Critical Illness-Related Corticosteroid Insufficiency
1. Description of the problem
What every clinician should know
There is increasing evidence that in many critically ill patients activation of the hypothalamic-pituitary-adrenal (HPA) axis and the release of cortisol is impaired (adrenal insufficiency). The relative adrenal insufficiency results in inadequate down-regulation of NF-Kb and other transcription factors with an excessive pro-inflammatory response. This dysregulated immune response results in a systemic inflammatory response (SIRS) together with progressive organ dysfunction. Until recently the exaggerated pro-inflammatory response that characterizes patients with SIRS has focused on suppression of the HPA axis and “adrenal failure.” However, experimental and clinical data suggest that corticosteroid tissue resistance may also play an important role. This complex syndrome is referred to as “Critical Illness-Related Corticosteroid Insufficiency” (CIRCI). CIRCI is defined as inadequate cellular corticosteroid activity for the severity of the patient’s illness. CIRCI manifests with insufficient corticosteroid mediated down-regulation of inflammatory transcription factors.
CIRCI is most common in patients with severe sepsis (septic shock) and ARDS. In addition, patients with liver disease have a high incidence of adrenal insufficiency (AI; hepato-adrenal syndrome). CIRCI should also be considered in patients with pancreatitis. A subset of patients may suffer structural damage to the adrenal gland from either hemorrhage (Waterhouse-Friderichsen syndrome) or infarction, and this may result in long-term adrenal dysfunction. Furthermore, a number of drugs are associated with adrenal failure. However, most patients with AI (and CIRCI) develop reversible dysfunction of the HPA system; this is probably mediated by inflammatory mediators, may be self-perpetuating, and follows the same time course of the immune deregulation seen in patients with sepsis and SIRS.
The immune dysregulation associated with sepsis and ARDS appears to persist long after the clinical signs have resolved. Provocative data suggest that those patients with the highest levels of circulating pro-inflammatory mediators (particulalry IL-6) at discharge and at day 32 may have an increased risk of death in the first year after discharge. This suggests that patients may require a more prolonged course of treatment with corticosteroids.
Key management points
Occasionally patients with pre-existent primary AI (Addison’s disease) will be admitted to the ICU. Adrenal crisis may be the presenting complaint or it may be present as a comorbidity. Patients with chronic AI usually present with a history of weakness, weight loss, anorexia, and lethargy, with some patients complaining of nausea, vomiting, abdominal pain, and diarrhea. Clinical signs include orthostatic hypotension and hyperpigmentation. Laboratory testing may demonstrate hyponatremia, hyperkalemia, hypoglycemia, and a normocytic anemia. Patients require glucocorticoid replacement therapy titrated to the level of stress.
2. Emergency Management
In patients with septic shock and ARDS, treatment with glucocorticoids has been demostrated to reduce vasopressor dependency, reduce length of stay, and reduce mortality. In patients with sepsis this usually manifests as hypotension that is poorly responsive to fluids and vasopressors. In patients with ARDS it manifests as a progressive decline in oxygenation with worsening bilateral infiltrates.
CIRCI is essentially a clinical diagnosis. Treatment with glucocorticoids should be based on clinical features rather than diagnostic tests.
At the current time there are no clinically useful tests to assess the cellular actions of cortisol; the accurate clinical diagnosis of CIRCI therefore remains somewhat elusive. Furthermore, while the diagnosis of AI in the critically ill is fraught with difficulties, at this time this diagnosis is best made by:
1) a random (stress) cortisol of <10 ug/dl or
2) a delta cortisol of <9 ug/dl after a 250-ug ACTH stimulation test
These diagnostic criteria have a high specificity (95%) but a low sensitivity (36%). Based on the results of the cosyntropin stimulation test it may be useful to divide CIRCI into two subgroups, namely Type I, characterized by a random (stress) cortisol <10 ug/dl, and Type II, by a random cortisol >10 ug/dl and a delta cortisol <9 u/g/dl. Patients with Type II CIRCI have been reported to have high circulating level of pro-inflammatory mediators, a significantly higher severity of illness (higher SAPS score), and a higher mortality than patients with Type I CIRCI. The therapeutic implications of these subgroupings are unclear at this time.
Normal lab values
Unlike patients with chronic AI (Addison’s disease) patients with CIRCI do not have specific clinical and laboratory findings. CIRCI manifests as an exaggerated pro-inflammatory response. In patients with sepsis this manifests as hypotension poorly responsive to fluids and vasopressor agents. In patients with ARDS this manifests as progressive lung injury. In addition, adrenal insufficiency may present as unexplained hypotension or altered mental status. An eosinophilia has been reported to be a useful screening test for acute AI.
