IM MINI REVALIDA

ENDOCRINOLOGY: ADRENAL CRISIS

Prepared by: ​CC Pelingo, Frances Andrea & CC Pengal, Daniel

DEFINITION

Adrenal Crisis
- aka ​Acute​ adrenal insufficiency
- Extreme decompensated form of adrenal insufficiency characterized by deficiency in glucocorticoids with or
without mineralocorticoid deficiency → decrease in peripheral vascular resistance → vascular collapse & shock
- Should be differentiated from adrenal insufficiency since adrenal crisis is fatal if left untreated
- Acute life-threatening condition with a mortality rate of 0.5/100 patients/year

EPIDEMIOLOGY

(StatPearls)
- In the 1930s, tuberculosis was the most common cause (70%)
- With discovery of cortisone in late 1940s, life expectancy of patients with adrenal insufficiency
dramatically improved / normalized
- Exact frequency in the general population is difficult to estimate
- Estimated incidence in Europe: 4.4 to 6.2 new cases/million/year in different studies, but increasing over time
- Estimated risk of an adrenal crisis in a patient with adrenal insufficiency: 6-10 cases per 100 patient-years (PY)

(Harrison’s)
- 5 in 10,000 → Well-documented, permanent adrenal insufficiency
- Hypothalamic-pituitary origin (most frequent) → 3 in 10,000
- Primary adrenal insufficiency → 2 in 10,000
- 50% are acquired, mostly autoimmune destruction of adrenal glands
- 50% are genetic, distinct enzyme blocks in adrenal steroidogenesis affecting glucocorticoid synthesis
- Adrenal insufficiency due to HPA axis suppression
- Much more common, 0.5-2% of population in developed countries
- Due to exogenous glucocorticoid treatment

ETIOLOGY/RISK FACTORS

Underlying Causes
- Any disorder affecting HPA axis leading to glucocorticoid deficiency can cause adrenal crisis
- Primary Adrenal Insufficiency
- problem in the adrenal cortex itself
- Inability to produce sufficient amounts of glucocorticoids and/or mineralocorticoids
- Addison’s disease ​(most common 1​o​)
- Autoimmune adrenalitis, first described by Thomas Addison
- Autoimmune destruction of adrenal gland → deficiency of ​both​ mineralo- and glucocorticoids
- Additional dysfunction in the RAAS → adrenal crisis is ​more common and severe
- Congenital Adrenal Hyperplasia
- Rare, <1% of cases
- 21-hydroxylase deficiency (most common enzyme affected)
- Increase in androgens, decrease in cortisol and aldosterone
- Adrenal hemorrhage
- Infections (HIV, TB) → TB is the most common infectious cause worldwide
- Secondary Adrenal Insufficiency
- Problem in the pituitary gland (e.g. mass lesion, trauma, irradiation, surgery, apoplexy, Sheehan’s)
- Results in deficiency of glucocorticoid ​alone​ (mineralocorticoid production is not ACTH dependent)
- Adrenals are intact and can still regulate RAAS
- Tertiary Adrenal Insufficiency
- Problem in the hypothalamus
- Both 2​o ​and 3​o​ → Decreased ACTH production by the pituitary, most often due to cessation of long-term
glucocorticoid treatment
- Most common cause of the adrenal crisis → sudden withdrawal of long-term corticosteroid therapy
(usually more than 5 mg prednisone and greater than 4 weeks)

Risk Factors
- elderly (older than 60 years old)
- patients with thyroid or other endocrine disorders
- autoimmune polyglandular endocrinopathy (10.9/100 patients/year)
- type 1 diabetes (12.5/100 patients/year)

Precipitating Factors
- Infections:
- Bacterial (Streptococcus, Pseudomonas, ​H. influenzae, T. pallidum​ (reported in case reports)),
mycobacteria​, fungal (Histoplasmosis, Pneumocystis carinii, Candida), parasitic (Toxoplasmosis,
 African trypanosomiasis) or viral (HIV, Herpes Simplex, CMV, Echovirus)
- Trauma, Pregnancy, Surgery
- Emotional stress, Strenuous physical activity
- Thyrotoxicosis → increases cortisol metabolism
- Medications
- Antiadrenal medications, mitotane, metyrapone, anticancer medications, immune checkpoint inhibitors,
tyrosine kinase inhibitors (sunitinib, imatinib), ketoconazole, fluconazole, etomidate, rifampicin,
cyproterone acetate, diuretics, and megestrol acetate.
- Gastrointestinal (GI) illness, etc.
- Hot weather
- Dehydration
- Diabetes insipidus leads to dehydration and can be a precipitating factor for adrenal crisis
- Alcohol intoxication
- Severe migraine, Seizures

*However, regardless of the etiology, the adrenal crisis is an acute complication of adrenal insufficiency.

