded from the study. Forty-one patients were randomized (22 to receive active treatment, 19 to receive placebo).
Baseline plasma cortisol concentrations did not differ in the treatment group and in the placebo group. However, there were four patients with a maximal absolute increase of plasma cortisol concentration of less than 6 µg/dL after corticotropin administration in the treatment group vs. eight in the placebo group (P = 0.093). One might reasonably suppose that this difference could have influenced the results of the study, but there were no significant differences in outcome in the group of patients with an adequate response to corticotropin administration as compared with the group with an inadequate response (see Table 2). These findings support the view that either the beneficial effects of hydrocortisone replacement may be unrelated to adrenocortical deficiency or the biochemical diagnostic tools are inappropriate for ICU patients.8 Further randomized trials using the three-level classification of Annane et al could be helpful.10
| Table 2-Number (%) of Patients who Achieved Shock Reversal or Survived According to the Results of the Corticotropin Test11 |
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| Treatment (n = 22) |
Placebo (n = 19) |
P value | ||||
| Responders | n = 18 | n = 11 | ||||
| 7-day shock | ||||||
| reversal 12 (67) | 2 (18) | 0.03 | ||||
| 28-day survival | 12 (67) | 4 (36) | 0.22 | |||
| Nonresponders | n = 4 | n = 8 | ||||
| 7-day shock | ||||||
| reversal | 3 (75) | 2 (25) | 0.03 | |||
| 28-day survival | 3 (75) | 3 (37) | 0.54 | |||
| Responders are patients with a maximal absolute increase of plasma cortisol concentration ³ 6 µg/dL after corticotropin administration. Nonresponders are patients with a maximal absolute increase of plasma cortisol concentration < 6 µg/dL after corticotropin administration. |
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Therapeutic Implications
In the meantime, what conclusions can be drawn from all this? Should we consider treating all septic patients who remain dependent for several days on cathecholamines with stress doses of hydrocortisone?8,9
Certainly, studies showing a beneficial effect of corticosteroids have comprised small groups of patients. Moreover, it remains to be seen whether corticosteroids can improve survival. Added to that, we must not forget the side effects of hydrocortisone. It is worth stating at this point that patients with a recent history of gastroduodenal ulcer or gastrointestinal bleeding were excluded from the study of Bollaert et al.11 Anyway, all in all, the new randomized clinical trials testing corticosteroids in septic shock did not report differences in the rates of gastrointestinal bleeding and secondary infections between treated patients and placebo patients.11,12
Undoubtedly, more studies are needed to elucidate the role of corticosteroids in the treatment of septic shock. However, if one weighs the pros and cons, treatment with stress doses of hydrocortisone may be considered in patients with septic shock unresponsive to fluid resuscitation and dependent of vasopressor therapy for more than 96 hours as some authors maintain, provided that: careful elimination of curable causes of hypotension is performed; absolute adrenocortical deficiency is checked with corticotropin stimulation testing; and, corticosteroids are used for at least five days and progressively reduced.11 (Dr. Baigorri works for Intensive Care Services, Corporacio Sanitaria Parc Tauli, Sabadell, Spain.)
References
1. Lamberts SWJ, et al. Drug therapy: Corticosteroid therapy in severe illness. N Engl J Med 1997;337: 1285-1292.
2. Saito T, et al. Corticosteroid effect on early beta-adrenergic down-regulation during circulatory shock: Hemodynamic study and beta-adrenergic receptor assay. Intensive Care Med 1995;21:204-210.
3. Briegel J, Kilger E, Schelling G. Stress doses of hydrocortisone in septic shock: Beyond the hemodynamic effects. In: Vincent JL, ed. Yearbook of Intensive Care and Emergency Medicine. Berlin: Springer, 1999.
4. Lefering R, Neugebauer EAM. Steroid controversy in sepsis and septic shock: A meta-analysis. Crit Care Med 1995;23:1294-1303.
5. Cronin L, et al. Corticosteroid treatment for sepsis: A critical appraisal and meta-analysis of the literature. Crit Care Med 1995;23:1430-1439.
6. Schneider AJ, Voerman HJ. Abrupt hemodynamic improvement in late septic shock with physiological doses of glucocorticoids. Intensive Care Med 1991;17: 436-437.
7. Briegel J, et al. Haemodynamic improvement in refractory septic shock with cortisol replacement therapy. Intensive Care Med 1992;18:318.
8. Bollaert PE. Stress doses of glucocorticoids in cathecolamine dependency: A new therapy for a new syndrome? Intensive Care Med 2000;26:3-5.
9. Spijkstra JJ, Girbes ARJ. The continuing story of corticosteroids in the treatment of septic shock. Intensive Care Med 2000;26:496-500.
10. Annane D, et al. A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin. JAMA 2000;283:1038-1045.
11. Bollaert PE, et al. Reversal of late septic shock with supraphysiologic doses of hydrocortisone. Crit Care Med 1998;26:645-650.
12. Briegel J, et al. Stress doses of hydrocortisone reverse hyperdynamic septic shock: A prospective, randomized, double-blind, single-center study. Crit Care Med 1999;27:723-732.
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