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The document provides information on Addisonian crisis, also known as an acute adrenal crisis. It begins with objectives of being able to promptly identify and treat an Addisonian crisis to save a patient's life, as the presentation can mimic other conditions. The document then contrasts acute adrenal crisis with Addison's disease, which develops more gradually over months to years. It provides an overview of epidemiology, anatomy, physiology of the adrenal glands and cortisol. It describes the signs and symptoms of Primary/Addison's adrenal insufficiency and discusses various causes including autoimmune disease and exogenous steroid use. Acute adrenal crisis can be fatal if not identified and treated immediately with cortisol replacement.

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ADDISONIAN CRISIS EFFIOM, VICTOR E. (MD)
Table of Contents • Objective • Overview • Epidemiology • Anatomy & Physiology • Addison’s Disease & Adrenal Insufficiency • Addisonian Crisis (Presentation, Mgt.) • Medication Profiles • Complications & Prognosis • Resources
OBJECTIVE • To be able to promptly identify Addisonian Crisis and initiate appropraite measures to save the patient’s life. • It presents masked like many other ailments – making prompt identification, life saving.
• Do not confuse acute adrenal crisis with Addison disease. • In 1885, Thomas Addison described a syndrome of long term adrenal insufficiency that develops over months to years with: o weakness, o Fatigue, o Anorexia, o Weight loss and hyperpigmentation as the primary symptoms. • In contrast, an acute adrenal crisis can manifest with vomiting, abdominal pain and hypovolemic shock. Overview
Overview • Hahner et al investigated the frequency and causes of, as well as the risk factors for, adrenal crisis in patients with chronic adrenal insufficiency. • Using a disease-specific questionnaire, the authors analyzed data from 444 patients, including 254 with primary adrenal insufficiency and 190 with secondary adrenal insufficiency. • At least 1 adrenal crisis was reported by 42% of patients, including 47% of those with primary adrenal insufficiency and 35% of patients with the secondary condition. • GI infection and fever were the most common precipitating causes of crisis. • Identified risk factors for adrenal crisis were, for patients with primary adrenal insufficiency, concomitant nonendocrine disease and for patients with secondary adrenal insufficiency, female sex and diabetes insipidus
Lets Paint an Overview Picture • “Anyone on Prednisolone for long enough to suppress the PA axis or who has overwhelming sepsis, or has metastatic cancer may suddenly develop adrenal insufficiency with deadly hypovolemic shock”
Epidemiology • “Addison's disease was frequently consequent upon affectation of the glands by tuberculosis. Pulmonary Tuberculosis (PTB) is still very common in Nigeria but no report on the functional status of the adrenal cortex in patients with PTB in Nigeria exists” • “Adrenocortical insufficiency, mostly at the subclinical level, is common in persons with PTB infection, occurring in about 23% of patients. We therefore recommend that basal cortisol levels should not be used to detect adrenocortical insufficiency; rather stimulation tests should be used to exclude or confirm suspected adrenocortical insufficiency in patients with PTB”. Odeniyi I.A et al Mar.2011
• Studies of critically ill patients with septic shock demonstrate a de novo (excluding patients with known adrenal insufficiency or patients on glucocorticoid therapy) incidence ranging from 19-54%. • Annane et al's landmark 2002 study found a very high rate, ie, 76% of all enrolled patients with septic shock • In a study of 2000 consecutive general hospital autopsies, only 22 (1.1%) revealed bilateral adrenal hemorrhage; however, as many as 15% of patients dying in shock have been demonstrated to have BMAH. • No description regarding racial data, sexual predilection, or age is available in the literature.
• The prevalence of primary adrenal insufficiency (Addison's disease) has been reported to be 39 to 60 per million population. May M. et al • Most cases in Nigeria due to TB & HIV Mortality/Morbidity • In the absence of bilateral adrenal hemorrhage, the survival rate of patients with acute adrenal crisis that is diagnosed promptly and treated appropriately approaches that of patients without acute adrenal crisis with similar severity of illness. • Patients who developed BMAH before the availability of hormonal testing or computed tomography (CT) scanning rarely survived. In one series, patients who were diagnosed using CT scanning had an 85% rate of survival. Because the true incidence of adrenal crisis and BMAH are unknown, the actual mortality rate also is unknown.
Adrenal Anatomy • The adrenals are endocrine organs that sit on top of each kidney
Anatomy & Physiology • Each adrenal gland has two parts – Adrenal Medulla (inner area) •Secretes catecholamines which mediate stress response (help prepare a person for emergencies). »Norepinephrine »Epinephrine »Dopamine
• The adrenal medulla comprises approximately 28% of the total adrenal mass. • Although we think of the ‘stress’ catecholamines as being necessary for ‘fight or flight’, they are actually circulating in our bodies, in minute quantities, at all times, and act in concert with other hormones and the vagus nerve to support daily activities.
• Adrenal Cortex (outer area, encloses Adrenal Medulla) – Secretes steroid hormones • Glucocorticoids (Cortisol): exert a widespread effect on metabolism of carbohydrates and proteins • Mineralocorticoids (Aldosterone, 11- Deoxycortocosterone): are essential to maintain sodium and fluid balance • sex hormones (Androgens: DHEA) secondary source
Interestingly… • A functioning adrenal cortex (or the steady availability of replacement hormone) is essential for survival. • A person can survive without a functioning adrenal medulla.
Survive without my Medulla?! • This seems counter-intuitive doesn’t it? You would think we would need epinephrine/norepinephrine as a critical component to survive. • Research has shown that even after the adrenal medulla has been destroyed by radiation or removal, small amounts of those catecholamines are found in the body. • The source is unknown, however the amount is sufficient for survival.
The Essential Steroids • Primary glucocorticoid: – Cortisol (a.k.a. hydrocortisone) • Primary mineralocorticoid: – Aldosterone “These steroids, especially cortisol, are essential for life.”
Cortisol • A glucocorticoid • Frequently referred to as the ‘stress hormone’ – Released in response to physiological or psychological stress •Examples: exercise, illness, injury, starvation, extreme dehydration, electrolyte imbalance, emotional stress, surgery, etc.
Cortisol • When cortisol is not produced or released by the adrenal glands, humans are unable to respond appropriately to physiologic stressors. • Rapid deterioration resulting in organ damage and shock/coma/death can occur, especially in children.
Cortisol Values
Why we need cortisol • Cortisol has a necessary effect on the vascular system (blood vessels, heart) and liver during episodes of physiologic stress
Vascular Reactivity • In adrenally-insufficient individuals experiencing a physiologic stressor, the vascular smooth muscle will become non-responsive to the effects of norepinephrine and epinephrine, resulting in vasodilation and capillary ‘leaking’. • The patient may be unable to maintain an adequate blood pressure • The blood vessels cannot respond to the stress and will eventually collapse
• This is an important reason why adrenally- insufficient people must receive emergency cortisol as soon as possible after a serious stress event such as trauma or a period of nausea/vomiting. • The vasculature becomes unable to constrict to make effective use of circulating body volume. • Replacement IV fluid challenges often have poor effect in the adrenally-insufficient patient until cortisol is administered.
