Endocrine Emergencies: Adrenal Crisis

Kina M. Merwin McDougallEndocrinology PGY4Western University

EMS called for 21 ♀ w/ confusion, fever, SOB and abdominal pain. Cough and malaise for several days prior.

PHx: Fetal Alcohol Syndrome (group home) Asthma BMI 34

Meds: Salbutamol prn

Case History

Febrile: 38.9 Hypotension: 78/50 Tachycardia: 125 Tachypnea: 35 Hypoxic: O2 Sat 87% Disoriented and very anxious

Acetaminophen given EMS bolused 2L NS Combivent Nebs & 15L O2 by NRB

Case: EMS

Vitals: T 38.8, BP 84/52, HR 125, Sat 89%, BG 7 Patient becoming combative & taking O2 off

Intubation Midazolam & Fentanyl (large doses required) SBP 60: peripheral dopamine & RL under pressure

Central line inserted & norepinephrine added CXR: bilateral lower lobe infiltrates Ceftriaxone, Levofloxacin & Tamiflu started

Case: In the Emergency Room

21 ♀ with pneumonia & septic shock Intubated and on pressors with SBP 90 Fighting ventilator on high-dose

midazolam and fentanyl infusions so propofol added

Initial labs: ABG 7.24|51|72|20 Lactate 3.7

Case: ICU Consult

133 102 7.13.2 21 135

14.1 102 248 Acute respiratory acidosis & metabolic acidosis: respiratory

fatigue & sepsis

Brought to ICU immediately On stretcher-bed transfer, sheets noted

to be wet and bloody Rapid physical exam found a tense

abdomen and vaginal bleeding Nurse notes that abdomen is

alternating between tense and soft

“Obstetric 25 to MSICU!”

Case: ICU Overnight

45 minutes later ~ 24wk boy delivered NICU Our patient:

Ongoing hypoxia CXR white-out ARDS PEEP ladder initiated

Ongoing hypotension norepi & dopamine infusions Resolving hemorrhage after 2u PRBC & oxytocin

Group home collateral: 19 yo boyfriend lives in same group home Pregnancy unknown but boyfriend’s mother offering

adoption for the baby Another group home resident known swab +ve for

H1N1

Case: ICU Overnight

Case: ICU Morning Rounds Nurse reports:

Insulin infusion never initiated D5W up-titrated to 175cc/hr for BG 4 to 6 BG now 3.7 (last ABG: glucose 3.5)

Attending says You’re going into endocrinology; what

should we do about her blood sugar?▪ Amp of D50 BG 4.3▪ Change maintenance fluid to D10W

Case: Hypoglycemia

DDx in ill patient: Medications:

▪ Insulin or oral glycemic medications▪ Quinolones

Critical illness Cortisol deficiency Insulinoma or nonislet cell tumour

Severe Sepsis vs Adrenal Crisis+/- Levofloxacin

✗

✗

?✓✓

Objectives

1. Define adrenal crisis 2. Discuss epidemiology & frequency3. Review the causes of adrenal crisis    4. Examine the pathophysiology5. Outline how to make the diagnosis6. Delineate management7. Summarize complications 

What is adrenal crisis? Acute adrenal insufficiency/failure Life-threatening condition due to insufficient

