1. Critical Illness-related Corticosteroid Insufficiency (CIRCI) Your Name Here, Pharm.D. Candidate Date

2. Objectives Patient case presentation Understand the pathophysiology related to adrenal insufficiency in critical illness Determine the appropriate measures for diagnosis of adrenal insufficiency in critically ill Explain the pharmacotherapeutic approach to treatment of adrenal insufficiency Review primary literature associated with adrenal insufficiency of critical illness Discuss current controversies related to adrenal insufficiency Summarize current recommendations

3. Patient Case - AD AD is a 74 year old black male presenting to Dorn VA emergency room on 11/12/2008 Chief Complaint: ▫Patient states that “he has been coughing a lot, has chills, and probably has aspiration pneumonia” History of present illness: ▫Patient states that for the past 5 days he has had chills, SOB, N/V, productive cough, and a home temp of 102˚. AD has had multiple hospital visits in the last year since his partial gastrectomy, esophagectomy, and tracheostomy. AD was previously hospitalized for aspiration pneumonia (discharged 9/08) due to chronic issues with decreased motility and gastric residuals. AD recently began home TPN with bolus enteral feedings.

4. Patient Case PMH: ▫Gastic cancer, GERD, COPD, BPH, recurrent pneumonia, SVT, HTN, dyslipidemia, chronic pain, parenteral nutrition requirement, iron-deficiency anemia, gastric residuals associated with N/V and regurgitation ▫Surgeries: partial gastrectomy (3/08), esophagogastroduodenoscopy (3/08), thoracotomy (3/08), G and J tube placement (3/08), tracheostomy (3/08), drainage of chest wall abscess (3/08), G-J tube placement (5/08) PSH: ▫Denies tobacco (quit 1960’s); drinks about 3 beers/day ▫FH: mother – died of TB; father – died of colon cancer; brother – died of lymphoma; sister – died of lung cancer

5. Patient Case VitalsPhysical exam/Procedures Hgt: 70 in. Wgt: 53.5 kg Temp: 102.1˚F ↑ BP: 105/46 mmHg ↓ MAP: 65 ↓ HR: 117 bpm ↑ RR: 16 General: cachetic, ill appearing, shallow respirations, raspy voice Lungs: crackles bilaterally CV: irregular, no MRG All others non-remarkable Chest x-ray: new infiltrates in RLL and LLL

6. Patient Case – Admission Labs Chem 7, CBC & ABGCultures & Cosynotropin Na: 136 K : 3 ↓ Cl: 90 ↓ CO2: 40.2 ↑ BUN: 18 Scr:0.5 Glucose: 92 WBC: 12.1 ↑ Hgb: 10.6 ↓ Hct: 32.2 ↓ pH:7.44 pCO2: 62 ↑ pO2: 52 ↓ Blood x 2: gram (-) bacilli ; Serratia Sputum: 4+ gram (+) cocci, 3+ gram (-) bacilli, 1+ gram (-) rod; Pseudomonas and MRSA Urine: no growth UA: urine RBC’s Cortisol: ▫Baseline: 16.3 mcg/dL ▫1 hr: 25.3 mcg/dL ▫Δ cortisol: 8 mcg/dL

7. Problem List - Admission Septic Shock – hypotension, tachycardia, fever Aspiration pneumonia/PICC line infection/fungal prophylaxis Metabolic alkalosis with respiratory compensation – TPN vs. contraction alkalosis Electrolyte abnormalities – hypokalemia, hypochloremia, hypocalcemia Supraventricular tachycardia Iron deficiency anemia BPH, COPD, N/V, pain DVT prophylaxis Stress ulcer prophylaxis Nutrition – enteral feeds on upon admission

8. Medications - Admission Levophed 16 mcg/ml titrated to MAP > 65 Normal saline 200 ml/hr piperacillin/tazobactam 4.5 g Q 6 hours vancomycin 1 g Q 12 hours tobramycin 150 mg daily fluconazole 400 mg daily KCL 20 MEQ BID terazosin 1 mg HS oxybutynin 5 mg TID ranitidine 150 mg BID metoclopramide 10 mg AC & HS erythromycin susp. 200 mg BID gabapentin 100 mg TID APAP 650 mg Q 6 hour PRN albuterol/ipratropium Q 6 hours via nebulizer fluticasone/salmeterol 250/50 BID ondansetron 4 mg ODT Q 6 hours lactobacillus BID heparin 5000 SQ Q 8 hours TwoCal 45 ml/hour

