Adrenal Anatomy
Cortex
Capsule
Zona Glomerulosa
Zona Fasciculata
Zona Reticularis
Medula
Chromaffin Cells
Blood supply
Superior suprarenal artery branches from the inferior phrenic artery
Middle suprarenal artery branches off the abdominal aorta
Inferior suprarenal artery branches off the renal artery
Right suprarenal vein drain into the IVC
Left suprarenal vein drains into left renal vein or the left inferior phrenic vein
Cortisol Synthesis
Cholesterol = principal precursor (80%)
Rate limiting step: cholesterol --> pregnenolone
20% of synthesized in-situ from acetate,etc…
The HPA Axis
Stress-->hypothalamus --(LIF, vasopressin) CRH --> pituitary --ACTH-->adrenals-->cortisol
Cortisol has negative feedback on hypothalamus and pituitary
Cortisol stimulates periphery to release: TNF, TGF beta, Endotoxin, IL-6, LIF, IL-11, IL-1
Adrenal Physiology
Cortisol
- major endogenous glucocorticoid
- 90% bound to corticosteroid-binding globulin
- small amount bound to albumin
- CBG decreases with physiologic stress
- Half life of cortisol = 70 -120 minutes
Cortisol Effects
Metabolism
Cardiovascular Function
Immunology
Metabolic Effects of Cortisol
Increased blood glucose
- Stimulation of hepatic gluconeogenesis
- Inhibition of peripheral (eg. muscle) glucose uptake
- Increase catecholamine and glucagon levels
- Increased lipolysis --> increased free FA
- Decreased protein synthesis
CV Effects of Cortisol
Increased Vascular Tone
- Increased sensitivity to catecholamines
- Increased sensitivity to angiotensin II
Increased microvascular perfusion
- Increased endothelial NO synthetase
Immunologic Effects of Cortisol
Anti-inflammatory actions
- Decreased number and function of WBCs at inflammatory site
- Decreased cytokine, chemokine and eicosanoid production
- Increased production of macrophage migration inhibition factor
Normal Stress Response
Increased cortisol production
- Normal basal cortisol secretion = 8-10 mg/day
- Minor surgery --> ~50 mg/day
- Major surgery --> ~100 mg/day
- Severe stress --> 200-500 mg/day
Increased % of Free Cortisol
- Cortisol binding globulin levels decrease up to 50% with acute illness
- ? role for free cortisol levels for assessment of adrenal function in future
Increased translocation of GC complex (ie enhanced steroid responsiveness)
Abnormal Stress Response
Decreased/failure to increase CRH, ACTH, & Cortisol
GC receptor dysfunction
Systemic Inflammation-associated GC resistance
Structural damage to Adrenal Gland (adrenal apoplexy, infarction)
10-20% of critically ill patients, 60% of septic shock patients develop renal insufficiency
STEROID ISSUES IN SURGICAL PATIENTS
Stress dose steroids
Unmasked Addison's Disease
Bilateral Adrenal Apoplexy (Waterhouse–Friderichsen syndrome)
CIRCI in Septic Shock
Steroids in ARDS
Stress Dosing of Steroids
Exogenous steroid administration --> suppression of HPA axis --> adrenal atrophy --> inadequate response to stress
Low risk: on steroids < 3 weeks, non-nocturnal doses < 5mg/day prednisone, QOD steroids
High Risk: Prolonged steroid use, nocturnal dosing, 20 mg/day prednisone, cushingnoid appearance
Can also see with topical and inhaled steroid use ~20% rate with long term use of high doses
Consider stress dosing in any pt on > 5 mg daily for > 3 weeks within the last year
For elective cases consider preop stim testing to guide periop management
- Minor procedure like local excisions or inguinal hernias - continue usual daily dosing
- Moderate procedure like fem-pop, total joint, segmental colectomy - daily dosing + 50 mg IV preop then 25 mgIV q8hr x 24 hrs
- Major procedure like esophagectomy, total colectomy - daily dosing plus 100 mg IV preop then 50 mg IV q8hr x 24 hours then taper by 1/2 daily until baseline return
Steroid - approximate equivalent dose - relative anti-inflammatory activity - relative mileralocorticoid activty - action in hours
Cortisol - 20 - 1 - 1 - 8 to 12
Cortisone acetate - 25 - 0.8 - 0.8 - 8 to 12
Hydrocortisone - 20 - 1 - 1 - 8 to 12
Prednisone - 5 - 4 - 0.8 - 12 to 36
Prednisolone - 5 - 4 - 0.8 - 12 to 36
Methylprednisolone - 4 - 5 - 0.5 - 12 to 36
Triamcinolone - 4 - 5 - 0 - 12 to 36