Energy Metabolism • In adrenally-insufficient individuals under increased physiologic stress, the liver is unable to metabolize carbohydrates properly, which may result in profoundly low blood sugar that is difficult to reverse without administration of replacement cortisol • Impaired gluconeogenesis, lipolysis and proteolysis
• The speed at which patient deterioration occurs is difficult to predict and is related to the underlying stressor, patient age, general health, etc. • Young children can be at high risk for rapid deterioration, even when experiencing a ‘simple’ gastrointestinal disorder.
• The steroid hormones, especially cortisol, are mediated by the hypothalamic-pituitary- adrenal (HPA) axis. • The onset of stress as well as our sleep/wake cycles influences the activity of the HPA axis.
Endocrinologist Testimony… • “…In adrenal insufficiency, because of the inability to produce glucocorticoids and often mineralocorticoids from the adrenal glands, there is a risk of life-threatening hyponatremia, hyperkalemia, hypoglycemia, seizures and cardiovascular collapse, in particular at times of physiologic stress to the body, such as in injury or illness…” • Support letter, Dr. Christine Leudke, Boston Children’s Hospital 12/12/2009
Who has adrenal insufficiency? • Anyone whose adrenal glands have stopped producing steroids as a result of: – Long-term administration of steroids – Pituitary gland problems, including growth hormone deficiency, tumor, etc. – Trauma, including head trauma that affects pituitary – Loss of circulation to adrenals/Adrenal Hemorrhage/removal of tissue – Auto-immune disease – Surgical Removal(For Cushing's) + Inadequate Replacement Therapy. – Cancer and other diseases (TB and HIV may cause) • There is also an inherited form of adrenal insufficiency (CAH) • Acute Vs. Chronic
CAUSES CONTD. • Rapid withdrawal of long-term steroid therapy. • Ketoconazole, Etomidate, Metyrapone • Phenytoin (Pan-endocrine Disturbances: DI, Hyperglycemia, glycosuria osteomalacia). • Rifampin, Aminogluthemide • Mitotane • Septic shock
Parent testimony… • “… People without adrenal insufficiencies naturally produce up to ten times the normal amount of cortisol during times of physical stress. If an unaffected person is unresponsive, goes into cardiac arrest or is vomiting, you can treat the shock, heart, or dehydration and help them. For James, however, immediate, appropriate emergency response is vital. I have watched James, as a fever quickly spiked, go from alert and playful to grayish-white and lethargic, in a matter of minutes. It is scary. I have seen how a stress dose of Cortef quickly brought him back to where I could then manage his illness with the “common” treatment of Motrin and fluids…” • Oral Testimony, Alex Dubois, December 12, 2009
Adrenal Insufficiency: Take Note of this group of Pxts. • Can occur from long-term administration of steroids (over-rides body’s own steroid production) Examples: – Organ transplant patients – Long-term COPD – Long-term Asthma – Severe arthritis – Certain cancer treatments
Organ Transplant Patients • These individuals must take immunosuppressive medications (usually steroids) DAILY for life. • Their own adrenal glands stop producing cortisol because of external source of steroid.
Long-term Asthma and COPD • These individuals are at high risk of adrenal crisis from illness or trauma • Keep in mind that many children and teens with severe asthma take steroid medication every day and may be at significant risk of adrenal crisis. • A severely asthmatic teen may have been started on a steroid 10+ years ago
• In some situations steroids are administered long-term and then tapered off. Often it can take up to a year for a person’s own adrenal glands to become fully functioning again. • These patients remain at risk of adrenal crisis until such time. • Too rapid withdrawal of exogenous steroid may precipitate adrenal crisis, or sudden stress may induce cortisol requirements in excess of the adrenal glands' ability to respond immediately. • In acute illness, a normal cortisol level may actually reflect adrenal insufficiency because the cortisol level should be quite elevated
Why? • Adrenal glands tend to get ‘lazy’ when steroids are regularly administered by mouth, I.M. injection or I.V. infusion. • To illustrate how quickly…Just 4 weeks of daily oral cortisone administration is sufficient to cause the adrenals to be slightly less responsive to stressors.
ADDISON DISEASE
Primary Adrenal Insufficiency= Addison’s Disease • The adrenal glands are damaged and cannot produce sufficient steroid • 80% of the time, damage is caused by an auto- immune response that destroys the adrenal cortex • Addison’s can affect both sexes and all age groups
ADRENAL GLAND (1o ) PITUITARY GLAND (2o ) Autoimmune idiopathic destruction •Adrenal cortex alone is affected •Shows atrophy with lymphocytic infiltration and abnormal T-cell action directed against it --20 to hypopituitarism Destruction of adrenal gland by TB Due to suppression of the HPA axis by exogenous steroids Destruction by amyloidosis and Hemochromatosis Decreased pituitary ACTH production. Hence with 20 adrenal insufficiency, no skin hyperpigmentation due to low ACTH and its precursor POMC. Infiltration of gland by secondary carcinoma, Hodgkin’s lymphoma or leukemia These cases are mostly cortisol deficient. Mineralocorticoid Prod remains normal. Hence Hyponatremia and hyperkalemia not common. Infarction of gland caused by meningococcal septicemia *WaterHouse Friderischen syndrome* Hemorrhage destruction from use of anticoagulants or lupus anticoagulant CAH and use of drugs which block steroid synthesis e.g ketoconazole,
Congenital Adrenal Hyperplasia • CAH is inherited (recessive gene, each parent contributes) – Diagnosed by newborn screening; prior to successful screening techniques most children died – Daily replacement oral hormones are required at a maintenance dose for LIFE – I.M. or I.V. hormones necessary for stressors (illness, surgery, fever, trauma, etc.) – 21-Hydroxylase Def. Most common. Deficient cortisol and aldosterone. Excess Androgens. Masucilinization and occasionally Na loss and AI.
Defect Deficient Hormones Excess Effects Desmolase deficiency ALL steroids Cholesterol Accumulation (lipoid hyperplasia) • AI • Disease is seldom compatible with life • All affected persons appear to be phenotypic females as there is lack of androgens in affected males. 3 Beta Hydroxysteroid DH Cortisol & Aldosterone DHEA • Affected patients are severely cortisol and aldosterone deficient • Salt losers • Males have hypospadias • Females mild virilism • Elevated 17 OHCS in urine 11 Beta Hydroxylase Cortisol and aldosterone Androgens 11-deoxycortisol • Masculinization • HTN from excess 11- deoxycorticosterone • Excretion of 11- deoxycortisol is raised 17 Hydroxylase Deficiency Androgens and Estrogens Cortisol Corticosterone 11-dexoycorticosterone HTN Hypokalemia Alkalosis Ambiguous genitalia in males Immature female 18-hydroxylase deficiency Aldosterone corticosterone Salt loss Elevated plasma renin No genital anomaly
Addison’s symptoms • This disease has a gradual onset and can be difficult to diagnose: – Chronic, worsening fatigue; weak, listless and dehydrated – Apathy + Mood disorders – Anorexia, Weight loss – Muscle weakness, Abdominal pain (unexplained) – Loss of appetite, Nausea/vomiting – Hypothermia – Low blood pressure, Pulse is thready, Postural Hypotension invariably present – Low blood sugar – Skin hyperpigmentation(Palmar, Buccal, Gingival, skinfolds, pressure points) – Salt-craving
Investigations & Findings For Adrenal Insufficiency • Low levels of plasma cortisol; diurnal variation Is lost. Plasma ACTH is elevated (1o AI especially). • A random morning cortisol determination is not sufficient to make a diagnosis in MILD Adrenal insufficiency since normal levels overlap with levels found in such pts. • Morning level of <3ug/dl is suggestive of AI • The finding of a plasma cortisol level < 20ug/dl in a PATIENT UNDER STRESS e.g. Hypotensive pt., pt. under intensive care, suggests Adrenal insufficiency. • .