9. Added problems over patient course.. Adrenal insufficiency of critical illness ▫Hydrocortisone 100 mg Q 8 hours tapered over 7 days Enteral feeding intolerance ▫TPN initiated Hypophosphatemia – Refeeding Syndrome ▫Potassium phosphate 30 mmol

10. Critical Illness-related Corticosteroid Insufficiency (CIRCI)

11. What are adrenal glands again?!? The adrenal glands are small triangular glands located on the top of both kidneys Composed of an outer region called the adrenal cortex and an inner region known as the adrenal medulla ▫Adrenal cortex – secretes steroid hormones that control the body’s metabolism, chemicals, and characteristics (cortisol, aldosterone, androgens) ▫Adrenal medulla – helps the body cope with physical or emotional stress (epinephrine and norepinephrine)

12. How does it work? Hypothalamus-Pituitary-Adrenal Axis ▫In response to physical/psychological stresses the hypothalamus in the brain secretes corticotrophin releasing factor ▫CRF binds to receptors in the pituitary which in turn produce adrenocorticotropic hormone ▫ACTH is then transported to the adrenal glands and stimulates secretion of steroid hormones ▫Cortisol secreted from adrenal glands acts as feedback inhibitor on production of CRF and ACTH and mediates stress response

13. What do the hormones do? Glucocorticoids – Cortisol (hydrocortisone) is major glucocorticoid in humans ▫Bind to glucocorticoid receptors which are present in almost every organ tissue in our body  Stimulate gluconeogenesis, inhibit glucose uptake, stimulate lipolysis, anti-inflammatory and immunosuppressive effects through regulation of gene transcription Mineralocorticoids – Aldosterone ▫Increased renal reabsorption of sodium and H2O ▫Increased renal excretion of potassium Epinephrine and Norepinephrine ▫Initiate the “fight or flight” reflex – increased inotropic and chronotropic actions, vasoconstriction, brochial and pupil dilation, inhibition of “non-essential” body processess

14. The body’s response to stress.. Body prepares to handle any situation that it encounters ▫Preservation of vital organs ▫Increased energy formation ▫Increased alertness

15. Stress-free ACTH release Cortisol is released normally in response to circadian rhythms When the body senses any type of stress (psychological or physical) activation of the HPA axis occurs as a defense mechanism for the body (under autonomic control) In critically ill patients the diurnal pattern of ACTH release is disrupted

16. What happens in critically ill patients? Pain, fever, hypotension, hypovolemia, and tissue damage associated with critical illness all activate HPA axis ▫Hypotension and sepsis have been shown to be the most significant stressors ▫Increased free cortisol levels due to decreased cortisol binding globulin Cytokines released during critical illness can also inhibit the HPA axis ▫Decreased production of cortisol or ACTH is common in patients with severe sepsis or septic shock ▫TNF-α impairs CRF-stimulated ACTH release and IL-6 elevation may blunt ACTH release ▫Tissue corticosteroid resistance in inflammatory states

17. Critical illness-related corticosteroid insufficiency (CIRCI) Definition ▫Inadequate cellular corticosteroid activity for the severity of the patients illness ▫Reversible condition caused by the persistence of proinflammatory mediators ▫Due to decreased steroid production or tissue resistance and may occur anywhere along HPA axis ▫Can be primary (adrenal gland destruction) or secondary (pituitary or hypothalamic disorders) Incidence ▫Prevalence is 10-20% in critically ill patients ▫Up to 60% of patients with septic shock

18. CIRCI Causes: ▫Reversible:  Sepsis/SIRS (1˚ or 2˚ AI)  Drug related  Hypothermia (1˚ AI) ▫Primary:  HIV, CMV, systemic fungal infections, TB, APLA, cancer  Hemorrhage  Carcinoma ▫Secondary:  Pituitary carcinoma  HIV  Head trauma Signs and Symptoms: ▫Septic patients with hypotension resistant to fluid resucitation ▫Vasopressor-dependent patients ▫Eosinophilia ▫Hyponatremia and hyperkalemia ▫Hypoglycemia ▫Non-specific: N/V, weakness, fatigue, anemia, AMS, fever

19. Drug related adrenal insufficiency Chronic use of oral corticosteroids ▫Induce adrenal atrophy Inhaled corticosteroids ( ↓ risk) Megesterol Etomidate ▫Inhibit glucocorticoid synthesis Ketoconazole Phenytoin Rifampin ▫Increased metabolism or cortisol to cortisone