Fludrocortisone - changes - 10 - 125 - 12 to 36
Dexamethasone - 0.75 - 30 - 0
Prednisone and prednisolone are potent glucocorticoids and weak mineralocorticoids
Methylprednisolone and dexamethasone have no mineralocorticoid effect
Glucocorticoid doses with equivalent mineralocorticoid effect to 0.1 mg fludrocortisone are: prednisone or prednisolone 50mg or hydrocortisone 20mg
Major side effects with corticosteroid use
Skin thinning and purpura - cushingoid appearance, alopecia, acne, hirsutisim, striae, hypertrichosis
Eye - posterior subcapsular cataract, elevated intraocular pressure/glaucoma, exophthalmos
Cardio - HTN, perturbations in serum liproproteins, premature artherosclerotic disease, arrhythmias with pulse infusions
GI - gastritis, peptic ulcer disease, pancreatitis, steatohepatitis, visceral perforation
Renal - hypokalemia, fluid volume shifts
GU and reproductive - amenorrhea/infertility, intrauterine growth retardation
Bone - osteoporosis, avascular necrosis
Muscle - myopathy
Neuropsychiatric - euphoria, dysphoria/depression, insomnia/akathisia, psychosis, pseudo tumor cerebri
Endocrine - DM, hypothalamic-pituitary-adrenal insufficiency
ID - heightened risk of typical infections, opportunistic infections
Corticosteroid use in the ICU at what cost? Britt, et al.
Retrospective case control study
100 trauma ICU patients at Norfolk 2002-2003 compared with matched non-steroid patients
Conclusion
"In conclusion, corticosteroid use is associated with an increased rate of infection, increased ICU and ventilator LOS, and a trend toward increased mortality. Caution must be taken to carefully consider the indications, risks, and benefits of corticosteroids when deciding on their use
Commentary: “Given the paucity of documented benefit, the infectious risks of steroids need to be carefully considered before initiation of therapy.”
Argument against article: they used higher doses/differing indications of steroids
Marik PE, Varon J. Arch Surgery 2008:
Meta analysis
In conclusion, patients receiving therapeutic doses of corticosteroids who undergo a surgical procedure do not routinely require stress doses of corticosteroids so long as they continue to receive their ususal daily dose of corticosteroids. Adrenal fucntion testing is not required in these patients because the test is overly sensitive and does not predict which patients will develop an adrenal crisis. However, patients receiving physiologic replacement doses of corticosteroids owing to primary disease of the HPA axis require supplemental doses of corticosteroids in the perioperative period.
Unmasked Chronic Addison’s Dz
Primary (Addison’s Dz)
- Autoimmune (80%), TB, Bacterial adrenal hemorrhage, other (fungal infections, scleroderma, amyloidosis, etc...)
Secondary
- Decreased ACTH secretion from pituitary disorders
Tertiary
- Decreased corticotropin-releaseing hormone secretion from hypothalamic dysfunction
Autoimmune Addison’s Dz
80% of Chronic Adrenal Insufficiency Cases
2 Patterns:
- Isolated
- Polyglandular autoimmune syndrome
Type 1 PGA: manifest in childhood with hypoparathyroidisim and adrenal failure
Type 2 PGA: adrenal failure + thyroid dysfunction (hyper or hypo) or DM
Adison's disease + hypothyroidism = schmidt's syndrome --> if hypothyroidism treated without adrenal insufficiency treatment, can cause acute adrenal crisis
Clinical manifestations of chronic adrenal insufficiency:
Symptoms: VAGUE - Weakness, tiredness, fatigue, anorexia, GI symptoms n/v/c/d/pain, salt craving, postural dizziness, muscle or joint pains,
Signs: weight loss, hyperpigmentation (from increased ACTH), hypotension, vitiligo, auricular calcifications
Labs: Hyponatremia, hyperkalemia, more rare hypercalcemia, azotemia, anemia, eosinophilia
Treatment of Chronic Adrenal Insufficiency
Glucocorticoid replacement (given right away)- Dexamethasone 0.5 or prednisone 5 PO at bedtime
Mineralocorticoid replacement (slower effect, only PO) - fludrocortisone 0.1 (0.05 to 0.2 mg orally), liberal salt intake
Androgen replacement - dehydroepiandrosterone 25-50mg orally in women
Patient eduction
Emergency precautions - med-alert bracelet etc.
