Hemodynamic Effects of Early Versus Late Glucocorticosteroid Administration in Experimental Septic Shock

Abstract

Recent findings in human septic shock suggest that glucocorticosteroids can limit and even reverse hemodynamic disturbances and dependence on catecholamines. In a rodent model of hypotensive and hypokinetic septic shock, we investigated the effects of early or late dexamethasone administration on hemodynamics, response to catecholamines, and cardiac beta-adrenergic signalling. As compared with sham-operated rats, the untreated septic rats displayed significant arterial hypotension and reduced aortic blood flow. However, in vivo pressor response to epinephrine and phenylephrine was not different among sham and septic animals. Conversely, the chronotropic response to isoproterenol was significantly attenuated in septic animals. Steroid-treated septic animals displayed complete reversal of hypotension, improvement in aortic blood flow, and reduced plasma lactate and nitrite/nitrate concentrations as compared with untreated septic animals. The number of myocardial beta-adrenergic receptors and in vivo isoproterenol-stimulated myocardial cAMP content were similar in sham and septic animals. Glucocorticosteroids, although not changing these patterns, significantly decreased the receptors affinity when administered late, but not early. In this model of septic shock, hemodynamic abnormalities may not be related to adrenergic receptor desensitization. That steroids can improve them suggests that they could act mainly distal to adrenergic receptors, for instance, on myocardial and vascular smooth fiber contraction properties through mechanisms probably including inducible nitric oxide synthase inhibition.

Practice parameters for hemodynamic support of sepsis in adult patients: 2004 update

“…In a rodent endotoxemia model, pretreatment with dexamethasone prevented endotoxin-induced vascular hyporesponsiveness to norepinephrine (152), probably by inhibiting extracellular release of lipocortin-1 (153). In a rodent model of hypotensive and hypokinetic septic shock, dexamethasone administration resulted in a complete reversal of hypotension, improvement in aortic blood flow, and reduced plasma lactate and nitrite/nitrate concentrations without affecting myocardial ␤-adrenergic receptor numbers or myocardial cyclic adenosine monophosphate, suggesting an effect on inducible nitric oxide synthase rather than on adrenergic receptor sensitivity (154). In healthy volunteers, the profound reduction in venous contractile response to norepinephrine induced by local instillation of endotoxin was completely prevented with pretreatment with 100 mg of oral hydrocortisone (155).…”

Modulation of the Triggering Receptor Expressed on the Myeloid Cell Type 1 Pathway in Murine Septic Shock

“…The procedure we used has been described in detail elsewhere (22). Briefly, rats (n ϭ 6 to 10 per group) were anesthetized by i.p.…”

“…Immediately after LPS administration as well as 16 h after CLP, arterial blood pressure (systolic, diastolic, and mean), heart rate, abdominal aortic blood flow, and mesenteric blood flow were recorded using a procedure described elsewhere (22). Briefly, the left carotid artery and the left jugular vein were cannulated with PE-50 tubing.…”

Corticosteroids in Sepsis: From Bench to Bedside?

“…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 ␤-adrenergic signaling (126). As compared with sham-operated rats, the untreated septic rats were hypotensive and had reduced aortic blood flow.…”