Ruminations on Sepsis
“Except on a few occasions the patient appears to die from the body’s response to infection rather than from the infection itself.” William Osler, The Evolution of Modern Medicine, 1904.
Septic
Ruminations on Sepsis
“Except on a few occasions the patient appears to die from the body’s response to infection rather than from the infection itself.” William Osler, The Evolution of Modern Medicine, 1904.
Septic shock is difficult to diagnose and difficult to treat. One of the most daunting problems facing a clinician is a patient who is known to have good heart function, but who has refractory shock despite aggressive fluid resuscitation and the institution of vasopressor drugs, such as dopamine or norepinephrine. It is estimated that septic shock results in approximately 215,000 deaths per year in the United States, a number similar to the number of deaths from acute myocardial infarction.1
Physiology of steroids (in illness)
Addison first noted the essential role of the adrenal for survival in 1855.2 An increase in corticosteroid levels during illness is an important protective response.3 Free cortisol, rather than the protein bound hormone, is thought to be responsible for its physiological effects.4 Corticosteroid release is regulated by the hypothalamic-pituitary axis in a pulsatile manner.2 Vasopressin also plays an important physiological role in adrenal stimulation.5 In sepsis, inflammatory mediators such as cytokines, promote and maintain a high production of corticosteroids.2 The hypothalamic-pituitary-adrenal axis is itself massively activated in septic shock.4 There are many causes for adrenal insufficiency, and certainly this can occur with diseases, bleeding into the adrenal and infections, such as HIV.3 The concept of relative or functional adrenal insufficiency is somewhat controversial and difficult to define.2, 6
Rationale for using steroids in septic shock
Cortisol is commonly referred to as a “stress hormone” because it has several functions in the body’s response to stress. The role of cortisol in sepsis is associated with two factors: (1) hemodynamics and (2) inflammation. Cortisol maintains vascular tone by increasing the number of both alpha and beta adrenergic receptor as well as prevention of receptor desensitization, thereby enhancing vascular tone and cardiac contractility. In addition, cortisol improves vascular tone by blocking nitric oxide synthesis. Cortisol also suppresses the pro-inflammatory process that occurs in sepsis.
- Rashmi Rathor
Critically ill patients at some stage may develop adrenal insufficiency. Glucocorticoid insufficiency may be related to adrenal insufficiency or to a reduced delivery of glucocorticoid to target tissues and cells.7 Resistance of target tissues to steroids may also occur.2 In an animal model of sepsis, bacteremia was induced in male Sprague-Dawley rats by a intravenous injection of Escherichia coli.8 Dexamethasone alone afforded significant protection against Gram-negative bacteremic shock up to eight hours after the bacterial challenge.8 Dexamethasone plus antibiotics improved outcome more than either intervention alone.8 In a monkey model of endotoxemia, dexamethasone was shown to prevent lactic acidosis and hypoglycemia.9
Early experience with steroids in septic shock
In 1976, Schumer published a study in the Annals of Surgery that showed benefit from a short course of high dose corticosteroids in the treatment of septic shock.10 In a double-blind and randomized study, 172 patients in septic shock admitted over an 8-year period were treated with either high-dose steroid or saline. In the saline-treated patients, the mortality rate was 38.4% (33/86); in the steroid-treated patients, it was 10.4% (9/86).10 This was an impressive reduction in mortality.
Negative studies with steroids in septic shock
In a subsequent randomized controlled trial (RCT), however, which enrolled 59 patients with septic shock, high-dose steroids (30 mg/kg methylprednisolone or 6 mg/kg dexamethasone) were shown to improve hemodynamics, but not outcome.11 The same investigators were also unable to show that steroid administration decreased the likelihood of acute respiratory distress syndrome (ARDS).12 A study by Schein showed that plasma cortisol concentrations are increased in patients with septic shock, but that the degree of increase is variable.13 They found that neither patients who reversed their shock nor those who survived to hospital discharge had significantly different plasma cortisol concentrations from those who did not.13 High dose steroids were actually found to increase mortality through infectious complications.14 Among some intensivists, steroids acquired the reputation of accompanying the administration of “last rites.”15 The prudent warning was issued 