adrenal (stress) hormones to mount an appropriate response to stresses like an

infection

Adrenal Crisis

Adrenal Anatomy

Mineralocorticoids

Glucocorticoids

Androgens

Catecholamines

Adrenal Function

McGraw Hill

Zona glomerulosa Zona fasciculata Zona reticularisCHOLESTEROL

17 -a Hydroxy-pregnenolone

Dehydroepi-androsterone DHEA

Pregnenolone

17 -a Hydroxy-progesterone AndrostenedioneProgesterone

11-DeoxycortisolDeoxycorticosterone

CortisolCorticosterone

Aldosterone

Zona glomerulosa Zona fasciculata Zona reticularisCHOLESTEROL

17 -a Hydroxy-pregnenolone

Dehydroepi-androsterone DHEA

Pregnenolone

17 -a Hydroxy-progesterone AndrostenedioneProgesterone

11-DeoxycortisolDeoxycorticosterone

CortisolCorticosterone

Aldosterone

11β Hydroxylase

21 Hydroxylase

17α - hydroxylase

Aldo Synthase

100-150 mcg/day

C: 10-20 mg/dayA: > 20 mg/day

Hypothalamic-Pituitary-Adrenal Axis

Hypothalamus

Anterior Pituitary

Adrenal Cortex

CRH

+

ACTH

+

Systemic

Effects

Cortisol

_

_

+

Circadian RegulationStress: physical, emotional, illness

Systemic Glucocorticoid Effects

Epidemiology of Adrenal Crisis

Rare: episode reported by 42% of chronic Chronic Primary Adrenal Insufficiency:

Prevalence: 93-144 cases/million Incidence: 4.4-6 new cases/million/year ♀ > ♂ but near 1:1 Any age: most frequently 30-50years

Chronic Central Adrenal Insufficiency: Prevalence: 150-280 cases/million ♀ > ♂ Any age: most frequently 50’s

Etiology of Adrenal Crisis

1. Steroid withdrawal Exogenous formulations Adrenalectomy Drug-induced: ketoconazole, etomidate, rifampin, anti-epileptics

2. Acute exacerbation of chronic insufficiency Sepsis Surgical stress

3. Pituitary trauma Head injury Surgical intervention or irradiation Hemorrhage or infarct Infection/Infiltration

4. Bilateral adrenal hemorrhage Antiphospholipid Antibody Syndrome Anticoagulants Malignancy Septic Waterhouse-Friderichsen Syndrome (menigiococcemia: Neisseria)

Primary Adrenal Insufficiency: Adult Etiology

Autoimmune 80% of cases in developed countries 60% associated with autoimmune

polyendocrinopathy syndromesTuberculosis

Leading cause historically Still top cause in endemic areas

Primary Adrenal Insufficiency: Etiology

Autoimmune Infection:

tuberculosis, fungal, viral Iatrogenic

predominately via cytochrome P450 mechanisms Hemorrhage Metastatic malignancy:

lung, stomach, breast, colon Infiltration:

lymphoma, amyloidosis, hemochromatosis Genetic:

Congenital adrenal hyperplasia, Adrenoleukodystrophy, Familial glucocorticoid deficiency or ACTH-insensitivity

Central Adrenal Insufficiency: Etiology

Secondary (Pituitary) Trauma & Space-occupying Lesions

▪ Tumors▪ Surgery & Irradiation▪ Infection & Infiltration▪ Apoplexy & Sheehan’s Syndrome

Genetic▪ Prader-Willi Syndrome▪ Mutations of transcription factors involved in pituitary

development Tertiary (Hypothalmus)

Trauma & Space-occupying Lesions▪ As above

Drug-induced

Central Adrenal Insufficiency: Etiology

Drug-induced: Corticosteroids (secondary AI)

▪ <10mg pred/day for 2wks Ketoconazole (primary AI) Etomidate (primary AI)

▪ only one dose required Megesterol acetate (secondary AI)

▪ progestin w/ mild glucocorticoid activity Rifampin (increased cortisol metabolism) Phenytoin (increased cortisol metabolism) Metyrapone (primary AI) Mitotane (primary AI) Opioids (secondary & tertiary AI)

Symptoms & SignsC

harm

andari

et

al. L

ance

t. 2

01

4 Jun 2

1;3

83

(99

35

):2

15

2-

67

Biochemical Presentation

Charmandari et al. Lancet. 2014 Jun 21;383(9935):2152-67

Adrenal Crisis

NEVER withhold treatment while making the diagnosis!