Acute Adrenal Insufficiency
Nomenclature
Acute Adrenal Failure
Addisonian Crisis
Relative Adrenal Insufficiency (RAI)
Critical Illness Related Corticosteroid Insufficiency (CIRCI)
Signs/symptoms: fever, nausea/vomiting, abdominal pain, hypotension, abdominal distention, obtundation/lethargy, hyponatremia, hyperkalemia
Treatment:
Establish IV acces, draw serum electrolytes and glucose,
Draw blood for immediate serum electrolytes and glucose and routine measurement of plasma cortisol and ACTH (don't wait for results)
Infuse 2 to 3 L NS or D5NS monitoring hemodynamics
Give 4 mg dexamethasone IV bolus over five to ten minutes then q12 minutes
Dexamethasone used because it does not interfere with measurment of plasma cortisol (ACTH stim test)
Use supportive measures
Once stable, continue IVF, treat infections, Short ACTH stim test to confirm diagnosis, determine type and cause of insufficiency, taper
Bilateral Adrenal Apoplexy
Waterhouse-Friedrich syndrome
Adrenal Hemorrhage Proposed hypothesis: venous thrombosis causing outflow obstruction and hemorrhage
Adrenal Apoplexy: Etiologies
Hemorrhage
Emboli
Thrombosis
Rarely can be associated with HIT as outlined by case presentation on HIT Associated Adrenal Apoplexy
Review article by Rosenberger, et al. 2011 described 18 cases of this rare phenomenon:
- 7 females / 11 males, 16 postsurgical, 12 orthopedic procedures, 2 cardiovascular procedures, 2 abdominal surgeriesm, 16 unfractionated heparin
- Thrombocytopenia diagnosed 7-12 days after initiation of heparin, Average 73% decrease in platelet count, Fever and abdominal pain most common symptoms, Hypotension in all pt, Hyponatremia seen in 15/18, Bilateral adrenal hemorrhage associated with HIT
- Diagnosis (difficult): More than half underwent sepsis workups, 12 cases had corticotropin-stimulation test, 14 cases had CT revealing hemorrhage, 3 diagnosed at autopsy
- Morbidity & Mortality: 8 pulmonary emboli, 3 DVT, 1 acute limb ischemia, 2 MI, 2 ARF, 5 Deaths, 3 undiagnosed (uniformly fatal)
CIRCI in Septic Shock
2 trials:
- 2002 JAMA Annane Study
- 2008 NEJM CORTICUS Study
2 Consensus Statements
- 2008 Surviving Sepsis Recommendations
- 2008 American College of Critical Care Medicine Recommendations
2002 Annane Study
French multi-center study with 299 patients - 40% surgical patients
Inclusion criteria: Sepsis, SBP < 90 for > 1 hr despite fluids/pressors
Randomized early to placebo or Hydrocortisone & Fluodrocortisone
Time limit from onset to enrollment: 8 hours
All pts underwent ACTH stim-testing - if cortisol failed to increase by 9, test was positive for relative adrenal insufficiency
Outcomes: 10% decreased 28 day mortality with RAI treated with:
- Hydrocortisone 50mg IV Q6hr, Fluodrocortisone 50 mcg po QD
Median time to vasoppressor discontinuation: 7 days with steroids, 9 days with placebo
No difference between steroid & placebo group’s complication rates
Conclusion: Patients with relative adrenal insufficiency & refractory septic shock benefit from a 7 day course of low dose hydrocortisone & fludrocortisone without increased incidence of complications
2008 NEJM CORTICUS Study
Multicenter, randomized, double-blind, placebo-controlled study
52 European Centers, 499 patients between March 2002 – Nov. 2005, 65% surgical patients
Inclusion Criteria: Sepsis, SBP < 90 for > 1 hr despite fluids, Hypoperfusion or Organ Dysfunction
Time limit from onset to enrollment 72 hours
Method: Hydrocortisone 50 mg IV Q 6 hr x 5 days then Q 12 hr x 3 days then Q 24 hr x 3days, No Fluodrocortisone
Results
Conclusion: “Hydrocortisone did not improve survival or shock reversal in patients with septic shock” In patients who ultimately recovered, Hydrocortisone hastened the speed of their recovery from shock.
