Adrenal Insufficiency in ICU. Immunostained cross-section of a human adrenal gland. zM = adrenal medulla zR = zona reticularis zF = zona fasciculata zG.

Adrenal Insufficiency in Adrenal Insufficiency in ICUICU

Immunostained cross-section of a human adrenal gland.zM = adrenal medullazR = zona reticulariszF = zona fasciculatazG = zona glomerulosa, Caps = adrenal capsule

Outer zona glomerulosa: site of mineralocorticoid production (e.g. aldosterone), mainly regulated by angiotensin II, potassium, and ACTH. In addition, dopamine, atrial natriuretic peptide (ANP) and other neuropeptides modulate adrenal zona glomerulosa function.

Central zona fasciculata, responsible mainly for glucocorticoid synthesis, is regulated by ACTH. In addition, several cytokines (IL-1, IL-6, TNF), neuropeptides and catecholamines influence the biosynthesis of glucocorticoids.

Inner zona reticularis, site of adrenal androgen (predominantly dehydroepiandrostenedione [DHEA], DHEA sulfate and androstenedione) secretion, as well as some glucocorticoid production (cortisol and corticosterone).

Exposure of the host to diverse noxious timuli results in a “general adaption syndrome” (or stress response) to restore homeostasis and improve survival.

The stress response is mediated primarily by the hypothalamic-pituitary-adrenal (HPA) axis as well as the sympathoadrenal system.

Activation of HPA axis results in increased secretion from the paraventricular nucleus of the hypothalamus of corticotropin-releasing hormone (CRH) and arginine vasopressin.

CRH stimulates production of ACTH by anterior pituitary gland zona fasciculata of adrenal cortex to produce more glucocorticoids.

Arginine vasopressin is a weak ACTH secretagogue and vasoactive peptide that acts synergistically with CRH to increase secretion of ACTH.

Increased cortisol production results in multiple effects (metabolic, cardiovascular, and immune) aimed at restoring homeostasis during stress.

HPA axis and immune system are closely integrated in multiple positive and negative feed-back loops.

Activation of the sympathoadrenal system results in the secretion of epinephrine and norepinephrine from the adrenal medulla and leads to increased production of inflammatory cytokines such as interleukin-6 (IL-6).

Cortisol Physiology Cortisol (hydrocortisone) - major endogenous glucocorticoid

secreted by the adrenal cortex. > 90% circulating cortisol is bound to corticosteroid

binding globulin (CBG) 10% free, biologically active

CBG is the predominant binding protein (lesser albumin binding).

During acute illness (ie. Sepsis) CBG levels fall by as much as 50%, resulting increased free cortisol %.

The circulating half-life of cortisol varies from 70 to 120 min, with a biological half-life of approximately 6 to 8 h.

The adrenal gland does not store cortisol; increased secretion arises due to increased synthesis under the control of ACTH.

Cholesterol is the principal precursor for steroid biosynthesis in steroidogenic tissue.

Cortisol Physiology (cont)

Cortisol Physiology (cont) At rest and during stress

approx 80% circulating cortisol derived from plasma cholesterol

20% being synthesized in situ from acetate and other precursors.

The activity of glucocorticoids are mediated by both the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR).

GR and MR share both functional and structural homology. Both aldosterone and glucocorticoid hormones bind to both GR

and MR.

11 beta-hydroxysteroid dehydrogenase (11-HSD) enzyme prevents glucocorticoid access to cells that express the MR.

This enzyme has two isoforms, 11 β-HSD-2 and 11 β-HSD-1.

11β -HSD-2 is found in tissues with high levels of MR activity (kidney, sweat and salivary glands, placenta, and colon).

Cortisol Physiology (cont)

11β-HSD-2 converts cortisol to cortisone (inactive), unable to bind to the GR and MR.

11 β-HSD-1 converts cortisone to active cortisol.

IL-1β and TNF-α increase activity of 11β-HSD-1, while decreasing that of 11 -HSD-2.

Critical Illness-Related Corticosteroid Insufficiency (CIRCI)

CIRCI is defined as inadequate corticosteroid activity for the severity of the illness of a patient.