Investigations & Findings For Adrenal Insufficiency • FBS: LOW • Electrolytes: initially normal, later on 1. Low Na+ 2. High K+ 3. Raised Blood urea 4. Low Hco3 (Na/k <5meq/l) FBC + ESR Anemia Leucopenia with lymphocytosis Increased eosinophil count Increased ESR ECG: Low voltage complexes Increased PR (?1o HB) and QT interval (?Hypocalcaemia)
Investigation and Findings • ACTH STIMULATION TEST Lack of increase in cortisol secretion by the adrenals to *tetracosactide/tetracosatrin/synacthen* SHORT SYNACTHEN (1/2 Hour screening test) LONG SYNACTHEN Measures serum cortisol response to 250ug of synacthen given I.M Do plasma cortisol before and 1/2 our after synacthen Test. Exclude Addison if 2nd cortisol >550nmol/l Done if short synacthen test response is flat. Helps distinguish also primary vs. secondary AI 1mg of synacthen given IM Normally: initial level of cortisol should be >200nmol/l Normal response: Serum cortisol should more than double in 1st hour. 45 min. Post synacthen: Plasma cortisol level ought to have risen to 600nmol/l or more 4 hours Post 1mg: conc. Of plasma cortisol ought to be >1000nmol/l Values less than above: In keeping with AI (Primary or secondary) Primary AI: NO RESPONSE @ all. Secondary AI: have higher values @ 24hrs compared to those @ 4hrs.
Investigations and Findings Contd. • Failure to increase plasma cortisol levels after administration of ACTH. • Circulating adrenal auto-antibodies(esp.21-Hydroxylase) in serum in those with auto-immune forms • 9AM ACTH levels increased (300ng/l). Low or undetectable levels of ACTH occurs in those due to pituitary disease • n/b Falsely elevated Cortisol levels in OCP use, Pregnancy • Insulin Hypoglycemia test (Insulin Tolerance test)  Used to detect 2o AI  Can be fatal in those with adrenal failure  0.1 to 0.15U/kg I.V  Cortisol level is determined during period of symptomatic hypoglycemia  Normal response occurs when the peak cortisol level is greater than 20ug/dl
AXR/CXR •Past TB: upper lung fibrosis or adrenal calcification Adrenal CT: •TB •Metastatic disease
Acute manifestation of Addison’s is called Addison Crisis • Severe vomiting/diarrhea • Dehydration • Hypotension • Sudden, severe pain in back, belly or legs • Loss of consciousness • Can be fatal
How Do I recognize it first time? Relevant clue? See the list below: •Unexplained shock, usually refractory to fluid and pressor resuscitation •Nausea, vomiting, abdominal or flank pain •Hyperthermia or hypothermia
Presentation of Adrenal Crisis • The patient may present with any illness or injury as the precipitating event. • A patient’s history of adrenal insufficiency warrants a careful assessment under specific protocols • Children may deteriorate into adrenal crisis from a simple fever, a gastrointestinal illness, a fall from a bicycle or some other injury. • A mild illness or injury can easily precipitate an adrenal crisis in any age group
Critical Clinical Presentation • The early indicators of an adrenal-crisis onset can be vague and non-specific. Some or all signs/symptoms may be present. • Infants: – Poor appetite – Vomiting/diarrhea – Lethargy/unresponsive • Unexplained hypoglycemia – Seizure/cardiovascular collapse/death
Critical Clinical Presentation (not all S&S may be present) Older Children/Adults • Vomiting • Hypotensive, often unresponsive to fluids/pressors – Pallor, gray, diaphoretic Hypoglycemia, often refractory to D50 • May have neurologic deficits – Headache/confusion/seizure – lethargy/unresponsive • Cardiovascular collapse • Death
• Clearly, the signs/symptoms of adrenal crisis are similar to other serious shock-type presentations. • For these patients, standard shock management requires supplementation with corticosteroid medication (Solu-Cortef or Solu-Medrol) • It is important to ANTICIPATE the evolution of an adrenal crisis and medicate appropriately under the specific protocols. • Do not wait until a full adrenal crisis has developed. Organ damage or death may result from delays.
Outline of Management • Quick, Brief History (Informant) • If AC suspected, treat before biochemical results • Meanwhile ABC started ASA patient is in ER. • IV Cortisol • IVF • Monitor blood glucose • Blood, urine, sputum for culture • Antibiotics
History • Prior steroid use: @least 20 mg daily of prednisone or its equivalent for at least 5 days within the past 12 months.. • Organisms associated with adrenal crisis (e.g., Haemophilus influenzae, Staphylococcus aureus, Streptococcus pneumonia, fungi) • Meningococcemia • Severe physiologic stress e.g. sepsis, trauma, Burns, surgery.
History •Anticoagulants, hemorrhagic diathesis •Azotemia •Newborn, complicated pregnancy •Adrenocorticotropin therapy, known primary or secondary adrenocortical insufficiency (medic-alert bracelet/necklace, OR by the child, parent or care provider verbally confirming a history of adrenal insufficiency). •AIDS •Invasive or infiltrative disorders •Tuberculosis •Topical steroids: Risk of adrenal crisis occurs when used over a large surface area for a prolonged duration, using occlusive dressings and a highly potent drug. •Inhaled steroids: Use of a high dose (>0.8mg/d) over a prolonged duration increases risk. Fluticasone may cause suppression at lower dose.
Remember! It is important to note that you are caring for a patient with multiple issues: 1. The precipitating event (a trauma/illness that may be a critical issue on its own) and 2. The evolution towards adrenal crisis, which will result in organ failure/death if not reversed.
Keep In Mind: • Administration of steroid medication should come as soon after appropriate A-B-C assessment and interventions as possible • Your emergency management priorities remain the same, with the addition of steroid administration. • Should I worry about CUSHINGOID?!
Lab Studies. • Serum chemistry: Abnormalities are present in as many as 56% of patients. Hyponatremia is common (although not diagnostic); hyperkalemia, metabolic acidosis, and hypoglycemia also may be present. However, the absence of laboratory abnormalities does not exclude the diagnosis of adrenal crisis. • 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. • CBC: Anemia (mild and nonspecific), lymphocytosis, and eosinophilia (highly suggestive) may be present. • Serum thyroid levels: Assess for autoimmune, infiltrative, or multiple endocrine disorders. • Cultures: Perform blood and other cultures as clinically indicated. Infection is a common cause of acute adrenal crisis.
