Critical Illness-related Corticosteroid Insufficiency (CIRCI)

Your Name Here, Pharm.D. CandidateDate

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

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.

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

Patient CaseVitals Physical 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

Patient Case – Admission LabsChem 7, CBC & ABG Cultures & 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

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

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

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

Critical Illness-related Corticosteroid Insufficiency (CIRCI)

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)

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

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

The body’s response to stress..

• Body prepares to handle any situation that it encounters▫ Preservation of vital organs ▫ Increased energy formation ▫ Increased alertness

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

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

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

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

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

Diagnosis of CIRCI

How do we measure adrenal function?

Diagnostic Tests Values 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

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

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

Algorithm for Diagnosis

Treatment of critical illness-related corticosteroid insufficiency

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

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)

Analysis of Primary LiteratureTwo Randomized Controlled Trials

Effect of Treatment With Low Doses of Hydrocortisone and Fludrocortisone on Mortality in Patients with Septic ShockStudy Objectives/Design Methods

• 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<90mmHg for at least 1 hr despite fluid and vasopressors, UOP<0.5ml/kg/hr for at least 1 hr, arterial lactate >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

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)

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)

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”

Hydrocortisone Therapy for Patients with Septic Shock (CORTICUS)

Study Design/Objectives Methods• 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

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

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

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

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 (<3 days) doesn’t show benefit but >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?

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

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.