2002 Annane VS 2008 CORTICUS
Annane trial enrolled only septic patients requiring moderate doses of vasopressors > 5 mcg/kg/min Dopamine or NE/E
Annane trial enrolled within 8 hr of shock
Annane trial utilized Fludrocortisone
Less surgical patients in Annane trial
Shorter course of treatment (no weaning) in Annane trial
Conclusions from Annane/CORTICUS
Reserve steroids for refractory septic shock
Use them early
Don’t use for long (& don’t taper)
Benefit may be less in surgical patients
Use with mineralocorticoid
? Utility of stim testing
2012 Surviving Sepsis Com. Steroid Guidelines
1. Not using intravenous hydrocortisone to treat adult septic shock patients if adequate fluid resuscitation and vasopresssor therapy are able to restore hemodynamic stability. In case this is not achievable, we suggest intravenous hydrocortisone alone at a dose of 200mg per day (grade 2C).
2. Not using the ACTH stimulation test to identify adults with septic shock who should receive hydrocortisone (grade 2B).
3. In treated patients hydrocortisone tapered when vasopressors are no longer required (grade 2D).
4. Corticosteroids not be administered for the treatment of sepsis in the absence of shock (grade 1D).
5. When hydrocortisone is given, use continuous flow (grade 2D). (associated with less hyperglycemia and hypernatremia)
2008 ACCCM Recs
Call it CIRCI (whatever...)
Best Dx is c stim test (delta cortisol < 9 or random cortisol < 10 mcg/dl), but don’t use stim test clinically (?/!)
Consider hydrocortisone with septic shock ("especially" with poor initial response to fluids/pressors) (duh)
Steroid Therapy in ARDS
Patients that fail to improve by day 7 of ARDS have a higher mortality
Systemic inflammation induced glucocorticoid receptor resistance is thought to be a process central to unresolving ARDS.
This process is potentially reversed by glucocorticoid therapy
Meduri JAMA 1998 - Steroids in ARDS
Small (n=16 in treatment arm, 8 in placebo arm) randomized trial
Methylprednisone administration (2mg/kg/d) initiated in patients with prolonged ARDS (9+ days)
Showed rapid, progressive, and sustained reduction in plasma, BAL inflammatory cytokines, chemokines, and procolloagen levels.
Resulting in improved lung injury scores and significant reduction in ventilator dependence and ICU mortality
ARDSNET NEJM 2006 - Steroids in ARDS
180 patients
Eligible 7 to 28 days after onset of ARDS
IV methylpred vs placebo
Conclusion regarding Steroids in ARDS: No benefit of steroids for in hospital survival in late (ie after 7 days) ARDS
Increased mortality with steroids started after 14 days
Chest 2007 January
Meduri et al
Investigation on the the effects of prolonged low dose* methylprednisolone on lung function in early ARDS (< 72 hr)
Double blind randomized trial across 5 centers in TN between 1997-200
Results - N= 91; 63 treated, 28 control (NOT MATCHED)
Treated received methylprednisilone (1mg/kg/day)
20.6% mortality vs 42.9 in the placebo group. (P=.03)
Attempt at strong support for early steroid use but skeptical of inclusion/exclusion criteria: 212 (> 2x the studied group) for various reasons
BMJ 5/2008 Meta-analysis by Peter et al
Meta analysis of nine randomized trials using variable dose and duration of steroids were identified
Conclusions
- Preventative steroids may increase the incidence of ARDS in patients receiving steroids for septic shock
- A definitive role of corticosteroids in the treatment of ARDS in adults is not established.
- A possibility of reduced mortality and increased ventilator free days with steroids started after the onset of ARDS was suggested
High dose steroids and ARDS
Several studies have found an increased risk of secondary infection and increased mortality when high dose steroids are use for ARDS and Sepsis.
Takeaway points:
- Steroids may have a role in some surgical patients with ARDS, but it doesn't seem like it
- Patients with early ARDS (less than day 7-14) can be considered for low dose steroid therapy, although with caution
- Pulse Steroids (high doses for short duration) is associated with increased mortality and increased risk of superinfection
- Steroids + Chemical Paralysis can cause an interval of myopathy.
- If using steroids, also use PPX for complications of steroid use: PPIs, Vitamin A, Avoidance of paralysis