Suspicious history & physical Initial investigations:

Random Cortisol < 400nmol/L very suggestive if critically ill ACTH TSH & fT4 Blood cultures and other labs as indicated

Diagnostic: ACTH stimulation test ACTH 250mcg IV Baseline ACTH & cortisol, then cortisol @ 30 & 60min Excludes insufficiency if cortisol doubles & > 550nmol/L Can be normal in ACUTE central insufficiency

Diagnose Adrenal Insufficiency

Primary Central

Baseline Cortisol Low Low

Baseline ACTH High Low to low Normal

Stimulated Cortisol Low Acute: HighChronic: Low

Diagnose Adrenal Insufficiency

Treatment: Emergency

ABCs & treat precipitant illness

New diagnosis: Dexamethasone 4mg IV while arranging ACTH stim

▪ Unless critically ill Then Hydrocortisone 100 mg IV q6-8h for dual mineralocorticoid and

glucocorticoid effect Correct fluid deficit with D5NS to avoid hypoglycemia BP should start responding in 4-6hrs if dx correct After 24hrs, reduce to HC 50mg IV q6h, then start taper

Chronic condition: Crisis: Hydrocortisone 100 mg IV q6-8h Stress: Double or triple baseline dose to prevent adrenal crisis After 24hrs, reduce to HC 50mg IV q6h, then start taper Continue stress dosing for minimum of 48-72h

Steroid Comparison

Drug Half life Equivalent anti-inflammatory dose mg

Relative mineralocorticoid potency

Short acting 8-12 h

Cortisone 25 2

Hydrocortisone 20 2

Intermediate acting

18-36 h

Methylprednisolone 4 0

Prednisolone 5 1

Prednisone 5 1

Long acting 36-54 h

dexamethasone 0.75 0

Mineralocorticoid

fludrocortisone 12-24 h 10 125

21 ♀ with ARDS (?H1N1) Preterm delivery @ 26wks w/ hemorrhage

requiring 2u PRBCs Intubated with high dose midazolam &

fentanyl infusions. Weaning propofol Norepi & dopamine to keep SBP 90 D10W at 100cc/hr to keep BG>6

What are you concerned about?Adrenal Crisis 2° Sheehan’s

Critical Illness Adrenal Hemorrhage

Back to Case

Adrenal Crisis

Cortisol, ACTH, Prolactin, TSH, fT4 pending

Hydrocortisone 100mg IV q8h Learned not to use Dexamethasone in ICU 2008 Critical Care Guidelines

MRI pituitary arranged for afternoon Endocrinology consulted

Case Management

Guideline Rational

2008 Joint Recommendations: Society of Critical Care Medicine European Society of Intensive Care Medicine

ICU conditions associated with adrenal failure: Shock Severe CAP Trauma Head injury Burns Liver failure Pancreatitis Post-operatively with cardiac surgery Brain dead organ donors After etomidate use

Guideline Rational

>90% bound to CBG & a little to albumin

CBG falls in acute illness by 50% Substantially increases free cortisol Measurement of total cortisol decreased

T1/2 of cortisol is 70-120 minutes No cortisol stored in adrenal gland Acute illness should up-regulate HPA

system Deficiency anywhere in HPA system

results in decreased cortisol

Dysfunction of HPA Axis

Reported prevalence of adrenal insufficiency Critically ill patients: 10-20% Septic shock: up to 60%

Mechanisms of dysfunction are poorly understood Decreased production of CRH, ACTH and cortisol Systemic Inflammation-Associated

Glucocorticoid Resistance▪ Dysfunction of CRH, ACTH and cortisol receptors▪ Multifactorial▪ Receptors down regulated by inflammatory cytokines

± structural damage to adrenal gland

Guidelines

1. “CIRCI” – Critical Illness-Related Corticosteroid Insufficiency

2. Avoid terms “absolute” and “relative” adrenal insufficiency in context of critical illness

3. Diagnosis of adrenal insufficiency best made by a delta cortisol of <9 μg/dL (248nmol/L) after 250μg cosyntropin or random total cortisol <10μg/dL (276nmol/L) (grade 2B)