PATHOPHYSIOLOGY

Normal
- The adrenal gland's main function is to produce both mineralocorticoids and glucocorticoids.
Cortex Zona glomerulosa Salt Mineralocorticoids Aldosterone

Zona fasciculata Sugar Glucocorticoids Cortisol

Zona reticularis Sex Androgens DHEA, Androstendione

Medulla Stress Catecholamines Nor/Epinephrine

- ACTH produced by pituitary, main function to stimulate the cortisol release from the adrenals
- Depends on level of underlying cause whether mineralo- or just glucocorticoid deficiency
- aldosterone → sodium retention and potassium secretion
- cortisol → promotes gluconeogenesis, increases sensitivity to catecholamines, and regulates the
immune system

Stressors
- Precipitate adrenal crisis and release inflammatory cytokines (TNF-a, IL- and 6) → activate HPA
- Normally, cortisol regulates these cytokines (preventing T-cell proliferation and preventing T-cells from
recognizing IL signals)
- With stress, TNF-a can promote cortisol resistance → increases mortality in patients with adrenal crisis
- Basal and stress-induced epinephrine release may be impaired → hypotension and/or hypoglycemia in crisis

Cortisol deficiency
- → decrease in vascular sensitivity to norepinephrine and angiotensin II → peripheral adrenergic tone is
reduced → vascular collapse and shock
- → hypoglycemia

Aldosterone deficiency
- → increased renal sodium loss and potassium reabsorption → decreased intravascular volume, vascular tone,
cardiac output, and renal perfusion → lowers arterial blood pressure → postural hypotension, compensatory
tachycardia → eventual vascular collapse
- → reduced renal perfusion → water retention → dilutes the extracellular fluid → causes the cells to leak
potassium → hyperkalemia and metabolic acidosis
- → circulatory collapse → impairs urinary excretion of waste products → elevated levels of BUN and creatinine
Pathophysiology of ​Adrenal Insufficiency​ (​Source​)
 Pathophysiology of ​Adrenal Crisis​ (​Source​)

CLINICAL MANIFESTATIONS

(include pertinent PE findings for the diagnosis and how to elicit)

● Elicit the patient's ​past medical history and past surgical history​. Identify home medications.
● Determine precipitating factors​ and confirm any history of long-term ​steroid use (oral, topical, or inhaled)
● Abrupt cessation​ or an acute process can precipitate adrenal crises in these patients
● Recurrent hypoglycemia can be a sign of adrenal insufficiency​ in patients with type 1 diabetes on insulin
therapy
● Unexplained shock which is ​refractory to vasopressors and fluids
● Weakness
● Fatigue
● Weight loss
● Decreased Appetite (anorexia)
● For children: ​Weight loss that may lead to failure to thrive & hypoglycemia with seizures
● Orthostatic hypotension ​(decrease of at least​ ​20 mmHg in SBP or decrease of 10 mmHg in DBP within two to
five minutes of standing, or if standing causes signs and symptoms. ​BE CAREFUL!​)
● Tachycardia
● Skin/mucosal hyperpigmentation ​(Increased ACTH)
● GI: Nausea, vomiting, diarrhea. ​May or may not have abdominal pain
● Less common: ​amenorrhea, decreased libido, and depression
● Rare: ​Salt-craving
● In pregnant patients, watch out for Sheehan Syndrome-> Secondary adrenal insufficiency via reduced ACTH
● Bacterial infections with H. Influenzae, S. Aures, S. Pneumoniae, and some fungi may cause adrenal crisis
● Severe physiologic stress (trauma, burns, or surgery) may trigger adrenal crisis

DIFFERENTIAL DIAGNOSIS
(Identify at least 2 differential diagnoses, and bases)
● Rarely an independent process, the differential diagnosis may be very broad
● Altered mental status, abdominal pain, nausea vomiting, fever, and hypotension and known adrenal
insufficiency, the adrenal crisis should be the top differential
● Determine the precipitating cause of the adrenal crisis whether that is sepsis, infection, trauma, physical or
emotional stress, myocardial infarction, and so forth