20. Diagnosis of CIRCI

21. How do we measure adrenal function? Diagnostic TestsValues indicative of AI Random serum cortisol Short ACTH test ▫High Dose= 250 mcg ACTH ▫Low Dose= 1 mcg ACTH Free cortisol Metyrapone Insulin tolerance test Baseline random serum cortisol < 10 mcg/dL Delta cortisol after 30 and 60 minutes after ACTH administration < 9 mcg/dL ▫250 mcg ACTH is a supraphysiological dose ▫1 mcg ACTH is a physiologic dose Free cortisol < 0.8 mcg/dL Metyrapone diagnostic of secondary adrenal insufficiency ▫ACTH < 150 pg/mL

22. Limitations to diagnostic tests Random serum cortisol ▫In critically ill patients adrenal function should be stimulated due to intense amounts of stress, to the appropriate cutoff for inappropriate serum cortisol is difficult to define  Some people use a cutoff of < 15 mcg/dL or< 25 mcg/dL  Guidelines recommend < 10 mcg/dL as cutoff ▫The amount of cortisol is critically ill patients is primarly unbound (free) which is currently not recommended as an approach to diagnosis ACTH stimulation test ▫In critically ill patients the adrenal gland may be maximally functioning and judging the Δ may not be an accurate way of diagnosing adrenal insufficiency ▫The adrenal glands are maximally stimulated with 5-10 mcg of ACTH and administration of 250 mcg has the potential to mask adrenal insufficiency by overriding adrenal resistance ▫Currently not enough evidence with the 1 mcg ACTH test to recommend its use

23. Limitations continued.. ACTH testing bypasses the hypothalamus and pituitary function and may mask a secondary adrenal insufficiency ▫Metyrapone test inhibits the formation of cortisol which should therefore result in increased production of CRF and ACTH by the hypothalamus and pituitary ▫Insulin tolerance test induces hypoglycemia which should result in compensation thru HPA axis but is not recommended in critically ill There is currently no way to measure the action of cortisol in the tissues, so no way to determine glucocorticoid resistance

24. Algorithm for Diagnosis

25. Treatment of critical illness-related corticosteroid insufficiency

26. Treatment Considerations Hydrocortisone therapy should be considered in patients with suspected adrenal insufficiency who present with septic shock which is poorly responsive to fluid and vasopressors Moderate dose hydrocortisone (200-300 mg/day) results in more rapid resolution of shock but effects on mortality are not clear ▫Meta-analysis of 5 trials (Annane) showed that lower doses and longer courses of steroids decreased 28 day, ICU, and hospital mortality; high dose short course steroids did not Effects on shock resolution were demonstrated in both ACTH responders and non-responders so patients should be treated based on clinical symptoms and not ACTH test results

27. Treatment Options Hydrocortisone (200-300 mg/day) ▫100 mg Q 8 hours (Bollaert, Chawla) ▫50 mg Q 6 hours (Annane, Sprung) ▫Or 100 mg bolus + 10 mg/hr continuous infusion Adding fludrocortisone 50 mcg daily is optional (Annane) Treatment duration should be based on the resolution of septic shock but should extend to ≥7 days Hydrocortisone should be tapered every 2-3 days instead of stopped abruptly Dexamethasone is no longer recommended for use either prior to or after ACTH test (doses ≤4 mg may not affect ACTH test but no longer recommended)

28. Analysis of Primary Literature Two Randomized Controlled Trials

29. Effect of Treatment With Low Doses of Hydrocortisone and Fludrocortisone on Mortality in Patients with Septic Shock Study Objectives/DesignMethods Randomized, placebo- controlled, double-blind trial performed in 19 ICUs in France Objective: ▫To assess whether replacement therapy with hydrocortisone and fludrocortisone could improve 28 day survival in patients with septic shock Treatment: hydrocortisone IV 50 mg Q 6 hrs + fludrocortisone 50 mcg PO daily X 7 days or placebo Patients: 300 patients randomized (149 placebo and 151 steroids) Inclusion criteria: presence of infection, hypo- or hyperthermia, HR>90bpm, SBP 2mmol/L, mechanical ventilation ▫Randomized within 8 hrs of septic shock Exclusion criteria: pregnant, MI, PE, advanced cancer, AIDS, CI to steroids, etomidate within 6 hrs (added 2 yrs later) Endpoints: 28-day survival, ICU, hospital and 1 yr mortality, vasopressor withdrawal