4. Free cortisol not recommended (grade 2B)5. ACTH stimulation test should not be used to

identify patients with septic shock or ARDS who should receive glucocorticoids

Marik et al. Crit Care Med 2008 Vol 36, No 6. 1937-1949

ACTH Stimulation Test

Delta cortisol <248 nmol/L has been shown to be an important prognostic marker in ICU

Studies in septic shock showed rapid shock reversal in patients treated with GC regardless of ACTH stim. test result

Stim test Down-falls: Doesn‘t assess adequacy of stress cortisol levels Doesn’t assess HPA axis integrity Currently no way to measure tissue cortisol

resistance Poorly reproducible, especially in septic shock

Guidelines

6. Consider hydrocortisone in the management strategy of septic shock, particularly those patients who respond poorly to fluid resuscitation and vasopressor agents (2B)

Evidence:▪ 6 RCT of HC 200-300mg/day in septic shock▪ Meta-analysis:

▪ Greater shock reversal at day 7▪ No mortality benefit▪ Not statistically significant higher rate of secondary

infections

Guidelines

7. Consider moderate dose GC in the management of early severe ARDS (PaO2/FiO2 < 200) and before day 14 in un-resolving ARDS (2B)

Role of GC in acute lung injury and less severe ARDS is not yet clear

No exact dose recommendation, as studies used doses from 200 to 750mg HC equivalence/day

Associated with improved PaO2/FiO2, reduction of days on mechanical vent and days in ICU

Guidelines

8. In septic shock, give IV hydrocortisone in a dose of 200 mg/d in four divided doses or as a bolus of 100 mg followed by a continuous infusion of 10mg/hr (240mg/d) (Grade 1B) Option in ARDS to give 1mg/kg/day of

methylprednisolone as a continuous infusion

Doses > 300mg/day of HC not recommended Increased myopathy & super infections

Continuous infusions give better glycemic control

Guidelines

9. Optimal duration of GC treatment unclear

Septic shock should be treated for ≥7 days before taper ▪ assuming no residual signs of sepsis or shock

Early ARDS should be treated for ≥14 days before taper (2B)

Guidelines

10. GC treatment should be tapered slowly and not stopped abruptly (2B)11. Treatment with fludrocortisone (50μg PO OD) is optional (2B)12. Dexamethasone is not recommended for treatment of septic shock or ARDS (1B)

Secondary significant suppression of HPA axis

? Lack of mineralocorticoid effect

Cortisol: 170 nmol/L (275-550 nmol/L @ 8) ACTH: 2.3 pmol/L (2.2-13 pmol/L @ 8) TSH: 0.09 mU/L (0.2-3 mU/L in 2nd T) Free T4: 6 pmol/L (10-23 pmol/L) Prolactin: 8 mcg/L (35-600 mcg/L @ term)

FSH & LH: suppressed in pregnancy Estrogen: high in pregnancy

MRI:

Case Results

Normal

HPA Axis Physiology

CBG is increased in high-estrogen states Pregnancy Oral contraceptive Liver disease

Rise in CBG elevates total plasma cortisol Threefold rise in total cortisol by pregnancy week 26 Adrenals hyper-responsive to ACTH ACTH and free cortisol levels also higher in

pregnancy No stigmata of high cortisol 2° anti-

glucocorticoid effect of elevated progesterone in pregnancy

HPA Axis Physiology

Case pt’s cortisol quite low for pregnancy & illness

ACTH should also be higher Low cortisol, low ACTH = central

insufficiency MRI was normal Fentanyl 50 mcg/hr

▪ Known HPA axis suppression

Opiate Effect on HPA Axis

Hypothalamus

Anterior Pituitary

Adrenal Cortex

CRH

+

ACTH

+

Systemic

Effects

Cortisol

_

_

Opiates

_

_

_

+

?