Imaging Studies: CXR (TB, Histoplasmosis, malignant disease, sarcoid and lymphoma) Abdominal CT Scan: Visualize for hemorrhage, atrophy, infiltrative disorders and metastatic disease. Adrenal hemorrhage appears as hyperdense, bilaterally enlarged adrenal gland
BMAH • Bilateral massive adrenal Hemorrhage occurs (BMAH) occurs under severe physiologic stress e.g. 1.Myocardial infarction 2.Septic shock 3.Complicated pregnancy 4.Concomitant coagulopathy or thromboembolic disorders
Others Electrocardiography •Prolongation of the QT interval can induce ventricular arrhythmias. •Deep negative T waves have been described in acute adrenal crisis. Histology •Depends on the cause of the adrenal failure. • In primary adrenocortical failure, histologic evidence of infection, infiltrative disease, or other condition may be demonstrated. •Secondary adrenocortical insufficiency may cause atrophy of the adrenals or no histologic evidence at all, especially if due to exogenous steroid ingestion. •Appearance of bilateral adrenal hemorrhage may be striking, as if bags of blood are replacing the glands.
Rx. Administration of glucocorticoids (+/- Mineralocorticoid) in supraphysiologic or stress doses is the only definitive therapy. •Dexamethasone does not interfere with serum cortisol assay and, thus, may be the initial drug of choice. However, because dexamethasone has little mineralocorticoid activity, fluid and electrolyte replacement are essential. •A short ACTH stimulation test may be performed during resuscitation. Once complete, hydrocortisone 100 mg IV every 6 hours is the preferred treatment to provide mineralocorticoid support. •Delaying glucocorticoid replacement therapy while awaiting the results of the ACTH stimulation test is inappropriate and dangerous.
Rx Protocol Updates • Adults “For patients with confirmed adrenal insufficiency, give hydrocortisone 100 mg IV, IM or IO OR methylprednisolone 125 mg IV, IM or IO” • Pediatric “For patients with confirmed adrenal insufficiency, give hydrocortisone 2mg/kg to maximum 100 mg IV, IM or IO OR methylprednisolone 2mg/kg to maximum 125 mg IV, IM or IO”
Rx. • In addition to corticosteroid replacement, aggressive fluid replacement with 5% or 10% intravenous dextrose and saline solutions and treatment of hyperkalemia is mandatory. • Fludrocortisone, a mineralocorticoid, may also be given. Dose of 50-300mcg • A thorough search for a precipitating cause and administration of empiric antibiotics is indicated. Reversal of coagulopathy should be attempted with fresh frozen plasma. • Pressors (eg, dopamine, norepinephrine) may be necessary to combat hypotension.
DIFFERENTIAL Dx. SEPTIC SHOCK
Patient’s Own Medication • Many adrenally-insufficient patients carry an emergency Act-O-Vial of Solu-Cortef. • Solu-Cortef is included in the required medication formulary, making it acceptable for paramedics to administer the patient’s own medication to the patient or to assist the patient in administering his/her own Solu- Cortef.
Profile: Solu-Cortef Trade name: Solu-Cortef Generic name: hydrocortisone sodium succinate Class: corticosteroid, Pregnancy Class C Mechanism: acts to suppress inflammation; Replaces absent glucocorticoids, acts to suppress immune response
Solu-Cortef Contra-Indications: Do not use in the newly-born or any individual with a known hypersensitivity to Solu-Cortef Given IM or slow I.V bolus.
Additional Notes • This product contains the preservative Benzyl Alcohol in negligible amounts which is found in many medications. • The exception is the newly-born and/or significantly underweight neonates. In these groups there is insufficient data; this medication may cause ‘gasping syndrome’, therefore use in this age-range is not recommended for pre-hospital setting
Additional Notes • Solu-Cortef is the first choice for management of adrenal insufficiency/adrenal crisis. • The other approved medication, Solu-Medrol, is an acceptable alternative choice for specific management of adrenal insufficiency/adrenal crisis
Why Solu-Cortef > Solu-Medrol • Solucortef is preferred because essentially it is a replacement form of the missing hormone, cortisol. It has both a corticosteroid and a mineralocorticoid effect. • Solu-Medrol also has a corticosteroid effect, but does not provide the mineralocorticoid action. In an emergency setting, it is an acceptable alternative to Solu-Cortef.
Drug Class Summary Dexamethasone (Decadron, Baldex, Dexone) •Used as empiric treatment of shock in suspected adrenal crisis or insufficiency until serum cortisol levels are drawn. Hydrocortisone (Hydrocortone, Hydrocort, SoluCortef) • DOC because of mineralocorticoid activity and glucocorticoid effects. Cortisone (Cortone) •Oral DOC for patients with adrenocortical insufficiency. •Use in patients undergoing moderate stress surgery (eg, vascular bypass, total joint replacement) who can take PO postoperatively.
Fludrocortisone (Florinef) •Acts on renal distal tubules to enhance reabsorption of sodium. •Increases urinary excretion of both potassium and hydrogen ions. •The consequence of these 3 primary effects, together with similar actions on cation transport in other tissues, appears to account for the spectrum of physiological activities characteristic of mineralocorticoids. •Used in adrenal insufficiency. Produces marked sodium retention and increased urinary potassium excretion. Methylprednisolone (Medrol, Solu-Medrol, Depo-Medrol) •Usually third-line DOC for adrenal crisis because of lack of mineralocorticoid activity. •Consider use in patients with fluid overload, edema, or hypokalemia.
Complications • Immunosuppression • Hypertension • Salt retention • Hypokalemia • Weight gain • Delayed wound healing • Hyperglycemia • Metabolic alkalosis
Prognosis • Prognosis is the same as for patients without adrenal insufficiency if the condition is diagnosed and treated appropriately.
Resources • CARES Foundation (www.caresfoundation.org) • Review of Medical Physiology 17th edition. Ganong, William F., Appleton & Lange • Prescribing Information, Solu-Cortef, Sept 2009 Pharmacia & Upjohn (division of Pfizer) • Prescribing information, Solu-Medrol, 2009, Pfizer • MA Statewide Treatment Protocols, version 8.03 • “Management of Adrenal Crisis, How Should Glucocorticoids Be Administered?” Stanhope, et al, Journal of Pediatric Endocrinology Vol 16, Issue 8 pp 99-100 • “Mortality in Canadian Children with Growth Hormone Deficiency Receiving GH Therapy 1967-1992” Taback, et al, Journal of Clinical Endocrinology & Metabolism Vol 81, #5 pp 1693-1696 • Adrenal Crisis: Lisa Kirkland, MD, FACP, FCCM, MSHA;

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Addisonian 1

  • 1.
  • 2.
    Table of Contents •Objective • Overview • Epidemiology • Anatomy & Physiology • Addison’s Disease & Adrenal Insufficiency • Addisonian Crisis (Presentation, Mgt.) • Medication Profiles • Complications & Prognosis • Resources
  • 3.