CIRCI manifests with insufficient corticosteroid mediated downregulation of inflammatory transcription factors.

Similar to type II diabetes (relative insulin deficiency), CIRCI arises due to corticosteroid tissue resistance together with inadequate circulating levels of free cortisol.

Tissue Corticosteroid Resistance During Critical Illness

Emerging data suggest that corticosteroid tissue resistance may develop in patients with acute inflammatory diseases, such as sepsis and acute lung injury (ALI).

Experiments have provided further evidence that the nuclear glucocorticoid-GR activity may be impaired in critically ill patients despite adequate cytoplasmic (serum) levels of cortisol.

Marik PE. Chest 2009; 135:181-193.

Meduri GU et al. Neuroimmunomodulation 2005; 12:321-338.

HPA Axis Failure in Acute Illness

HPA axis failure appears to be a common problem in patients with systemic inflammation.

Patients at risk for developing tissue glucocorticoid resistance are similarly at risk for HPA axis failure.

Overall incidence of adrenal insufficiency in critically ill pts ~20%. Incidence ~ 60% in pts w/ severe sepsis and septic shock.

The mechanisms leading to inadequate cortisol production during critical illness are complex, poorly understood, and likely include decreased production of CRH, ACTH, and cortisol.

A subset of patients may suffer structural damage to adrenal gland from either hemorrhage or infarction (result in long-term adrenal dysfunction.)

Causes of Adrenal Insufficiency

Reversible HPA dysfunction in critically ill patients with systemic inflammation assoc with sepsis, ALI, liver disease, and following cardiopulmonary bypass.

TNF-α reduces adrenal cortisol synthesis by inhibiting the stimulatory actions of ACTH and angiotensin II on adrenal cells.

Decreased cortisol production 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.

HPA Axis Failure in Acute Illness

Clinical Manifestations Chronic adrenal

insufficiency (Addison Disease) Weakness weight loss, anorexia, Lethargy nausea, vomiting, Abdominal pain diarrhea.

Clinical signs include Orthostatic hypotension hyperpigmentation

(primary AI)

Laboratory testing: hyponatremia, hyperkalemia, hypoglycemia, normocytic anemia.

CIRCI manifestations are consequent on an exaggerated proinflammatory immune response.

Hypotension refractory to fluids and requirement of vasopressors is a common manifestation of CIRCI.

The variability in hemodynamics reflects the combination of CIRCI and the underlying disease.

CIRCI should also be considered in patients with progressive ALI.

Laboratory: eosinophilia and hypoglycemia. Hyponatremia and hyperkalemia are uncommon.

Diagnosis of Adrenal Insufficiency and CIRCI

Traditionally AI in the critically ill based on: random total serum cortisol (stress cortisol) or change in the serum cortisol in response to 250

ug of synthetic ACTH (cosyntropin), (delta cortisol).

Both of these tests have significant limitations in the critically ill. Commercially available cortisol assays measure

total concentration rather than the biologically active, free cortisol concentration.

timing of cortisol measurements (large hourly variations).

poor reproducibility of ACTH stimulation test in critically ill patients.

non-uniform specificity, sensitivity, and performance of commercially available assays

presence of interfering heterophile Ab/cortisol precursors/ metabolites

Diagnosis of Adrenal Insufficiency and CIRCI

Despite above limitations, Annane et al reported that a delta cortisol of <9 mg/dL was the best predictor of adrenal insufficiency, as determined by overnight metyrapone testing, in patients with severe sepsis/septic shock.

Cortisol of <10 mg/dL was also highly predictive of adrenal insufficiency (PPV of 0.93); however, the sensitivity of the test was poor (0.19).

In this study, use of calculated free cortisol did not improve the performance of the tests.

Therefore, at this time a random cortisol of <10 mg/dL or a delta cortisol of <9 mg/dL are the best tests for the diagnosis of adrenal insufficiency in the critically ill (high specificity, low sensitivity).

Annane et al. Am J Resp Crit Care Med 2006: 174.

Diagnosis of Adrenal Insufficiency and CIRCI

Annane et al. Am J Resp Crit Care Med 2006: 174.

