Transcript Endocrine Emergencies: Adrenal Crisis

Kina M. Merwin McDougall
Endocrinology PGY4
Western 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






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

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

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


133 102 7.1
3.2 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!”


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

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

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
Define adrenal crisis
Discuss epidemiology & frequency
Review the causes of adrenal crisis
Examine the pathophysiology
5. Outline how to make the diagnosis
6. Delineate management
7. Summarize complications
1.
2.
3.
4.

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
Mineralocorticoids
Glucocorticoids
Androgens
Catecholamines
McGraw Hill
Zona glomerulosa
Zona fasciculata
Zona reticularis
CHOLESTEROL
Pregnenolone
17a-Hydroxypregnenolone
Dehydroepiandrosterone DHEA
Progesterone
17a- Hydroxyprogesterone
Androstenedione
Deoxycorticosterone
11-Deoxycortisol
Corticosterone
Cortisol
Aldosterone
Zona glomerulosa
Zona fasciculata
Zona reticularis
CHOLESTEROL
17a-Hydroxypregnenolone
Pregnenolone
Dehydroepiandrosterone DHEA
17α - hydroxylase
Progesterone
17a- Hydroxyprogesterone
21 Hydroxylase
Deoxycorticosterone
11-Deoxycortisol
11β Hydroxylase
Aldo Synthase
Corticosterone
Cortisol
Aldosterone
Androstenedione
100-150 mcg/day
C: 10-20 mg/day
A: > 20 mg/day
Hypothalamus
Circadian Regulation
Stress: physical, emotional, illness
CRH
+
Anterior Pituitary
ACTH
+
_
Adrenal Cortex
Systemic
Effects
_
+
Cortisol


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
Steroid withdrawal
1.
 Exogenous formulations
 Adrenalectomy
 Drug-induced: ketoconazole, etomidate, rifampin, anti-epileptics
Acute exacerbation of chronic insufficiency
2.
 Sepsis
 Surgical stress
Pituitary trauma
3.




Head injury
Surgical intervention or irradiation
Hemorrhage or infarct
Infection/Infiltration
Bilateral adrenal hemorrhage
4.




Antiphospholipid Antibody Syndrome
Anticoagulants
Malignancy
Septic Waterhouse-Friderichsen Syndrome (menigiococcemia: Neisseria)

Autoimmune
 80% of cases in developed countries
 60% associated with autoimmune polyendocrinopathy
syndromes

Tuberculosis
 Leading cause historically
 Still top cause in endemic areas


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

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

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)
Charmandari et al. Lancet. 2014 Jun 21;383(9935):2152-67
Charmandari et al. Lancet. 2014 Jun 21;383(9935):2152-67



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
Primary
Central
Baseline Cortisol
Low
Low
Baseline ACTH
High
Low to low Normal
Stimulated Cortisol
Low
Acute: High
Chronic: Low

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
Drug
Short acting
Half life
Equivalent antiinflammatory
dose mg
Relative
mineralocorticoid
potency
8-12 h
Cortisone
25
2
Hydrocortisone
20
2
Methylprednisolone
4
0
Prednisolone
5
1
Prednisone
5
1
0.75
0
10
125
Intermediate acting
Long acting
18-36 h
36-54 h
dexamethasone
Mineralocorticoid
fludrocortisone
12-24 h

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


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


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


>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

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
“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
1.
Marik et al. Crit Care Med 2008 Vol 36, No 6. 1937-1949
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
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
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
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
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)
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
ACTH: 2.3 pmol/L
TSH: 0.09 mU/L
Free T4: 6 pmol/L
Prolactin: 8 mcg/L


FSH & LH: suppressed in pregnancy
Estrogen: high in pregnancy

MRI:
Normal
(275-550 nmol/L @ 8)
(2.2-13 pmol/L @ 8)
(0.2-3 mU/L in 2nd T)
(10-23 pmol/L)
(35-600 mcg/L @ term)

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° antiglucocorticoid effect of elevated progesterone in
pregnancy
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
Hypothalamus
_
Opiates
CRH
_
?
+
Anterior Pituitary
ACTH
_
+
_
Adrenal Cortex
Systemic
Effects
_
+
Cortisol

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”
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




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




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

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
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



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

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

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

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
References available upon request