    OBJECTIVE • To beable to promptly identify Addisonian Crisis and initiate appropraite measures to save the patient’s life. • It presents masked like many other ailments – making prompt identification, life saving.
  • 4.
    • Do notconfuse acute adrenal crisis with Addison disease. • In 1885, Thomas Addison described a syndrome of long term adrenal insufficiency that develops over months to years with: o weakness, o Fatigue, o Anorexia, o Weight loss and hyperpigmentation as the primary symptoms. • In contrast, an acute adrenal crisis can manifest with vomiting, abdominal pain and hypovolemic shock. Overview
  • 5.
    Overview • Hahner etal investigated the frequency and causes of, as well as the risk factors for, adrenal crisis in patients with chronic adrenal insufficiency. • Using a disease-specific questionnaire, the authors analyzed data from 444 patients, including 254 with primary adrenal insufficiency and 190 with secondary adrenal insufficiency. • At least 1 adrenal crisis was reported by 42% of patients, including 47% of those with primary adrenal insufficiency and 35% of patients with the secondary condition. • GI infection and fever were the most common precipitating causes of crisis. • Identified risk factors for adrenal crisis were, for patients with primary adrenal insufficiency, concomitant nonendocrine disease and for patients with secondary adrenal insufficiency, female sex and diabetes insipidus
  • 6.
    Lets Paint anOverview Picture • “Anyone on Prednisolone for long enough to suppress the PA axis or who has overwhelming sepsis, or has metastatic cancer may suddenly develop adrenal insufficiency with deadly hypovolemic shock”
  • 7.
    Epidemiology • “Addison's diseasewas frequently consequent upon affectation of the glands by tuberculosis. Pulmonary Tuberculosis (PTB) is still very common in Nigeria but no report on the functional status of the adrenal cortex in patients with PTB in Nigeria exists” • “Adrenocortical insufficiency, mostly at the subclinical level, is common in persons with PTB infection, occurring in about 23% of patients. We therefore recommend that basal cortisol levels should not be used to detect adrenocortical insufficiency; rather stimulation tests should be used to exclude or confirm suspected adrenocortical insufficiency in patients with PTB”. Odeniyi I.A et al Mar.2011
  • 8.
    • Studies ofcritically ill patients with septic shock demonstrate a de novo (excluding patients with known adrenal insufficiency or patients on glucocorticoid therapy) incidence ranging from 19-54%. • Annane et al's landmark 2002 study found a very high rate, ie, 76% of all enrolled patients with septic shock • In a study of 2000 consecutive general hospital autopsies, only 22 (1.1%) revealed bilateral adrenal hemorrhage; however, as many as 15% of patients dying in shock have been demonstrated to have BMAH. • No description regarding racial data, sexual predilection, or age is available in the literature.
  • 9.
    • The prevalenceof primary adrenal insufficiency (Addison's disease) has been reported to be 39 to 60 per million population. May M. et al • Most cases in Nigeria due to TB & HIV Mortality/Morbidity • In the absence of bilateral adrenal hemorrhage, the survival rate of patients with acute adrenal crisis that is diagnosed promptly and treated appropriately approaches that of patients without acute adrenal crisis with similar severity of illness. • Patients who developed BMAH before the availability of hormonal testing or computed tomography (CT) scanning rarely survived. In one series, patients who were diagnosed using CT scanning had an 85% rate of survival. Because the true incidence of adrenal crisis and BMAH are unknown, the actual mortality rate also is unknown.
  • 10.
    Adrenal Anatomy • Theadrenals are endocrine organs that sit on top of each kidney
  • 11.
    Anatomy & Physiology •Each adrenal gland has two parts – Adrenal Medulla (inner area) •Secretes catecholamines which mediate stress response (help prepare a person for emergencies). »Norepinephrine »Epinephrine »Dopamine
  • 12.
    • The adrenalmedulla comprises approximately 28% of the total adrenal mass. • Although we think of the ‘stress’ catecholamines as being necessary for ‘fight or flight’, they are actually circulating in our bodies, in minute quantities, at all times, and act in concert with other hormones and the vagus nerve to support daily activities.
  • 13.
    • Adrenal Cortex(outer area, encloses Adrenal Medulla) – Secretes steroid hormones • Glucocorticoids (Cortisol): exert a widespread effect on metabolism of carbohydrates and proteins • Mineralocorticoids (Aldosterone, 11- Deoxycortocosterone): are essential to maintain sodium and fluid balance • sex hormones (Androgens: DHEA) secondary source
  • 14.
    Interestingly… • A functioningadrenal cortex (or the steady availability of replacement hormone) is essential for survival. • A person can survive without a functioning adrenal medulla.
  • 15.
    Survive without myMedulla?! • This seems counter-intuitive doesn’t it? You would think we would need epinephrine/norepinephrine as a critical component to survive. • Research has shown that even after the adrenal medulla has been destroyed by radiation or removal, small amounts of those catecholamines are found in the body. • The source is unknown, however the amount is sufficient for survival.
  • 16.
    The Essential Steroids •Primary glucocorticoid: – Cortisol (a.k.a. hydrocortisone) • Primary mineralocorticoid: – Aldosterone “These steroids, especially cortisol, are essential for life.”
  • 20.
    Cortisol • A glucocorticoid •Frequently referred to as the ‘stress hormone’ – Released in response to physiological or psychological stress •Examples: exercise, illness, injury, starvation, extreme dehydration, electrolyte imbalance, emotional stress, surgery, etc.
  • 21.
    Cortisol • When cortisolis not produced or released by the adrenal glands, humans are unable to respond appropriately to physiologic stressors. • Rapid deterioration resulting in organ damage and shock/coma/death can occur, especially in children.
  • 22.
  • 23.
    Why we needcortisol • Cortisol has a necessary effect on the vascular system (blood vessels, heart) and liver during episodes of physiologic stress
  • 24.
    Vascular Reactivity • Inadrenally-insufficient individuals experiencing a physiologic stressor, the vascular smooth muscle will become non-responsive to the effects of norepinephrine and epinephrine, resulting in vasodilation and capillary ‘leaking’. • The patient may be unable to maintain an adequate blood pressure • The blood vessels cannot respond to the stress and will eventually collapse
  • 25.
    • This isan important reason why adrenally- insufficient people must receive emergency cortisol as soon as possible after a serious stress event such as trauma or a period of nausea/vomiting. • The vasculature becomes unable to constrict to make effective use of circulating body volume. • Replacement IV fluid challenges often have poor effect in the adrenally-insufficient patient until cortisol is administered.
  • 26.
    Energy Metabolism • Inadrenally-insufficient individuals under increased physiologic stress, the liver is unable to metabolize carbohydrates properly, which may result in profoundly low blood sugar that is difficult to reverse without administration of replacement cortisol • Impaired gluconeogenesis, lipolysis and proteolysis
  • 27.
    • The speedat which patient deterioration occurs is difficult to predict and is related to the underlying stressor, patient age, general health, etc. • Young children can be at high risk for rapid deterioration, even when experiencing a ‘simple’ gastrointestinal disorder.
  • 28.