Patients with a baseline total cortisol level <10 mcg/dl, or a cortisol increment after cosyntropin <9 mcg/dl, are very likely to have adrenal insufficiency.

Conversely, in patients with a ACTH-stimulated total cortisol level of 44 g/dl or greater, or a cortisol increment after cosyntropin stimulation of 16.8 g/dl or greater, adrenal insufficiency can be ruled out.

When the baseline cortisol level is between 10 and 44 g/dl, and the cortisol increment after cosyntropin stimulation is between 9 and 16.8 g/dl, assessment of adrenal function requires metyrapone testing.

Meta-analysis demonstrates that LDCT is superior to SDCT in diagnosing HPA insufficiency.

All study subjects were ambulatory and presumably had normal sleep-wake cycles, these findings may not generalize to hospital settings or patients with acute illnesses.

Subjects with suspected chroninc HPA insufficiency

Basal cortisol < 5 mcg/dl best predicted HPAI Basal cortisol > 13mcg/dl best predicted normal

HPA.

Low dose vs. standard dose Cosyntropin Test

Kazlauskaite et al. JCEM 2008;93:4245-5253.

The Value of DHEA-S Measurements in Assessment of Adrenal Function

Dehydroepiandrosterone (DHEA) and its sulfated ester (DHEA-S) are adrenal androgen precursors secreted by the zona reticularis, under the dominant regulation of corticotropin.

This study examined serum DHEA-S levels as possible markers for HPA function in patients with large pituitary adenomas. 47 pts with normal HPA 35 pts with abnormal HPA fxn (based on insulin-induced

hypoglycemia test). Patients also underwent low-dose Cortrosyn and

standard-dose Cortrosyn stimulation testing.

Result: A normal DHEA-S level makes the diagnosis of corticotropin deficiency extremely unlikely, especially when Cortrosyn stimulation test is normal. Nasrallah MP, Arafah BM. JCEM 2003;

88:5293-5298.

Limitations to Diagnostic Use of DHEA-S Measurements

Best diagnostic accuracy is in young subjects.

Low DHEA-S is not diagnostic of AI Prior exposure to GC Older age Low serum protein/ albumin

Normal or high DHEA-s levels Significant hyperprolactinemia Exogenous intake of DHEA supplement

Nasrallah MP, Arafah BM. JCEM 2003; 88:5293-5298.

Treatment With Corticosteroids: Who and How?

Over the last three decades, approx 20 randomized controlled trials (RCTs) have been conducted evaluating the role of glucocorticoids in patients with sepsis, severe sepsis, septic shock, and ARDS.

Varying doses (37.5 to 40,000 mg of hydrocortisone eq/day), dosing strategies (eg, single bolus, repeat boluses, continuous infusion, and dose taper) and duration of therapy (1 to 32 days) were used in these studies.

Nonstressed daily cortisol production in adults: 15-25 mg/day.

Maximal stressed daily production of cortisol: 200-350 mg/day.

Based on this data, a daily dose of hydrocortisone low dose: 25-200 mg/day Physiologic stress dose: 200-350 mg/day Supra-physiologic dose: 351-1,000 mg/day High dose corticosteroid: 1,000 mg/day

Annane et al: a systemic review and meta-analysis to assess the effects of corticosteroids on mortality in patients with severe sepsis and septic shock.

Regardless of duration of treatment and dose, use of corticosteroids did not significantly affect mortality.

Long courses of low dose corticosteroids reduce mortality at 28 days and hospital mortality.

Long courses of low dose corticosteroids did not significantly alter the risk of gastroduodenal bleeding, superinfections, or hyperglycemia.

Annane et al. BMJ 2004; 329:480-489.

Minneci et al: Meta-analysis: the effect of steroids on survival and shock during sepsis depends on the dose.

Data Sources: Systematic MEDLINE search for studies published between 1988 and 2003.

Study Selection: Randomized, controlled trials of sepsis that examined the effects of glucocorticoids on survival or vasopressor requirements.

