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980 PART 8: Renal and Metabolic Disorders

CHAPTER Critical Illness–Related secretion from the paraventricular nucleus of the hypothalamus of
corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP).
102 Corticosteroid Insufficiency CRH plays a pivotal integrative role in the response to stress. CRH
stimulates the production of ACTH by the anterior pituitary, causing the
Paul E. Marik zona fasciculata of the adrenal cortex to produce more glucocorticoids
(cortisol in humans). AVP is a weak ACTH secretagogue and vasoactive
2
peptide that acts synergistically with CRH to increase secretion of ACTH.
The increase in cortisol production results in multiple effects (metabolic,
KEY POINTS
cardiovascular, and immune) aimed at restoring homeostasis during
• Acute adrenal insufficiency in critically ill patients is best referred stress. In addition, the HPA axis and immune system are closely inte-
to as critical illness–related corticosteroid insufficiency (CIRCI). grated in multiple positive and negative feedback loops (see Fig. 102-1).
• CIRCI may arise due to adrenal insufficiency or tissue resistance Activation of the SAS results in the secretion of epinephrine and norepi-
to cortisol. nephrine from the adrenal medulla and to an increased production of
• Adrenal insufficiency is best diagnosed by a random cortisol inflammatory cytokines such as interleukin-6 (IL-6).
<10 µg/dL (Type 1 CIRCI) or a delta of <9 µg/dL after a 250 µg
cosyntropin stimulation test (Type II CIRCI). CORTISOL PHYSIOLOGY
• The diagnosis of adrenal insufficiency/CIRCI should not be made
on the basis of laboratory criteria alone. Cortisol (hydrocortisone) is the major endogenous glucocorticoid
secreted by the adrenal cortex. Over 90% of circulating cortisol is bound
• Treatment with low-dose hydrocortisone (200 mg/day) or meth- to corticosteroid-binding globulin (CBG) with less than 10% in the free,
ylprednisolone (60 mg/day) should be considered in patients with biologically active form. CBG is the predominant binding protein with
septic shock who have responded “poorly” to resuscitation with flu- albumin binding a lesser amount. During acute illness, particularly sep-
ids and vasopressor agents and those with ARDS who have failed to sis, CBG levels fall by as much as 50%, resulting in a significant increase
show an improvement within 48 hours of supportive care. The role in the percentage of free cortisol. The circulating half-life of cortisol
of low-dose hydrocortisone in patients with severe sepsis and other varies from 70 to 120 minutes, with a biological half-life of about 6 to
clinical situations in the ICU remains to be determined.
8 hours. 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.
Exposure of the host to diverse noxious stimuli results in a stereotypic In a series of sequential enzymatic steps, cholesterol is converted to preg-
and coordinated response, referred to by Hans Selye as the general adap-
tion syndrome (or stress response) which serves to restore homeostasis nenolone and then to the end products of adrenal biosynthesis, namely,
aldosterone, dehydroepiandrostenedione, and cortisol. At rest and during
and enhance survival. The stress response is mediated primarily by the
1
hypothalamic-pituitary-adrenal (HPA) axis as well as the sympatho- stress about 80% of circulating cortisol is derived from plasma choles-
terol, the remaining 20% being synthesized in situ from acetate and other
adrenal system (SAS). Activation of the HPA axis results in increased
precursors. High-density lipoprotein (HDL) is the preferred cholesterol
source of steroidogenic substrate in the adrenal gland. 3
The activities of glucocorticoids are mediated by both the glucocorticoid
Stress (GR) and mineralocorticoid receptors (MR). The GR and MR share both
CRH gene 4
transcription functional and structural homology. Both aldosterone and glucocorticoid
hormones bind to both the GR and MR. At low basal levels cortisol binds
to the high-affinity, low-capacity MR. However, with increased cortisol
CRH secretion the MR are saturated and cortisol then binds to the low affinity,
IL-1
TNF CRH LIF high-capacity GR. In addition, the 11β-hydroxysteroid dehydrogenase
Vasopressin (11β-HSD) enzymes play an important role in preventing glucocorticoid
access to cells that express the MR. This enzyme has two isoforms: an
5,6
IL-6 POMC gene NAD+-dependent form (11β-HSD-2) and an NADP+-dependent form
LIF transcription (11β-HSD-1). 11β-HSD-2 is found in tissues with high levels of MR
IL-11
activity such as the kidney, sweat and salivary glands, placenta, and colon.
11β-HSD-2 converts cortisol to cortisone, its inactive reduced metabolite
Cortisol which is unable to bind to the GR and MR. 11β-HSD-1, which is found in
glucocorticoid target tissues, catalyzes the conversion of cortisone to the
TNF ACTH active glucocorticoid cortisol. Proinflammatory cytokines modulate the
TGF-beta activity of the 11β-HSD enzymes, with interleukin-1β (IL-1β) and tumor
endotoxin
necrosis factor-α (TNF-α) increasing the activity of 11β-HSD-1 while
decreasing that of 11β-HSD-2. 7,8
Cortisol
Cortisol diffuses rapidly across cell membranes binding to the GR.
Two isoforms of the GR have been isolated, namely GR-α and GR-β.
The GR-β isoform fails to bind cortisol and activate gene expression and
thus functions as a negative inhibitor of GR-α. The GR-β binds to the
9
FIGURE 102-1. Activation of the hypothalamic-pituitary adrenal axis (HPA) and the glucocorticoid antagonist RU-486 and may play a role in regulating gene
interaction with the inflammatory response. ACTH, adrenocorticotrophic hormone; CRH, corti- expression. Seven isoforms of GR-α have been reported; these isoforms
10
cotropin releasing hormone; IL-6, interleukin-6; IL-11, interleukin-11; LIF, leukemia inhibitory may be selectively expressed by different tissues with each isoform elicit-
factor; POMC, proopiomelanocortin; TGF-β, transforming growth factor-beta; TNF, tumor ing a distinct response. 11,12 Through the association and disassociation
necrosis factor. (Reproduced with permission from Marik PE, Pastores SM, Annane D, et al. of chaperone molecules, the glucocorticoid-GR-α complex moves into
Recommendations for the diagnosis and management of corticosteroid insufficiency in criti- the nucleus where it binds as a homodimer to DNA sequences called
cally ill adult patients: consensus statements from an international task force by the American glucocorticoid-responsive elements (GREs); these are located in the pro-
College of Critical Care Medicine. Crit Care Med. June 2008;36(6):1937-1949.) moter regions of target genes which then activate or repress transcription of

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