    • The steroidhormones, especially cortisol, are mediated by the hypothalamic-pituitary- adrenal (HPA) axis. • The onset of stress as well as our sleep/wake cycles influences the activity of the HPA axis.
  • 29.
    Endocrinologist Testimony… • “…Inadrenal insufficiency, because of the inability to produce glucocorticoids and often mineralocorticoids from the adrenal glands, there is a risk of life-threatening hyponatremia, hyperkalemia, hypoglycemia, seizures and cardiovascular collapse, in particular at times of physiologic stress to the body, such as in injury or illness…” • Support letter, Dr. Christine Leudke, Boston Children’s Hospital 12/12/2009
  • 30.
    Who has adrenalinsufficiency? • Anyone whose adrenal glands have stopped producing steroids as a result of: – Long-term administration of steroids – Pituitary gland problems, including growth hormone deficiency, tumor, etc. – Trauma, including head trauma that affects pituitary – Loss of circulation to adrenals/Adrenal Hemorrhage/removal of tissue – Auto-immune disease – Surgical Removal(For Cushing's) + Inadequate Replacement Therapy. – Cancer and other diseases (TB and HIV may cause) • There is also an inherited form of adrenal insufficiency (CAH) • Acute Vs. Chronic
  • 31.
    CAUSES CONTD. • Rapidwithdrawal of long-term steroid therapy. • Ketoconazole, Etomidate, Metyrapone • Phenytoin (Pan-endocrine Disturbances: DI, Hyperglycemia, glycosuria osteomalacia). • Rifampin, Aminogluthemide • Mitotane • Septic shock
  • 32.
    Parent testimony… • “…People without adrenal insufficiencies naturally produce up to ten times the normal amount of cortisol during times of physical stress. If an unaffected person is unresponsive, goes into cardiac arrest or is vomiting, you can treat the shock, heart, or dehydration and help them. For James, however, immediate, appropriate emergency response is vital. I have watched James, as a fever quickly spiked, go from alert and playful to grayish-white and lethargic, in a matter of minutes. It is scary. I have seen how a stress dose of Cortef quickly brought him back to where I could then manage his illness with the “common” treatment of Motrin and fluids…” • Oral Testimony, Alex Dubois, December 12, 2009
  • 33.
    Adrenal Insufficiency: TakeNote of this group of Pxts. • Can occur from long-term administration of steroids (over-rides body’s own steroid production) Examples: – Organ transplant patients – Long-term COPD – Long-term Asthma – Severe arthritis – Certain cancer treatments
  • 34.
    Organ Transplant Patients •These individuals must take immunosuppressive medications (usually steroids) DAILY for life. • Their own adrenal glands stop producing cortisol because of external source of steroid.
  • 35.
    Long-term Asthma andCOPD • These individuals are at high risk of adrenal crisis from illness or trauma • Keep in mind that many children and teens with severe asthma take steroid medication every day and may be at significant risk of adrenal crisis. • A severely asthmatic teen may have been started on a steroid 10+ years ago
  • 36.
    • In somesituations steroids are administered long-term and then tapered off. Often it can take up to a year for a person’s own adrenal glands to become fully functioning again. • These patients remain at risk of adrenal crisis until such time. • Too rapid withdrawal of exogenous steroid may precipitate adrenal crisis, or sudden stress may induce cortisol requirements in excess of the adrenal glands' ability to respond immediately. • In acute illness, a normal cortisol level may actually reflect adrenal insufficiency because the cortisol level should be quite elevated
  • 37.
    Why? • Adrenal glandstend to get ‘lazy’ when steroids are regularly administered by mouth, I.M. injection or I.V. infusion. • To illustrate how quickly…Just 4 weeks of daily oral cortisone administration is sufficient to cause the adrenals to be slightly less responsive to stressors.
  • 38.
  • 39.
    Primary Adrenal Insufficiency= Addison’sDisease • The adrenal glands are damaged and cannot produce sufficient steroid • 80% of the time, damage is caused by an auto- immune response that destroys the adrenal cortex • Addison’s can affect both sexes and all age groups
  • 40.
    ADRENAL GLAND (1o )PITUITARY GLAND (2o ) Autoimmune idiopathic destruction •Adrenal cortex alone is affected •Shows atrophy with lymphocytic infiltration and abnormal T-cell action directed against it --20 to hypopituitarism Destruction of adrenal gland by TB Due to suppression of the HPA axis by exogenous steroids Destruction by amyloidosis and Hemochromatosis Decreased pituitary ACTH production. Hence with 20 adrenal insufficiency, no skin hyperpigmentation due to low ACTH and its precursor POMC. Infiltration of gland by secondary carcinoma, Hodgkin’s lymphoma or leukemia These cases are mostly cortisol deficient. Mineralocorticoid Prod remains normal. Hence Hyponatremia and hyperkalemia not common. Infarction of gland caused by meningococcal septicemia *WaterHouse Friderischen syndrome* Hemorrhage destruction from use of anticoagulants or lupus anticoagulant CAH and use of drugs which block steroid synthesis e.g ketoconazole,
  • 41.
    Congenital Adrenal Hyperplasia •CAH is inherited (recessive gene, each parent contributes) – Diagnosed by newborn screening; prior to successful screening techniques most children died – Daily replacement oral hormones are required at a maintenance dose for LIFE – I.M. or I.V. hormones necessary for stressors (illness, surgery, fever, trauma, etc.) – 21-Hydroxylase Def. Most common. Deficient cortisol and aldosterone. Excess Androgens. Masucilinization and occasionally Na loss and AI.
  • 44.
    Defect Deficient Hormones Excess Effects Desmolasedeficiency ALL steroids Cholesterol Accumulation (lipoid hyperplasia) • AI • Disease is seldom compatible with life • All affected persons appear to be phenotypic females as there is lack of androgens in affected males. 3 Beta Hydroxysteroid DH Cortisol & Aldosterone DHEA • Affected patients are severely cortisol and aldosterone deficient • Salt losers • Males have hypospadias • Females mild virilism • Elevated 17 OHCS in urine 11 Beta Hydroxylase Cortisol and aldosterone Androgens 11-deoxycortisol • Masculinization • HTN from excess 11- deoxycorticosterone • Excretion of 11- deoxycortisol is raised 17 Hydroxylase Deficiency Androgens and Estrogens Cortisol Corticosterone 11-dexoycorticosterone HTN Hypokalemia Alkalosis Ambiguous genitalia in males Immature female 18-hydroxylase deficiency Aldosterone corticosterone Salt loss Elevated plasma renin No genital anomaly
  • 45.
    Addison’s symptoms • Thisdisease has a gradual onset and can be difficult to diagnose: – Chronic, worsening fatigue; weak, listless and dehydrated – Apathy + Mood disorders – Anorexia, Weight loss – Muscle weakness, Abdominal pain (unexplained) – Loss of appetite, Nausea/vomiting – Hypothermia – Low blood pressure, Pulse is thready, Postural Hypotension invariably present – Low blood sugar – Skin hyperpigmentation(Palmar, Buccal, Gingival, skinfolds, pressure points) – Salt-craving
  • 46.