4. Specific Treatment
Hydrocortisone 50 mg IV q 6 hourly or a 100-mg bolus then 10 mg/hr via continuous infusion for at least 7 days, and ideally for 10-14 days. Patients should be vasopressor and ventilator “free” before taper. Corticosteroids should never be stopped abruptly; this will lead to a “rebound” of inflammatory mediators, with an increased likelihood of hypotension and/or rebound inflammation. A continuous infusion of glucocorticoid may be associated with better (smoother) glycemic control. Since blood glucose variability has been demonstrated to have prognostic implications, this may be the preferable method of dosing.
Fludrocortisone 50 ug PO is considered optional. Hydrocortisone and methylprednisolone are considered interchangeable. Dexamethasone should be avoided; it lacks mineralocorticoid activity. Dexamethasone has a long half-life and suppresses the HPA axis; it should therefore NOT be used pending an ACTH stimulation test.
Hydrocortisone 50 mg IV q 8 hourly for 3-4 days
Hydrocortisone 50 mg IV/PO q 12 hourly for 3-4 days
Hydrocortisone 50 mg IV/PO daily for 3-4 days
Re-institution of full-dose hydrocortisone with recurrence of shock or worsening oxygenation
The approach to corticosteroid replacement therapy has changed over the years. Studies done 2 to 3 decades ago used large doses of corticosteroids (e.g., 1000 mg methyprednisolone) over a short period of time (1-2 days). These massive doses of corticosteroids resulted in profound immune paresis and were not associated with improved outcomes. Furthermore, this approach is not in line with the pathophysiology of CIRCI (i.e., prolonged immune dysregulation). It should be noted that the maximal adrenal output in a highly stressed human is approximately 300 mg/day. In addition, prolonged glucocorticoid treatment is associated with downregulation of the glucocorticoid receptor and suppression of the HPA axis, affecting systemic inflammation after discontinuing treatment.
The current approach to corticosteroid replacement is to provide stress (or physiological) doses over a more prolonged period of time. The duration of therapy is currently controversial and under investigation; however, patients with sepsis should be treated for at least 14 days (full dose and taper) and patients with ARDS for at least 21 days (full dose and taper).
One of the great myths concerning stress doses of corticosteroids is that they increase the risk of infection and impair wound healing. Contrary to older studies investigating a time-limited (24-48 h) massive daily dose of glucocorticoids (methylprednisolone, up to 120 mg/kg/day), recent trials investigating “stress-dose” glucocorticoids have not reported an increased rate of nosocomial infections. The effect of glucocorticoids on immune suppression is critically dose dependent. It is well know from the organ transplant experience that high-dose corticosteroids effectively abolish T-cell-mediated immune responsiveness and are very effective in preventing/treating graft rejection. However, while stress doses of corticosteroids downregulate (but do not suppress) systemic inflammation with decreased transcription of pro-inflammatory mediators, they maintain innate and Th1 immune responsiveness and prevent an overwhelming compensatory anti-inflammatory response (CARS).
In fact, new cumulative evidence indicates that downregulation of life-threatening systemic inflammation with prolonged low- to moderate-dose glucocorticoid treatment improves innate immunity and provides an environment less favorable to the intra- and extracellular growth of bacteria. At stress doses, corticosteroids have been shown to increase neutrophil activity, increase the homing of dendritic cells with preservation of monocyte function, preserve interleukin-12 function, and attenuate the overwhelming inflammatory response. In the ARDSnet study corticosteroid treatment was associated with a reduction in nosocomial pneumonia. These data are supported by the HYPOLYTE study, which randomized patients with multiple trauma to hydrocortisone or placebo. The major end-point of this study, hospital-acquired pneumonia, was significantly reduced in the patients randomized to hydrocortisone (35.6% vs. 51.3%, p = 0.007).
5. Disease monitoring, follow-up and disposition
As glucocorticoids may mask the features of infection (fever, etc.), active surveillance for infection is important. In addition, the combination of glucocorticoids and neuromuscular blocking agents should be avoided as this combination has been associated with a severe necrotizing myopathy.
