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Kina M. Merwin McDougall Endocrinology PGY4 Western University.

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Presentation on theme: "Kina M. Merwin McDougall Endocrinology PGY4 Western University."— Presentation transcript:

1 Kina M. Merwin McDougall Endocrinology PGY4 Western University

2  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

3  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

4  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

5  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 Acute respiratory acidosis & metabolic acidosis: respiratory fatigue & sepsis

6  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!”

7  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

8  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

9  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 ✗ ✗ ? ✓ ✓

10 1. Define adrenal crisis 2. Discuss epidemiology & frequency 3. Review the causes of adrenal crisis 4. Examine the pathophysiology 5. Outline how to make the diagnosis 6. Delineate management 7. Summarize complications

11  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

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13 Mineralocorticoids Glucocorticoids Androgens Catecholamines McGraw Hill

14 Zona glomerulosa Zona fasciculata Zona reticularis CHOLESTEROL 17  Hydroxy- pregnenolone Dehydroepi- androsterone DHEA Pregnenolone 17  Hydroxy- progesterone Androstenedione Progesterone 11  Deoxycortisol Deoxycorticosterone Cortisol Corticosterone Aldosterone

15 Zona glomerulosa Zona fasciculata Zona reticularis CHOLESTEROL 17  Hydroxy- pregnenolone Dehydroepi- androsterone DHEA Pregnenolone 17  Hydroxy- progesterone Androstenedione Progesterone 11  Deoxycortisol Deoxycorticosterone Cortisol Corticosterone Aldosterone 11β Hydroxylase 21 Hydroxylase 17α - hydroxylase Aldo Synthase

16 mcg/day C: mg/day A: > 20 mg/day

17 Hypothalamus Anterior Pituitary Adrenal Cortex CRH + ACTH + Systemic Effects Cortisol _ _ + Circadian Regulation Stress: physical, emotional, illness

18

19  Rare: episode reported by 42% of chronic  Chronic Primary Adrenal Insufficiency:  Prevalence: cases/million  Incidence: new cases/million/year  ♀ > ♂ but near 1:1  Any age: most frequently 30-50years  Chronic Central Adrenal Insufficiency:  Prevalence: cases/million  ♀ > ♂  Any age: most frequently 50’s

20 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)

21  Autoimmune  80% of cases in developed countries  60% associated with autoimmune polyendocrinopathy syndromes  Tuberculosis  Leading cause historically  Still top cause in endemic areas

22  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

23  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

24  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)

25 Charmandari et al. Lancet Jun 21;383(9935):

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28  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 30 & 60min  Excludes insufficiency if cortisol doubles & > 550nmol/L  Can be normal in ACUTE central insufficiency

29 PrimaryCentral Baseline CortisolLow Baseline ACTHHighLow to low Normal Stimulated CortisolLowAcute: High Chronic: Low

30  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

31 DrugHalf lifeEquivalent anti- inflammatory dose mg Relative mineralocorticoid potency Short acting8-12 h Cortisone252 Hydrocortisone202 Intermediate acting18-36 h Methylprednisolone40 Prednisolone51 Prednisone51 Long acting36-54 h dexamethasone0.750 Mineralocorticoid fludrocortisone12-24 h10125

32  21 ♀ with ARDS (?H1N1)  Preterm 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

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34  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

35  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

36  >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 minutes  No cortisol stored in adrenal gland  Acute illness should up-regulate HPA system  Deficiency anywhere in HPA system results in decreased cortisol

37  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

38 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

39  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

40 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 mg/day in septic shock ▪Meta-analysis: ▪Greater shock reversal at day 7 ▪No mortality benefit ▪Not statistically significant higher rate of secondary infections

41 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

42 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

43 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)

44 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

45  Cortisol: 170 nmol/L( )  ACTH: 2.3 pmol/L( )  TSH: 0.09 mU/L(0.2-3 mU/L in 2 nd T)  Free T4: 6 pmol/L(10-23 pmol/L)  Prolactin: 8 mcg/L( term)  FSH & LH: suppressed in pregnancy  Estrogen: high in pregnancy  MRI: Normal

46  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

47  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

48 Hypothalamus Anterior Pituitary Adrenal Cortex CRH + ACTH + Systemic Effects Cortisol _ _ Opiates _ _ _ + ?

49  TSH normal ranges by trimester:  1 st : 0.1 to 2.5 mU/L  2 nd : 0.2 to 3.0 mU/L  3 rd : 0.3 to 3.0 mU/L  “Sick Euthyroid Syndrome”

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51  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

52  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

53  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

54  Hydrocortisone 10-20mg after waking & 5-10mg in early afternoon  Alternate regimens: ▪Hydrocortisone TID (symptomatic between doses) ▪Prednisone dose typically mg daily ▪Dexamethasone mg once daily  Normal liver function required to activate cortisone & prednisone  Adjust dose to symptoms

55 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

56  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

57  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

58  Aldosterone  Replace with Fludrocortisone 0.1mg daily  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

59  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

60  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 3 rd 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

61 References available upon request


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