Results: Short courses of high-dose glucocorticoids decreased

survival during sepsis. A 5-7 day course of physiologic hydrocortisone doses

(200-300mg/d) with subsequent tapering (5-7 day) increases survival rate and shock reversal in patients with vasopressor-dependent septic shock.

Minneci et al. Ann Intern Med 2004; 141:47-56.

Minneci et al. Ann Intern Med 2004; 141:47-56.

The relationship between the dose of steroids administered in the first 24 hours after enrollment in a sepsis trial and relative survival benefit (black circles) is presented. There is a linear relationship (that is, the relativesurvival benefit decreases with high-dose steroids but increases with lower doses) (P 0.02). One study (white circle) was overly influential in our regression analysis, was a statistical outlier (P 0.001) compared with the other trials, and was therefore excluded. This study was performed a decade before all of the other trials, included children, and had a high percentage of patients with meningitis.

Minneci et al. Ann Intern Med 2004; 141:47-56.

Ideally, the corticosteroid dose should be sufficient to downregulate the proinflammatory response without causing excessive immune-paresis and interfering with wound healing.

Similarly, the duration of glucocorticoid therapy should be guided by the duration of CIRCI and the associated duration of systemic inflammation.

In 1991, Schneider and Voerman were the first investigators to suggest that “physiologic and not pharmacologic doses of glucocorticoids in the course of septic shock”. They demonstrated reversal of shock in 3 of 8

patients given “100 mg HC IV followed by 100 mg q8hrs with dose tapering with improvement.”

Table 2: 10 RCTs in critically ill patients with sepsis, septic shock, and ARDS. Overall, this dosing strategy has been reported to be associated with a significant reduction in 28 day all-cause mortality, more rapid weaning of vasopressor agents (septic shock), a reduction in ICU length of stay, and an increase in ventilator-free days (ARDS).

Marik PE. Chest 2009; 135:181-193

Multicenter, randomized, double-blind, placebo-controlled trial 251 patients received 50 mg IV hydrocortisone q6hrs x 5 days 248 patients received placebo q 6 hrs x 5 days Tapered to 50mg IV q12 x6-8d, 50mg q24hrs x9-11 d, then stopped.

Results 233 of 499 study pts (46.7%) did not have a response to corticotropin (125 in

the hydrocortisone group and 108 in the placebo group).

At 28 days, no significant difference in mortality between patients in the 2 study groups who did not have a response to corticotropin (39.2% in the hydrocortisone group and 36.1% in the placebo group, P = 0.69) or between those who had a response to corticotropin (28.8% in the hydrocortisone group and 28.7% in the placebo group, P = 1.00).

At 28 days, 86 of 251 patients in the hydrocortisone group (34.3%) and 78 of 248 patients in the placebo group (31.5%) had died (P = 0.51).

In the hydrocortisone group, shock was reversed more quickly than in the placebo group. However, there were more episodes of superinfection, including new sepsis and septic shock.

Conclusions Hydrocortisone did not improve survival or reversal of shock in patients with septic shock, either overall or in patients who did not have a response to corticotropin, although hydrocortisone hastened reversal of shock in patients in whom shock was reversed.

Sprung et al. NEJM 2008; 358:111-24.

Of 357 study patients with culture-positive sepsis, 86 (24%) were considered not to have received appropriate antimicrobial therapy.

The actual mortality rates among patients receiving appropriate antimicrobial therapy as compared with those receiving inappropriate antimicrobial therapy are not provided.

CORTICUS study group enrolled patients who were not as severely ill, requiring only a SBP <90 mm Hg for 1 hour despite adequate fluid resuscitation or need for vasopressors.

The benefit of antiinflammatory agents in sepsis is directly proportional to the severity of illness.

The control-group mortality was 36% in CORTICUS study, as compared with 63% in the study by Annane et al.

The lack of a treatment benefit in the CORTICUS study may be due to the enrollment of a population of patients with a lower mortality, for whom the risk of side effects of corticosteroid therapy outweighs its potential benefit.

NEJM 2008; 358; 19

Inappropriate antimicrobial therapy (24%, 86 of 357 pts).