30. Effect of Treatment With Low Doses of Hydrocortisone and Fludrocortisone on Mortality in Patients with Septic Shock 229 nonresponders and 70 responders to 250 mcg ACTH test Nonresponders: 73 deaths in placebo group (63%) and 60 deaths in tx groups (53%) (p=0.02, NNT=7) ▫81 deaths (70%) in placebo and 66 (58%) in tx groups at end of ICU stay (p=0.02) ▫ ↓ hospital mortality in tx group (p=0.04) ▫No difference in 1 yr mortality ▫10 days to vasopressor withdrawal in placebo vs. 7 days in tx group (p=0.001) Responders: 18 deaths in placebo group (53%) and 22 deaths in the tx group (61%) ▫No significant differences in 28 day, ICU, hospital, or 1 yr mortality ▫Mean time to vasopressor withdrawal in placebo was 7 days vs. 9 days in tx group All patients: 91 deaths in placebo group (61%) and 82 deaths in tx group (55%) ▫No significant differences in 28 day, ICU, hospital, or 1 yr mortality in tx group ▫Time to vasopressor withdrawal was 9 days in placebo vs. 7 days in tx (p=0.01)

31. Effect of Treatment With Low Doses of Hydrocortisone and Fludrocortisone on Mortality in Patients with Septic Shock Conclusions ▫In vasopressor dependent patients in septic shock 7 day treatment with hydrocortisone 50 mg Q6 hr and fludrocortisone 50 mcg daily significantly reduced the incidence or short term and long term mortality and shortened the duration of vasopressor use in patients who have adrenal insufficiency as diagnosed by change in cortisol of < 9 mcg/dL after the 250 mcg ACTH test ▫Patients should be started on the steroid regimen immediately after ACTH test and may be withdrawn in responders ( Δ cortisol > 9 mcg/dL)

32. Effect of Treatment With Low Doses of Hydrocortisone and Fludrocortisone on Mortality in Patients with Septic Shock Limitations ▫Calculation of a one-sided statistics which can’t reveal if treatment had a negative effect on mortality ▫Sample size calculation not appropriate to detect differences in the “responder” group  Assumed a mortality of 95% in the nonresponder group which was unrealistically high  Assumed the frequency of nonresponders to be 40%  A more appropriate mortality rate (63%) and frequency (77%) used to calculate power would have shown an n=400 patients in each arm to detect 10% difference ▫Over 72 patients received etomidate prior to amendment and > 90% were considered to be “nonresponders” ▫Conclusions may not be able to be extrapolated to be people who are not as “sick”

33. Hydrocortisone Therapy for Patients with Septic Shock (CORTICUS) Study Design/ObjectivesMethods Randomized, double-blind, placebo- controlled trial conducted in 52 ICUs from 3/2002-11/2005 Objective: ▫To evaluate the safety and efficacy of low-dose hydrocortisone therapy in patients with septic shock ▫Assess the benefit in patients who respond to ACTH test Treatment: hydrocortisone 50 mg Q 6 hrs x 5 days, then 50 mg Q 12 hrs x 3 days, then 50 mg daily x 3 days, then stop Endpoints: rate of death at 28 days in responders and nonresponders, ICU, hospital and 1 yr mortality, reversal of shock, duration of stay in ICU & ward, adverse effects Patients: 500 patients randomized (252 treatment and 248 placebo) Inclusion criteria: >18 years in ICU, evidence of infection, onset of shock within 72 hours (SBP<90 despite fluids or vasopressors for at least 1 hr), hypoperfusion or organ damage related to sepsis Exclusion criteria: underlying disease with poor prognosis, life expectancy < 24 hours, immunosuppression, tx with chronic steroids within 6 months or short term steroids within 4 weeks