Septic Shock Peritonitis/Abdominal Sepsis

● Life threatening organ dysfunction
● Defined by persisting hypotension requiring
vasopressors to maintain a mean arterial
pressure of 65 mm Hg or higher and a serum
lactate level greater than 2 mmol/L (18
mg/dL)
● Fever (may have chills and/or rigors)
● Hypotension
● Suspected infection (localized S/Sx)
● Confusion
● Anxiety
● Dyspnea/Hyperventilation with respiratory
alkalosis
● Tachycardia/Narrow pulse pressure
● Fatigue
● Malaise/Nausea/Vomiting
● Decreased urine output
● Cyanosis
● Assess ABC, acutely ill, flushed, and toxic
appearance may be observed
● Signs of hypoperfusion
● Pallor or grayish or mottled skin are signs of
poor tissue perfusion
● Cool skin, cool extremities, and delayed
capillary refill
● Petechiae/Purpura -> DIC -> ominous!
● History should include recent abdominal
surgery, previous episodes of peritonitis,
travel history, use of immunosuppressive
agents, and the presence of diseases that
may predispose to intra-abdominal infections
● Presentation and the findings may be
entirely inconclusive or unreliable in patients
with significant immunosuppression
● Fever and chills
● Abdominal pain or discomfort
● Abdominal distention
● Abdominal wall rigidity
● Encephalopathy
● Diarrhea
● Ascites (unresponsive to diuretics)
● Acute kidney failure
● Ileus
● Generally appear unwell and in acute
distress
● Tachycardia
● Hypovolemia
● Progressive dehydration
● Hypotension (d/t third space losses)
● Tenderness on palpation, maximal on site of
infection
● Signs of hepatic failure (jaundice,
angiomata)

DIAGNOSTIC PLAN

(​Bases of each test, expected findings with normal/reference values)

● In an acutely ill patient with possible adrenal crisis, therapy should be started before the diagnosis is
established.The short ACTH stimulation test can be performed after initiation of glucocorticoid treatment
● Classic laboratory features may reveal:
○ Hyponatremia(due to mineralocorticoid deficiency)
○ Hyperkalemia (due to mineralocorticoid deficiency)
○ Hypoglycemia(due to decreased gluconeogenesis and glycogenolysis)
○ Low or low normal ACTH level in secondary adrenal insufficiency and high or high normal ACTH level
in primary adrenal insufficiency
○ Hypercalcemia(due to increased intestinal absorption and decreased renal excretion of calcium)
○ Prerenal failure with elevated creatinine level
○ Low aldosterone (due to mineralocorticoid deficiency)
○ High renin is expected in primary adrenal insufficiency as there is an increase in urinary sodium loss
and decreases in the blood volume)
○ Normocytic normochromic Anemia, lymphocytosis, and eosinophilia
○ TSH levels may be increased, usually between 4 and 10 IU/L
● Serum cortisol: Less than 20 mcg/dL in severe stress or after ACTH stimulation is indicative of adrenal
insufficiency
● ACTH test (diagnostic)​: Determine baseline serum cortisol, then administer ACTH 250 mcg intravenous push
(IVP), and then draw serum cortisol 30 and 60 minutes after ACTH administration. ​An increase of less than 9
mcg/dL is considered diagnostic of adrenal insufficiency
● Abdominal CT scanning​: Visualize adrenal glands for ​hemorrhage​. Adrenal hemorrhage appears as
hyperdense, bilaterally enlarged​ adrenal glands.
● Electrocardiography
○ Prolongation of the QT interval can induce ventricular arrhythmias.
○ Deep negative T waves​ have been described in acute adrenal crisis.
● In normal subjects, serum cortisol concentrations are ​higher in the early morning​ (about 6 AM), ranging from
10 to 20 mcg/dL (275 to 555 nmol/L), than at other times of the day. An early morning low serum cortisol
concentration (less than 3 mcg/dL [80 nmol/L]) is strongly suggestive of adrenal insufficiency
 MANAGEMENT

Remember: Treatment precedes diagnosis. Management should not be delayed while waiting for
results of lab tests.