Selection bias

Lack of adequate power (500 pts instead of projected 800 pts).

Lower severity of illness, lower mortality (risk thus outweights benefit).

24.8% of nonsresponders received etomidate (blocks 11β–hydroxylase and cortisol synthesis).

Premature termination of the study due to slow recruitment.

NEJM 2008; 358; 19

Limitations of CORTICUS

Complications associated with corticosteroid use

depend on the dose, dosing strategy, and duration of therapy.

In the ICU setting (short-term treatment of CIRCI), the most important complications include immune suppression with an increased risk of

infections (typical and opportunistic) impaired wound healing hyperglycemia Myopathy hypokalemic metabolic acidosis psychosis HPA axis and GR suppression.

Marik PE. Chest 2009; 135:181-193.

Marik PE. Chest 2009; 135:181-193.

The use of a continuous infusion of hydrocortisone: better glycemic control with less variability of blood

glucose reduction in the staff workload of managing

hyperglycemia. greater suppression of the HPA axis.

Abruptly stopping corticosteroids will likely result in a rebound of proinflammatory mediators with recurrence of the features of shock (and tissue injury).

Stress-doses of both hydrocortisone and methylprednisolone are believed to provide adequate mineralocorticoid activity, negating the need for fludrocortisone.

Additional Indications for Corticosteroids

RCTs have demonstrated the benefit of corticosteroids in patients with severe community acquire pneumonia, during weaning from mechanical

ventilation, in patients undergoing cardiac surgery. in critically ill patients with liver disease.

Cardiac Surgery Corticosteroids have been demonstrated to downregulate

activation of the proinflammatory cascade following cardiopulmonary bypass (CPB).

Clinical benefits of corticosteroids (similar to those of sepsis and ARDS) may, however, be dose dependent.

Increase in the shunt fraction, greater hemodynamic instability, and a delay in extubation in patients undergoing CABG following the use of high-dose methylprednisolone.

Kilger et al reported that the peri-operative use of physiologic stress-doses of hydrocortisone (100 mg before induction of anesthesia, 10 mg/h for 24 h, 5 mg/hr for 24 hrs, 20 mg/day x3, and 10 mg/day x3) improved the outcome of a high-risk group of patients after cardiac surgery.

Similarly, corticosteroids have been demonstrated to reduce the incidence of postoperative atrial fibrillation.

Kilger et al. Crit Care Med 2003; 31:1068-1074.

Posttraumatic Stress Disorder Patients with PTSD often show neuroendocrine system

alterations such as increased urinary norepinephrine excretion and low plasma or urinary cortisol excretion.

Patients with low cortisol blood levels after a major motor vehicle accident have a high risk of developing PTSD during follow up.

Administration of physiologic doses of hydrocortisone to critically ill patients with sepsis and following cardiac surgery results in a significant reduction of PTSD symptoms after recovery as well as improvements in health-related quality of life.

The mechanisms by which glucocorticoids improve PTSD may be a direct effect of glucocorticoids on neurotransmission; alternatively, the benefit may be due to the deceased use of catecholamines or the suppression of inflammatory mediators.

Liver Failure Sepsis and end-stage liver disease have a number of patho-

physiologic mechanisms in common (eg, endotoxemia, increased levels of proinflammatory mediators, and decreased levels of HDL), and it is, therefore, not surprising that adrenal insufficiency and CIRCI are common in patients with end-stage liver disease.

Tsai et al performed a corticotrophin stimulation test in 101 patients with cirrhosis and sepsis. (Tsai et al. Hepatology 2006;43:673-681.) 51.4% of patients were diagnosed with adrenal insufficiency; survival at 90 days was 15.3% in these patients in comparison

to 63.2% in patients with normal adrenal fxn. None of the patients were treated with corticosteroids.

Fernandez et al compared the survival of patients with cirrhosis and sepsis who underwent adrenal function testing in which patients with adrenal insufficiency were treated with hydrocortisone (group 1) to survival in a control group (group 2) that did not undergo cosyntropin testing and were not treated with corticosteroids. (Fernandez et al. Hepatology 2006;44:1288) The incidence of adrenal failure was 68% in group 1, and the

hospital survival was 64% in group 1 and only 32% in group 2 (p 0.003)2

Hepatic Cortisol Research and Adrenal Pathophysiology Study: 245 of 340 (72%) critically ill patients with liver disease were

diagnosed with adrenal insufficiency (the Hepato-Adrenal Syndrome).