    Investigations & FindingsFor Adrenal Insufficiency • Low levels of plasma cortisol; diurnal variation Is lost. Plasma ACTH is elevated (1o AI especially). • A random morning cortisol determination is not sufficient to make a diagnosis in MILD Adrenal insufficiency since normal levels overlap with levels found in such pts. • Morning level of <3ug/dl is suggestive of AI • The finding of a plasma cortisol level < 20ug/dl in a PATIENT UNDER STRESS e.g. Hypotensive pt., pt. under intensive care, suggests Adrenal insufficiency. • .
  • 47.
    Investigations & FindingsFor Adrenal Insufficiency • FBS: LOW • Electrolytes: initially normal, later on 1. Low Na+ 2. High K+ 3. Raised Blood urea 4. Low Hco3 (Na/k <5meq/l) FBC + ESR Anemia Leucopenia with lymphocytosis Increased eosinophil count Increased ESR ECG: Low voltage complexes Increased PR (?1o HB) and QT interval (?Hypocalcaemia)
  • 48.
    Investigation and Findings •ACTH STIMULATION TEST Lack of increase in cortisol secretion by the adrenals to *tetracosactide/tetracosatrin/synacthen* SHORT SYNACTHEN (1/2 Hour screening test) LONG SYNACTHEN Measures serum cortisol response to 250ug of synacthen given I.M Do plasma cortisol before and 1/2 our after synacthen Test. Exclude Addison if 2nd cortisol >550nmol/l Done if short synacthen test response is flat. Helps distinguish also primary vs. secondary AI 1mg of synacthen given IM Normally: initial level of cortisol should be >200nmol/l Normal response: Serum cortisol should more than double in 1st hour. 45 min. Post synacthen: Plasma cortisol level ought to have risen to 600nmol/l or more 4 hours Post 1mg: conc. Of plasma cortisol ought to be >1000nmol/l Values less than above: In keeping with AI (Primary or secondary) Primary AI: NO RESPONSE @ all. Secondary AI: have higher values @ 24hrs compared to those @ 4hrs.
  • 49.
    Investigations and FindingsContd. • Failure to increase plasma cortisol levels after administration of ACTH. • Circulating adrenal auto-antibodies(esp.21-Hydroxylase) in serum in those with auto-immune forms • 9AM ACTH levels increased (300ng/l). Low or undetectable levels of ACTH occurs in those due to pituitary disease • n/b Falsely elevated Cortisol levels in OCP use, Pregnancy • Insulin Hypoglycemia test (Insulin Tolerance test)  Used to detect 2o AI  Can be fatal in those with adrenal failure  0.1 to 0.15U/kg I.V  Cortisol level is determined during period of symptomatic hypoglycemia  Normal response occurs when the peak cortisol level is greater than 20ug/dl
  • 50.
    AXR/CXR •Past TB: upperlung fibrosis or adrenal calcification Adrenal CT: •TB •Metastatic disease
  • 51.
    Acute manifestation ofAddison’s is called Addison Crisis • Severe vomiting/diarrhea • Dehydration • Hypotension • Sudden, severe pain in back, belly or legs • Loss of consciousness • Can be fatal
  • 52.
    How Do Irecognize it first time? Relevant clue? See the list below: •Unexplained shock, usually refractory to fluid and pressor resuscitation •Nausea, vomiting, abdominal or flank pain •Hyperthermia or hypothermia
  • 53.
    Presentation of AdrenalCrisis • The patient may present with any illness or injury as the precipitating event. • A patient’s history of adrenal insufficiency warrants a careful assessment under specific protocols • Children may deteriorate into adrenal crisis from a simple fever, a gastrointestinal illness, a fall from a bicycle or some other injury. • A mild illness or injury can easily precipitate an adrenal crisis in any age group
  • 54.
    Critical Clinical Presentation •The early indicators of an adrenal-crisis onset can be vague and non-specific. Some or all signs/symptoms may be present. • Infants: – Poor appetite – Vomiting/diarrhea – Lethargy/unresponsive • Unexplained hypoglycemia – Seizure/cardiovascular collapse/death
  • 55.
    Critical Clinical Presentation (notall S&S may be present) Older Children/Adults • Vomiting • Hypotensive, often unresponsive to fluids/pressors – Pallor, gray, diaphoretic Hypoglycemia, often refractory to D50 • May have neurologic deficits – Headache/confusion/seizure – lethargy/unresponsive • Cardiovascular collapse • Death
  • 56.
    • Clearly, thesigns/symptoms of adrenal crisis are similar to other serious shock-type presentations. • For these patients, standard shock management requires supplementation with corticosteroid medication (Solu-Cortef or Solu-Medrol) • It is important to ANTICIPATE the evolution of an adrenal crisis and medicate appropriately under the specific protocols. • Do not wait until a full adrenal crisis has developed. Organ damage or death may result from delays.
  • 57.
    Outline of Management •Quick, Brief History (Informant) • If AC suspected, treat before biochemical results • Meanwhile ABC started ASA patient is in ER. • IV Cortisol • IVF • Monitor blood glucose • Blood, urine, sputum for culture • Antibiotics
  • 58.
    History • Prior steroiduse: @least 20 mg daily of prednisone or its equivalent for at least 5 days within the past 12 months.. • Organisms associated with adrenal crisis (e.g., Haemophilus influenzae, Staphylococcus aureus, Streptococcus pneumonia, fungi) • Meningococcemia • Severe physiologic stress e.g. sepsis, trauma, Burns, surgery.
  • 59.
    History •Anticoagulants, hemorrhagic diathesis •Azotemia •Newborn,complicated pregnancy •Adrenocorticotropin therapy, known primary or secondary adrenocortical insufficiency (medic-alert bracelet/necklace, OR by the child, parent or care provider verbally confirming a history of adrenal insufficiency). •AIDS •Invasive or infiltrative disorders •Tuberculosis •Topical steroids: Risk of adrenal crisis occurs when used over a large surface area for a prolonged duration, using occlusive dressings and a highly potent drug. •Inhaled steroids: Use of a high dose (>0.8mg/d) over a prolonged duration increases risk. Fluticasone may cause suppression at lower dose.
  • 60.
    Remember! It is importantto note that you are caring for a patient with multiple issues: 1. The precipitating event (a trauma/illness that may be a critical issue on its own) and 2. The evolution towards adrenal crisis, which will result in organ failure/death if not reversed.
  • 61.
    Keep In Mind: •Administration of steroid medication should come as soon after appropriate A-B-C assessment and interventions as possible • Your emergency management priorities remain the same, with the addition of steroid administration. • Should I worry about CUSHINGOID?!
  • 62.
    Lab Studies. • Serumchemistry: Abnormalities are present in as many as 56% of patients. Hyponatremia is common (although not diagnostic); hyperkalemia, metabolic acidosis, and hypoglycemia also may be present. However, the absence of laboratory abnormalities does not exclude the diagnosis of adrenal crisis. • 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. • CBC: Anemia (mild and nonspecific), lymphocytosis, and eosinophilia (highly suggestive) may be present. • Serum thyroid levels: Assess for autoimmune, infiltrative, or multiple endocrine disorders. • Cultures: Perform blood and other cultures as clinically indicated. Infection is a common cause of acute adrenal crisis.