PHARMACOLOGIC ​(include Dosage, Route of Administration)

(Harrison’s)
- Immediate rehydration, Correct volume depletion
- NSS infusion at initial rates of 1L/hr w/ continuous cardiac monitoring (more accurate: 15-20mL/kg/hr)
- Glucocorticoid replacement
- Initiated by bolus injection of 100mg hydrocortisone (alternative 4mg dexamethasone IV bolus)
- Dexamethasone may be preferred since it doesn’t interfere with diagnostic testing
- Followed by 200mg hydrocortisone over 24hr
- preferably by continuous infusion or alternatively by bolus IV or IM injections
- (or since infusion is not common in PH, 50mg IV every 6 hrs)
- Mineralocorticoid replacement
- Only for primary AI, no need for secondary AI
- Can be initiated once daily hydrocortisone has been reduced to <50mg
- Doses of hydrocortisone >50mg exert sufficient stimulation of mineralocorticoid receptors
 - (trans) ​Replace Adrenal Androgen
- DHEA 25-50 mg per day
- Treat underlying cause and correct other metabolic abnormalities

(StatPearls)
- Additional for IVF: need for further resuscitation should be addressed according hemodynamic status
(usually 4–6 liters are needed in the first 24 hours)
- Correction of hypoglycemia with IV dextrose with frequent monitoring of blood glucose is essential
- Avoid rapid correction of hyponatremia (>6-8 meq in the first 24 hrs) to avoid osmotic demyelination
syndrome
- Take into consideration: Cortisol replacement can induce water diuresis and suppress
antidiuretic hormone
- Monitor urine output
- Contact endocrinologist as soon as possible on further advice.
- Only taper steroids after there are a clinical improvement and the tapering should be gradual.

(Revalida Emergencies Script)

- 1​o ​ → glucocorticoid ​and​ mineralocorticoid replacement; 2​o ​or 3​o ​→ glucocorticoid replacement ​only
- 4S of Adrenal Crisis Management
- Salt
- IV access immediately, start IVF with PNSS for resuscitation and to address hyponatremia
- Steroid
- IV Hydrocortisone 100mg q8 or Dexamethasone should be started immediately
- Support
- 50% dextrose to correct hypoglycemia
- Vasopressors
- (statpearls) failure to respond to the initial IVF bolus → start on vasopressors to
maintain a MAP above 65 for adequate organ perfusion
- Oxygen​ as well as other supportive measures should be instituted as indicated
- Search
- Once stabilized, further labs can be requested to determine exact etiology
- Fludrocortisone may be given in those with concurrent mineralocorticoid deficiency (trans: not available in PH)
- Glucocorticoids should be tapered to maintenance dosage over 1-3 days once appropriate

NON-PHARMACOLOGIC ​(include Diet)

- can’t find anything specific to adrenal crisis
- Eating, Diet, and Nutrition for Adrenal Insufficiency & Addison's Disease (​source​)
- If low aldosterone, may benefit from a high-sodium diet
- High doses of corticosteroids → higher risk of osteoporosis
- protect bone health by getting enough dietary calcium and vitamin D (also, supplements)
- recommended calcium intake based on age
- Additional only: Adrenal Fatigue Diet (​source​)

TREATMENT RESPONSE AND COMPLICATIONS ​ (State anticipated treatment response and

complications)

● Mineralocorticoid replacement is not necessary acutely because it takes several days for its
sodium-retaining effects to appear, and adequate sodium replacement can be achieved by IV saline
alone. However, in patients with known primary adrenal insufficiency or those with potassium >6.0
mEq/L, hydrocortisone is preferred because of its mineralocorticoid activity
● Oral glucocorticoids are not recommended, as patients are too acutely ill, not able to eat or drink,
have nausea and vomiting, or are obtunded and cannot swallow
● Upon discharge, the patient will need to have a prescription for long-term glucocorticoid therapy, as
well as close followup with a primary care provider or endocrinologist
● Even with proper recognition and treatment, the adrenal crisis may result in death. Other
complications may include seizures, arrhythmias, coma, etc. due to electrolyte abnormalities such as
hyponatremia, hyperkalemia, and hypoglycemia. Hypotension may lead to hypoperfusion and organ
failure as well. However, many other complications may arise secondary to the precipitating disease
or event
● If left untreated, an Addisonian crisis can lead to complications such as:
○ Cardiac arrhythmias from multiple electrolyte abnormalities
○ Cardiac arrest

PREVENTIVE
● Instruct patients regarding the importance of careful attention to health and fluid intake and to double
maintenance doses when ill until medical attention is obtained
● Sick days rule: which includes doubling or tripling the daily oral dose during minor illness.
● Stress dose is needed during stressful situations including trauma, surgery, major procedures, and severe
 illness.
● The patient should be aware of signs and symptoms of adrenal insufficiency including nausea, vomiting,
abdominal pain, hypoglycemia, hypotension, weight loss, etc.
● The importance of wearing medical alert bracelets or necklaces.
● The patient should have additional supplies at home in case it is needed.
● An emergency kit should be available in case it is needed (100 mg hydrocortisone sodium succinate for
injection or dexamethasone 4 mg, along with vials of sterile 0.9 percent normal saline and syringes)
● In a special situation like pregnancy, during labor, the patients should receive 25 mg hydrocortisone IV every 6
hours. At the time of the delivery, 100 mg Hydrocortisone should be given. After the delivery, tapering the dose
in 3 days is recommended

