1. Risk Factors and Outcome of Changes in Adrenal Response to ACTH in the Course of Critical Illness Margriet Fleur Charlotte de Jong, MD, PhD, Albertus Beishuizen, MD, PhD, Rob Joris Maria Strack van Schijndel, MD, Armand Roelof Johan Girbes, MD, PhD, and Arie Bastiaan Johan Groeneveld, MD, PhD, FCCP, FCCM J Intensive Care Med 2012;27(1):37-44. R3 이민혜

2. Background Activation of the pituitary–adrenal axis : adapting to stress during critical illness Critical illness-related corticosteroid insufficiency (CIRCI) :  Particularly during sepsis and septic shock  Blunted adrenal corticosteroid response  Cortisol serum levels, even when supranormal, considered insufficient for the degree of stress and severity of disease  Poor response to additional stimuli Standard 250 mg adrenocorticotropic hormone (ACTH) stimulation test  evaluate CIRCI during sepsis and shock : cortisol response to ACTH is subnormal, baseline cortisol levels are high Controversy on CIRCI and the value of the ACTH test Hypothesis  fall in the cortisol response to ACTH(particularly to <100nmol/L)  increasing incidence of risk factors for CIRCI, increased mortality

3. Patients and Methods Retrospective longitudinal cohort study In a medical–surgical ICU of a university hospital 54 consecutive patients during a 3-year period Any patient suspected to have CIRCI : ACTH testing was perfomed  6-hour hypotension (<100 mmHg systolic) requiring repeated fluid challenges  Prolonged vasopressor/inotropic treatment, in the absence of treatment by corticosteroids Blood samples : before (T=0) and at T=30 and T=60 minutes after intravenous injection of 250 mg of synthetic ACTH Δcortisol and Δcortisol% : highest value of T=30 or T=60 for peak response and its increase, absolutely and relatively to baseline values Normal ranges  Baseline cortisol levels : ≥165 nmol/L  peak responses to ACTH : >500 ~ 550 nmol/L  increases in cortisol : >200 ~ 250 nmol/L

4. Patients and Methods Δcortisol over the 2 tests : increase (≥0, n=27) or a decrease (n=27) Δcortisol at the second ACTH test : <100 (n=11) and ≥100 nmol/L (n=43) Cortisol/albumin ratios : indicator of free cortisol Severity of disease  Simplified Acute Physiology Score II (SAPS II, 0-163)  Sequential Organ Failure Assessment score (SOFA, 0-24)

5. Patients and Methods http://clincalc.com/IcuMortality/SAPSII.aspx

6. Patients and Methods Ferreira FL et al, Serial evaluation of the SOFA score to predict outcome in critically ill patients. JAMA. 2001;286(14):1754-1758.

7. Results ICU mortality rate : 33% mortality until day 28 : 9% hospital mortality : 43%. Increased vs decrease in Δcortisol: mortality until day 28 of 19% vs 0%

8. Results Δcortisol in time : similar changes in Δcortisol/albumin independent of baseline cortisol (/albumin) levels SAPS II and SOFA Scores : decreased in patients with an increase in Δcortisol in Time but not in patients with a decrease in Δcortisol Decrease in Δcortisol : increasing frequency of SIRS, septic shock, and renal replacement therapy, relatively low increase in platelet counts mechanical ventilation and positivity of tracheal aspirate cultures decreased

9. Results SAPS II and SOFA Scores : Δcortisol ≥100  score decreased Δcortisol <100 : increased positivity of cultures from tracheal aspirates decreased platelet counts

10. Results

11. Discussion Increase in the cortisol response to ACTH testing  reversible CIRCI Developing or worsening CIRCI  persistent and complicated septic shock, high disease severity, and ultimate mortality, in spite of treatment by corticosteroids Renal replacement therapy and low platelet counts : risk factors for a fall in Δcortisol Limitations  Relatively low numbers  Retrospective design  Cortisol-binding globulin(CBG) and free cortisol levels were not measured : underestimated the baseline free cortisol levels and rises upon ACTH from total cortisol levels

12. Conclusion Repeated ACTH test : concept of dynamic adrenal function Development of CIRCI, particularly in complicated septic shock and indicated by a fall in Δcortisol (to <100 nmol/L) upon ACTH  poor prognosis, independently of baseline cortisol, cortisol binding in blood, and disease severity