The mechanisms leading to inadequate cortisol production during critical illness are complex and poorly understood and likely include decreased production of CRH, ACTH, and cortisol. TNF and IL-1 have been implicated in the reversible dysfunction of the HPA axis during critical illness. TNF impairs CRH-stimulated ACTH release, and a number of clinical studies have reported inappropriately low ACTH levels in patients with severe sepsis. TNF has been shown to reduce adrenal cortisol synthesis by inhibiting the stimulatory actions of ACTH and angiotensin II on adrenal cells. Decreased production of cortisol during acute illness may occur due to substrate deficiency. HDL has been shown to be substantially reduced in patients with many acute illnesses, including sepsis and burns, following myocardial infarction, and in patients undergoing surgical interventions. van der Voort and colleagues demonstrated that in critically ill patients, low HDL levels were associated with an attenuated response to cosyntropin.
Likewise, the mechanisms leading to glucocorticoid tissue resistance are complex and may be related to those causing AI. A number of mechanisms may contribute to glucocorticoid tissue resistance, including increased conversion of cortisol to cortisone, reduced number of glucocorticoid receptors (GR), increased expression of the beta isoform of the GR, and decreased binding of glucocorticoids to the receptor. However, decreased nuclear translocation of the glucocorticoid-receptor complex (GC-GR) may play a central role. Decreased translocation of the GC-RC into the nucleus has been demonstrated in patients with severe ARDS. This suggests that nuclear GC-GR activity may be impaired in critically ill patients despite adequate cytoplasmic (serum) levels of cortisol.
In 1911 Waterhouse described a case of bilateral adrenal hemorrhage in a child dying of apparent sepsis, and he reviewed several published cases. In 1918 Friderichsen wrote a similar review and added two more cases to the literature. Sudden onset of adrenal hemorrhage in the setting of sepsis was termed Waterhouse-Friderichsen syndrome. Most cases are associated with Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae. Cases of Waterhouse-Friderichsen syndrome due to S. pneumoniae almost always occur in patients with severe reticuloendothelial dysfunction, especially hyposplenism or splenectomy.The pathophysiology leading to adrenal hemorrhage is poorly understood. The leading theories postulate either exotoxin-mediated vasculitis or coagulopathy in association with DIC.
There is increasing evidence that in many critically ill patients activation of the HPA axis and the release of cortisol is impaired (AI). The reported incidence of AI varies widely (0-77%) depending upon the population of patients studied and the diagnostic criteria used. However, the overall incidence of AI in critically ill patients approximates 10-20%, with an incidence as high as 60% in patients with septic shock.
The prognosis of patients with CIRCI is largely dependent on that of the underlying disease. While controversial, replacement with stress doses of corticosteroids appears to improve the survival of patients with septic shock and those with severe ARDS. It must, however, be acknowledged that major methodological issues confound the interpretation of existing studies.
The most important sepsis studies are those of Annane et al. and the CORTICUS study. It should be appreciated that both of these studies have significant limitations. Etomidate (which inhibits cortisol synthesis) was used in a significant proportion of patients in both studies and the benefit of steroids in the Annane study may have been largely restricted to those patients who received etomidate. In addition, selection bias may limit the generalizability of the CORTICUS study. Similarly, a number of limitations exist with the ARDSnet study, most notably the sudden discontinuation of steroids, with a high rate of relapse in the steroid patients after stopping steroids.
Special considerations for nursing and allied health professionals.
What's the evidence?
Marik, PE, Pastores, Sm, Annane, D. “Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: Consensus statements from an international task force by the American College of Critical Care Medicine”. Crit Care Med. vol. 36. 2008. pp. 1937-49..
Marik, PE. “Mechanisms and clinical consequences of critical illness-associated adrenal insufficiency”. Curr Opin Crit Care. vol. 13. 2007. pp. 363-69.
Marik, PE. “Critical illness-related corticosteroid insufficiency”. Chest. vol. 135. 2009. pp. 181-93.
Marik, PE. “Glucocorticoids in sepsis: dissecting facts from fiction”. Crit Care. vol. 15. 2001. pp. 158
Annane, D, Sebille, V, Charpentier, C. “Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock”. JAMA. vol. 288. 2002. pp. 862-71..
Sprung, CL, Annane, D, Keh, D. “Hydrocortisone therapy for patients with septic shock”. N Engl J Med. vol. 358. 2008. pp. 111-24.
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- 1. Description of the problem
- 2. Emergency Management
- 3. Diagnosis
- 4. Specific Treatment
- 5. Disease monitoring, follow-up and disposition
- Special considerations for nursing and allied health professionals.
- What's the evidence?