PROGNOSIS

(State expected prognosis of the case)

● Adrenal crisis is not a common disease however it has a high mortality. Mortality can be as high as 25% of the
patients presenting with adrenal crises.
● If the Addisonian crisis is quickly identified and given prompt treatment with IVF and steroids, patients have a
good prognosis and recovery.
● Prompt recognition and treatment of both the underlying condition and adrenal crisis may lead to clinical
improvement, but in many cases, mortality remains high.
● Patients with autoimmune adrenal insufficiency should have a normal life-span and can lead a fully active life,
including vigorous exercise
● Linear growth and pubertal development proceed normally in correctly (ie, adequately but not overly) treated
children with adrenal insufficiency
● A Japanese study looking at an adrenal crisis in patients with known insufficiency found a mortality rate of
closer to 3% while a German study was just over 6%. In the Japanese study, older age, concomitant endocrine
disorders and impaired level of consciousness was associated with increased mortality.

Links to References:
- Include links to sample cases/case vignettes
- Adrenal Crisis Simulation
- A Challenging diagnosis that eventually results in a life-threatening condition: Addison’s disease
and adrenal crisis
- Include links to videos for History/PE
- https://youtu.be/QR5KpLGIV1s
- References Used:
- Harrison’s Principles of Internal Medicine, 20th Edition. Chapter 379, Page 2733
- B2021 Trans on Adrenal Disorders (Dr. Charlene Ann Balili, September 5, 2019)
- Oral Revalida Emergencies 2017 Script
- Elshimy, G., Alghoula, F., & Jeong, J. M. (2020). Adrenal crisis. ​StatPearls​ [Internet]. Retrieved from:
https://www.ncbi.nlm.nih.gov/books/NBK499968/
- Rathbun, K. M., Nguyen, M., & Singhal, M. (2020). Addisonian crisis. ​StatPearls​ [Internet]. Retrieved
from: https://www.ncbi.nlm.nih.gov/books/NBK441933/
- Bornstein, S. R., Allolio, B., Arlt, W., Barthel, A., Don-Wauchope, A., Hammer, G. D., ... & Torpy, D. J.
(2016). ​Diagnosis and treatment of primary adrenal insufficiency: an endocrine society clinical
practice guideline​. ​The Journal of Clinical Endocrinology & Metabolism​, ​101(​ 2), 364-389. Retrieved
from: ​https://academic.oup.com/jcem/article/101/2/364/2810222
- Dineen, R., Thompson, C. J., & Sherlock, M. (2019). ​Adrenal crisis: prevention and management in
adult patients​. ​Therapeutic advances in endocrinology and metabolism,​ 1 ​ 0​, 2042018819848218.
Retrieved from:​ ​https://journals.sagepub.com/doi/pdf/10.1177/2042018819848218
- Arlt, W. (2016). ​Emergency management of acute adrenal insufficiency (adrenal crisis) in adult
patients​. Retrieved from:​ ​https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5314805/pdf/ec-5-G1.pdf
- Lisa Kirkland, M. (2020, May 28). Adrenal Crisis. Retrieved February 02, 2021, from
https://emedicine.medscape.com/article/116716-overview
- Niemann, L. K., MD, Lacroix, A., MD, &amp; Martin, K. A., MD. (2019, October 16). Diagnosis of adrenal
insufficiency in adults. Retrieved February 02, 2021, from
https://www.uptodate.com/contents/diagnosis-of-adrenal-insufficiency-in-adults?search=adrenal+crisis&a
mp;source=search_result&amp;selectedTitle=6~150&amp;usage_type=default&amp;display_rank=6
- Niemann, L. K., MD, Lacroix, A., MD, &amp; Martin, K. A., MD. (2020, July 31). Treatment of adrenal
insufficiency in adults. Retrieved February 02, 2021, from
https://www.uptodate.com/contents/treatment-of-adrenal-insufficiency-in-adults#H25
- Brian J Daley, M. (2019, November 21). Peritonitis and Abdominal Sepsis. Retrieved February 02, 2021,
from ​https://emedicine.medscape.com/article/180234-overview
- Andre Kalil, M. (2020, December 06). Septic Shock. Retrieved February 02, 2021, from
https://emedicine.medscape.com/article/168402-overview