  • 63.
    Imaging Studies: CXR(TB, Histoplasmosis, malignant disease, sarcoid and lymphoma) Abdominal CT Scan: Visualize for hemorrhage, atrophy, infiltrative disorders and metastatic disease. Adrenal hemorrhage appears as hyperdense, bilaterally enlarged adrenal gland
  • 64.
    BMAH • Bilateral massiveadrenal Hemorrhage occurs (BMAH) occurs under severe physiologic stress e.g. 1.Myocardial infarction 2.Septic shock 3.Complicated pregnancy 4.Concomitant coagulopathy or thromboembolic disorders
  • 65.
    Others Electrocardiography •Prolongation of theQT interval can induce ventricular arrhythmias. •Deep negative T waves have been described in acute adrenal crisis. Histology •Depends on the cause of the adrenal failure. • In primary adrenocortical failure, histologic evidence of infection, infiltrative disease, or other condition may be demonstrated. •Secondary adrenocortical insufficiency may cause atrophy of the adrenals or no histologic evidence at all, especially if due to exogenous steroid ingestion. •Appearance of bilateral adrenal hemorrhage may be striking, as if bags of blood are replacing the glands.
  • 66.
    Rx. Administration of glucocorticoids(+/- Mineralocorticoid) in supraphysiologic or stress doses is the only definitive therapy. •Dexamethasone does not interfere with serum cortisol assay and, thus, may be the initial drug of choice. However, because dexamethasone has little mineralocorticoid activity, fluid and electrolyte replacement are essential. •A short ACTH stimulation test may be performed during resuscitation. Once complete, hydrocortisone 100 mg IV every 6 hours is the preferred treatment to provide mineralocorticoid support. •Delaying glucocorticoid replacement therapy while awaiting the results of the ACTH stimulation test is inappropriate and dangerous.
  • 67.
    Rx Protocol Updates •Adults “For patients with confirmed adrenal insufficiency, give hydrocortisone 100 mg IV, IM or IO OR methylprednisolone 125 mg IV, IM or IO” • Pediatric “For patients with confirmed adrenal insufficiency, give hydrocortisone 2mg/kg to maximum 100 mg IV, IM or IO OR methylprednisolone 2mg/kg to maximum 125 mg IV, IM or IO”
  • 68.
    Rx. • In additionto corticosteroid replacement, aggressive fluid replacement with 5% or 10% intravenous dextrose and saline solutions and treatment of hyperkalemia is mandatory. • Fludrocortisone, a mineralocorticoid, may also be given. Dose of 50-300mcg • A thorough search for a precipitating cause and administration of empiric antibiotics is indicated. Reversal of coagulopathy should be attempted with fresh frozen plasma. • Pressors (eg, dopamine, norepinephrine) may be necessary to combat hypotension.
  • 69.
  • 70.
    Patient’s Own Medication •Many adrenally-insufficient patients carry an emergency Act-O-Vial of Solu-Cortef. • Solu-Cortef is included in the required medication formulary, making it acceptable for paramedics to administer the patient’s own medication to the patient or to assist the patient in administering his/her own Solu- Cortef.
  • 71.
    Profile: Solu-Cortef Trade name:Solu-Cortef Generic name: hydrocortisone sodium succinate Class: corticosteroid, Pregnancy Class C Mechanism: acts to suppress inflammation; Replaces absent glucocorticoids, acts to suppress immune response
  • 72.
    Solu-Cortef Contra-Indications: Do notuse in the newly-born or any individual with a known hypersensitivity to Solu-Cortef Given IM or slow I.V bolus.
  • 73.
    Additional Notes • Thisproduct contains the preservative Benzyl Alcohol in negligible amounts which is found in many medications. • The exception is the newly-born and/or significantly underweight neonates. In these groups there is insufficient data; this medication may cause ‘gasping syndrome’, therefore use in this age-range is not recommended for pre-hospital setting
  • 74.
    Additional Notes • Solu-Cortefis the first choice for management of adrenal insufficiency/adrenal crisis. • The other approved medication, Solu-Medrol, is an acceptable alternative choice for specific management of adrenal insufficiency/adrenal crisis
  • 75.
    Why Solu-Cortef >Solu-Medrol • Solucortef is preferred because essentially it is a replacement form of the missing hormone, cortisol. It has both a corticosteroid and a mineralocorticoid effect. • Solu-Medrol also has a corticosteroid effect, but does not provide the mineralocorticoid action. In an emergency setting, it is an acceptable alternative to Solu-Cortef.
  • 76.
    Drug Class Summary Dexamethasone(Decadron, Baldex, Dexone) •Used as empiric treatment of shock in suspected adrenal crisis or insufficiency until serum cortisol levels are drawn. Hydrocortisone (Hydrocortone, Hydrocort, SoluCortef) • DOC because of mineralocorticoid activity and glucocorticoid effects. Cortisone (Cortone) •Oral DOC for patients with adrenocortical insufficiency. •Use in patients undergoing moderate stress surgery (eg, vascular bypass, total joint replacement) who can take PO postoperatively.
  • 77.
    Fludrocortisone (Florinef) •Acts onrenal distal tubules to enhance reabsorption of sodium. •Increases urinary excretion of both potassium and hydrogen ions. •The consequence of these 3 primary effects, together with similar actions on cation transport in other tissues, appears to account for the spectrum of physiological activities characteristic of mineralocorticoids. •Used in adrenal insufficiency. Produces marked sodium retention and increased urinary potassium excretion. Methylprednisolone (Medrol, Solu-Medrol, Depo-Medrol) •Usually third-line DOC for adrenal crisis because of lack of mineralocorticoid activity. •Consider use in patients with fluid overload, edema, or hypokalemia.
  • 78.
    Complications • Immunosuppression • Hypertension •Salt retention • Hypokalemia • Weight gain • Delayed wound healing • Hyperglycemia • Metabolic alkalosis
  • 79.
    Prognosis • Prognosis isthe same as for patients without adrenal insufficiency if the condition is diagnosed and treated appropriately.
  • 80.
    Resources • CARES Foundation(www.caresfoundation.org) • Review of Medical Physiology 17th edition. Ganong, William F., Appleton & Lange • Prescribing Information, Solu-Cortef, Sept 2009 Pharmacia & Upjohn (division of Pfizer) • Prescribing information, Solu-Medrol, 2009, Pfizer • MA Statewide Treatment Protocols, version 8.03 • “Management of Adrenal Crisis, How Should Glucocorticoids Be Administered?” Stanhope, et al, Journal of Pediatric Endocrinology Vol 16, Issue 8 pp 99-100 • “Mortality in Canadian Children with Growth Hormone Deficiency Receiving GH Therapy 1967-1992” Taback, et al, Journal of Clinical Endocrinology & Metabolism Vol 81, #5 pp 1693-1696 • Adrenal Crisis: Lisa Kirkland, MD, FACP, FCCM, MSHA;