Thyroid Physiology

TSH normal ranges by trimester: 1st: 0.1 to 2.5 mU/L 2nd: 0.2 to 3.0 mU/L 3rd: 0.3 to 3.0 mU/L

“Sick Euthyroid Syndrome”

Thyroid Physiology

Prolactin Physiology

Prolactin should be rising as pregnancy advances

Prolactin should be low in Sheehan’s Our pt’s prolactin was low MRI was normal

Dopamine suppresses prolactin Highest infusion rate: 1000 mcg/min

Case Conclusion

Pressor & glucose requirements dropped on hydrocortisone

H1N1 positive with severe ARDS CT Abdo ruled out adrenal hemorrhage Transferred to community ICU: final adrenal dx

unknown Baby boy survived for two weeks. Respiratory failure

Multifactorial Hypoglycemia: Critical Illness vs Adrenal Insufficiency Low cortisol & ACTH: Opiates vs ICU vs AI Thyroid dysfunction: Pregnancy vs ICU vs dopamine

▪ Dopamine can suppress TSH secretion Prolactin: High-dose dopamine suppression

Acute Management

ABCs Labs: lytes, glucose, cortisol, ACTH Fluid resuscitation: D5NS bolus 2-3L,

then maintenance infusion as appropriate

Hydrocortisone 100mg IV q6-8h Dexamethasone closely followed by ACTH

stim if not critically ill. Then hydrocortisone. Simultaneous management of inciting

illness If Primary AI, start fludrocortisone

0.1mg PO once NS infusion not required

Chronic Management

Hydrocortisone 10-20mg after waking & 5-10mg in early afternoon

Alternate regimens:▪ Hydrocortisone TID (symptomatic between

doses)▪ Prednisone dose typically 3.5-5 mg daily▪ Dexamethasone 0.25-0.5 mg once daily

Normal liver function required to activate cortisone & prednisone

Adjust dose to symptoms

Adequacy of Replacement

Scoring: For each sign or symptom present, add one point if suggestive of

over-replacement or subtract one point if suggestive of under replacement.

Scores between -2 to +2 reflect good replacement

No simple recipe to establish a dose Titrate to symptom improvement:

fatigue, nausea, energy, illness, hospitalizations

Tailor timing: night shifts, avoidance of sleep disturbance

Avoid over-replacement: BMI, central obesity, stretch marks, osteopenia, HTN

Adequacy of Replacement

Further Testing

Prolonged ACTH stimulation Cortisol rapidly peaks in primary Cortisol continues to rise throughout stim in central

Insulin tolerance test Gold standard Administer regular insulin until hypoglycemic (2.2) Induces stress response Adequate response is serum cortisol > 500 nmol/L

Metyrapone Inhibits 11 beta hydroxylase

CRH stimulation test Differentiates primary/secondary/tertiary AI

Other Hormones in Primary

Aldosterone Replace with Fludrocortisone 0.1mg daily 0.025 to 0.2 mg daily - titrate to BP & edema Dose may change with season or exercise Monitor sodium, potassium & plasma renin activity

DHEA Insufficient evidence for routine supplementation No evidence in males In females, DHEA therapy suggested only for

significantly impaired mood or sense of well-being despite optimal glucocorticoid and mineralocorticoid replacement

Stress Dosing of Steroids

Minor febrile illness or stress 2-3x GC for 3 days. No change to MC

Hospitalization or Surgery Moderate: Hydrocortisone 50mg PO BID. Rapid

taper Severe: Hydrocortisone 100mg IV q8h. Taper w/

recovery Severe stress or trauma

Emergency kit: dexamethasone 4mg IM Medic Alert and Emergency card in wallet

Identify as steroid dependent

The Details

Educate, educate, educate Patient self-advocacy

Calcium & Vit D supplementation Screen for osteoporosis as appropriate

Drug interactions anticonvulsants, anti-retrovirals, rifampin dose adjustments likely required

Pregnancy May require dose increase of 5-10 mg by 3rd trimester Labor: adequate saline hydration & hydrocortisone 2 mg

IV q6h Delivery or prolonged labour: hydrocortisone 100mg IV

q6h or infusion After delivery: taper rapidly to maintenance within 3 days

Questions?

References available upon request