Patients with liver failure and patients post-liver transplantation have an exceedingly high incidence of adrenal failure, which may be pathophysiologically related to low levels of high-density lipoprotein.

High baseline serum cortisol levels may be a maker of disease severity and portend a poor prognosis.

These data suggest that adrenal dysfunction and CIRCI are common in critically ill patients with end-stage liver disease and that treatment with corticosteroids may improve outcome.

Liver Failure

Marik PE. Crit Care Med 2005;33:1254-1259.

Summary Recommendation 1: Dysfunction of the HPA

axis in critical illness is best described by the term critical illness–related corticosteroid insufficiency (CIRCI).

Recommendation 2: The terms absolute or relative adrenal insufficiency are best avoided in the context of critical illness.

Recommendation 3: At this time, adrenal insufficiency in critical illness is best diagnosed by a delta cortisol (after 250mcg cosyntropin) of 9 mcg/dL or a random total cortisol of 10 mcg/dL.

Summary (cont) Recommendation 4: The use of free cortisol

measurements cannot be recommended for routine use at this time. Although the free cortisol assay has advantages over the total serum cortisol, this test is not readily available. Furthermore, the normal range of the free cortisol in critically ill patients is currently unclear. (2B)

Recommendation 5: The ACTH stimulation test should not be used to identify those patients with septic shock or ARDS who should receive GCs.

Summary (cont) Recommendation 6: Hydrocortisone should be

considered in the management strategy of patients with septic shock, particularly those patients who have responded poorly to fluid resuscitation and vasopressor agents.

Recommendation 7: Moderate-dose GC should be considered in the management strategy of patients with early severe ARDS (PaO2/FIO2 of 200) and before day 14 in patients with unresolving ARDS. The role of GC treatment in acute lung injury and less severe ARDS (PaO2/FIO2 of 200) is less clear.

Summary (cont) Recommendation 8: In patients with septic shock,

intravenous hydrocortisone should be given in a dose of 200 mg/day in four divided doses or as a bolus of 100 mg followed by a continuous infusion at 10 mg/hr (240 mg/day). The optimal initial dosing regimen in patients with early severe ARDS is 1 mg/kg/day methylprednisolone as a continuous infusion.

Recommendation 9: The optimal duration of GC treatment in patients with septic shock and early ARDS is unclear. However, based on published studies and pathophysiological data, patients with septic shock should be treated for 7 days before tapering, assuming that there is no recurrence of signs of sepsis or shock. Patients with early ARDS should be treated for 14 days before tapering.

Summary (cont) Recommendation 10: GC treatment

should be tapered slowly and not stopped abruptly.

Recommendation 11: Treatment with fludrocortisone (50 g orally once daily) is considered optional.

Recommendation 12: Dexamethasone is not recommended for the treatment of septic shock or ARDS.

Summary (cont) Recommendation 10: GC treatment

should be tapered slowly and not stopped abruptly.

Recommendation 11: Treatment with fludrocortisone (50 g orally once daily) is considered optional.

Recommendation 12: Dexamethasone is not recommended for the treatment of septic shock or ARDS.

Conclusions Critical illness-related corticosteroid insufficiency (CIRCI) is a

complex disease.

Who should be tested? Patients at risk ± clinical manifestations Patients to be treated.

What test(s) should be recommended? Serum cortisol (free, total) ± DHEA-S Need illness-specific data

Who should be treated with HC? In critically ill patients with catecholamine refractory septic

shock and patients with persistent severe ARDS for 48 h after supportive therapy, a course of stress-dose corticosteroids (200 to 350 mg/d of hydrocortisone or 40 to 70 mg/d of methylprednisolone) should be considered.

Treatment for at least 7 days (and up to 14 days) is suggested, followed by a slow taper.