34. Hydrocortisone Therapy for Patients with Septic Shock (CORTICUS) - Results 233 patients were nonresponders (46.7%) and 254 patients (50.9%) responded to 250 mcg ACTH test 96 patients received etomidate before or after study enrollment and 58 (60.4%) were nonresponders ▫Post hoc analysis showed increased 28 day mortality in patients who received etomidate (p=0.03) Nonresponders: At 28 days, 49 deaths in the tx group (39.2%) and 39 deaths in placebo (36.1%) (p=0.69) ▫There were no differences in mortality at any time Responders: At 28 days, 34 deaths in tx group (28.8%) and 39 deaths in placebo group (28.7%) (p=1) ▫No differences in mortality at any time Shock reversal: The proportion of patients who underwent reversal of shock was not significantly different between groups ▫Time to reversal was significantly shorter in patients receiving hydrocortisone in both the responder and nonresponder groups (p<0.001) The number of patients extubated on day 28 was similar between the 2 groups Adverse events: ▫Increased risk of superinfections including new episodes of sepsis or septic shock (33% tx vs. 26% placebo) ▫Increased incidence of hyperglycemia and hypernatremia in tx group

35. Hydrocortisone Therapy for Patients with Septic Shock (CORTICUS) Conclusions ▫Hydrocortisone 50 mg Q 6 hours tapered over 11 days cannot be recommended for treatment of patients in septic shock based on this patient population  Increased risk of adverse events associated with hydrocortisone therapy may have negated benefit  Omission of fludrocortisone may have changed outcomes  Patients included in this study tended to be less “sick” than in previous studies ▫Although hydrocortisone treated patients may have faster resolution of shock this does not effect mortality ▫Used of etomidate increases the risk of adrenal hyporesponsiveness and mortality ▫The ACTH test cannot the used to determine the appropriateness of hydrocortisone therapy

36. Hydrocortisone Therapy for Patients with Septic Shock (CORTICUS) Limitations ▫Inadequately powered – projected n=800 patients and actual n=500 patients  Slow recruitment and termination of funding ▫21 patients (4.2%) were receiving open-label steroids ▫Enrolled patients that were less “sick”, which lead to decreased mortality relative to previous studies ▫Didn’t require patients to be vasopressor dependent ▫Allowed a 72 hr window for enrollment after identification of shock which may have attenuated benefit of early treatment with steroids

37. Current Controversies How to diagnosis patients with CIRCI? ▫Different recommendations for random cortisol cutoffs (10- 25 mcg/dL) ▫Should we use the Δ cortisol after ACTH test to determine patients appropriate for steroid treatment? And if so, should be use LD (1 mcg) or HD (250 mcg)? ▫Should we be using the free cortisol test in critically ill patients? What is the appropriate duration of treatment? ▫Short course ( 7 days may increase adverse effects Should we add fludrocortisone to hydrocortisone? ▫2 studies (Annane and Gonzalez) say yes ▫Is it appropriately absorbed PO in a state of shock?

38. Summary of Current Guidelines American College of Critical Care Medicine recommendations for management: ▫Diagnosis best made with Δ cortisol <9 mcg/dL after 250 mcg ACTH test or a random total cortisol < 10 mcg/dL but these should not be used to judge who receives treatment ▫Treatment with hydrocortisone should be initiated in patients with septic shock who have not responded to fluids or vasopressors ▫Hydrocortisone should be given in a dose of 200 mg/day in 4 divided doses or as 100 mg bolus followed by CI or 10mg/hr ▫Patients should be treated for ≥7 days before tapering assuming no recurrence of symptoms ▫Addition of fludrocortisone 50mcg PO daily is optional ▫Dexamethasone is not recommended

39. References Annane D, et al. Effect of Treatment with Low Doses of Hydrocortisone and Fludrocortisone on Mortality in Patients with Septic Shock. JAMA. 2002; 288:862-871. Sprung CL, et al. Hydrocortisone Therapy for Patients with Septic Shock. NEJM. 2008;358: 111-124. Marik PE, et al. Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: Consensus statements from and international task force by the American College of Critical Care Medicine. Crit Care Med. 2008; 36:1937-1949. Thomas Z, Fraser GL. An Update of the Diagnosis of Adrenal Insufficiency and the Use of Corticotherapy in Critical Illness. The Annals of Pharmacotherapy. 2007; 41:1456-1465. Cooper MS, et al. Adrenal Insufficiency in Critical Illness. J Intensive Care Med. 2007; 22:348-362. Mesotten D, et al. The altered adrenal axis and treatment with glucocorticoids during critical illness. Nature Clinical Practice. 2008; 4:496-505. Annane D, et al. Corticosteroids for severe sepsis and septic shock: a systematic review and meta-analysis. BMJ. 2004; 1-9. Marik PE, et al. Adrenal Insufficiency in the Critically Ill: A new look at an old problem. CHEST. 2002;122: 1784-1796.