Subclinical Problems in the ICU:

Transcription

1 Subclinical Problems in the ICU: Corticosteroid Insufficiency C. S. Cutillar, M.D., FPCP, FPSEM Associate Professor Cebu Institute of Medicine

2 H-P-A Axis during Critical Illness CRH ACTH

3 H-P-A Axis during Critical Illness Effects of cortisol : Shifts CHO, fat and CHON metabolism ENERGY CRH Dampen down the inflammatory cascade Hemodynamic effects ACTH

4 H-P-A Axis during Critical Illness Effects of cortisol : Intravasular fluid retention Enhanced sensitivity to catecholamines and Angiotensin II Hemodynamic effects STABILIZES BLOOD PRESSURE

5 H-P-A Axis during Stress Critical Illness-Related Corticosteroid Insufficiency (CIRCI) Corticosteroid deficiency Corticosteroid resistance Vasopressor dependent refractory hypotension

6 H-P-A Axis during Stress Critical Illness-Related Corticosteroid Insufficiency (CIRCI) Inadequate cellular corticosteroid activity for the severity of the patient s illness. Crit Care Med 2008 Vol. 36, No. 6

7 Prevalence of CIRCI data not uniform depends upon the population studied and the criteria used

8 Prevalence of CIRCI Author Setting n Prevalence % Bouachor et al, 1995 Septic Shock Rivers et al, 1999 Emergency Room Annane et al, 2000 Septic Shock Rydvall et al, 2001 Surgical ICU Chang et al, 2001 Emergency Room Cutillar, et al, 2005 ICU Cutillar, et al, 2005 Sepsis & Septic Shock

9 Possible causes of cortisol deficiency in critical illness CNS disease Head injury / SAH Exogenous steroids Vasculature Pathogens Drugs (ketoconazole, etomidate)

10 Approach to CIRCI

11 Approach to CIRCI 60 y.o. female admitted for urosepsis 60 y.o. female admitted for urosepsis 80/50 mmhg on inotropic support (+) history of on and off oral steroid use for 80/50 mmhg on inotropic support No or unknown history of previous steroid intake bronchial asthma Give Steroids!!! Give Steroids???

12 Clinical Questions When to suspect cortisol insufficiency in patients with history of glucocorticoid use? Which patients should be placed on stress doses of steroids? How much to give? How do we diagnosed CIRCI? What is the current recommendations for the treatment?

13 Question: When to suspect cortisol insufficiency? Signs and symptoms are vague and non-specific Increased pigmentation (in Addison s disease) Symptoms of other pituitary hormone deficiency Hyperkalemia, hyponatremia, eosinophilia Vasopressor dependent refractory hypotension

14 Question: When to suspect cortisol insufficiency? Signs and symptoms are vague and non-specific Increased pigmentation (in Addison s disease) Symptoms of other pituitary hormone deficiency Hyperkalemia, hyponatremia, eosinophilia Vasopressor dependent refractory hypotension

15 Question: When to suspect cortisol insufficiency? NO HPA AXIS SUPPRESSION < 5 mg of prednisone or equivalent / day for any duration alternate day single AM dose of short acting GCC of any dose or duration Any dose of GCC for less than 3 weeks 5 mg of Prednisone is equivalent to: 20 mg hydrocortisone Rx: Give usual daily GCC dose during perioperative period 0.75 mg dexamethasone 0.6 mg betamethasone 4 mg methylprednisolone PERI-OPERATIVE SUPPLEMENTAL GCC Medical Clinics of North America Jan 2003

16 Question: When to suspect cortisol insufficiency? HPA AXIS SUPPRESSION DOCUMENTED OR PRESUMED >20 mg of prednisone or equivalent per day for > 3 wks Cushingoid appearance Biochemical AI on low-dose ACTH stim test MINOR PROCEDURES: give usual dose before surgery. No supplementation. MODERATE SURGICAL STRESS: 50 mg IV hydrocortisone prior to induction of anesthesia, THEN 50 mg q 8H for 24-48H then resume usual dose MAJOR SURGICAL STRESS: 100 mg IV hydrocortisone prior to induction of anesthesia THEN 50 mg hydrocortisone every 8H for H then resume usual dose PERI-OPERATIVE SUPPLEMENTAL GCC Medical Clinics of North America Jan 2003

17 Question: When to suspect cortisol insufficiency? HPA AXIS SUPPRESSION UNCERTAIN 5-20 mg of prednisone or equivalent per day for 3 wks or more 5 mg or greater of prednisone or its equivalent for 3 weeks or more in the year prior to surgery MINOR PROCEDURES: give usual dose before surgery. No supplementation. MODERATE OR MAJOR SURGICAL STRESS: Do ACTH testing Give glucocorticoids as if suppressed PERI-OPERATIVE SUPPLEMENTAL GCC Medical Clinics of North America Jan 2003

18 Question: How to diagnose CIRCI? Random cortisol level ACTH testing Both tests have significant limitations in critically ill patients

19 Question: How to diagnose CIRCI? Normal diurnal cortisol secretion Random cortisol level Cortisol (ug/dl) Clock time (hours) Normal cortisol level: 8 AM 12 noon = 5 25 ug/dl 12 noon 8 PM = 5 15 ug/dl 8 pm 8 AM up to 10 ug/dl Diurnal variation is lost during critical illness Manual of Endoc and Metab 2003

20 Question: How to diagnose CIRCI? Normal diurnal cortisol secretion Random cortisol level Cortisol (ug/dl) Clock time (hours) Normal cortisol level: 8 AM 12 noon = 5 25 ug/dl 12 noon 8 PM = 5 15 ug/dl 8 pm 8 AM up to 10 ug/dl Diurnal variation is lost during critical illness Manual of Endoc and Metab 2003

21 Question: How to diagnose CIRCI? Condition Cortisol Level (µg/dl) Trauma 35 Hemorrhage Post operative surgery 30 Cardiac arrest 40 Septic shock J Intensive Care Med 2007; 22; 348

22 Question: How to diagnose CIRCI? random total cortisol Standard (250 µg) ACTH testing < 10 µg/dl. cortisol of < 9 µg/dl. Strength of Recommendation: 2B (weak recommendation supported by moderate quality studies) Crit Care Med 2008 Vol. 36, No. 6

23 Question: How to diagnose CIRCI? measures both the bound and unbound form of cortisol affected by serum albumin levels more accurate to measure free cortisol level random total cortisol Standard (250 µg) ACTH testing < 10 µg/dl. cortisol of < 9 µg/dl. Strength of Recommendation: 2B (weak recommendation supported by moderate quality studies) Crit Care Med 2008 Vol. 36, No. 6

24 Question: How to diagnose CIRCI? Standard (250 µg) ACTH testing cortisol of < 9 µg/dl. 0:00 min Baseline cortisol 0:30 min Cortisol 0:60 min Cortisol = peak cortisol - baseline Crit Care Med 2008 Vol. 36, No. 6

25 Question: How to diagnose CIRCI? Standard (250 µg) ACTH testing cortisol of < 9 µg/dl. Poorly reproducible The right dose of cosyntropin is controversial It cannot measure glucocorticoid resistance Crit Care Med 2008 Vol. 36, No. 6

26 The ACTH stimulation test should not be used to identify those patients with septic shock or ARDS who should receive glucocorticoids. Crit Care Med 2008 Vol. 36, No. 6 A poor increment has been linked to poor outcome in septic shock even in people with very high basal cortisol values. J Intensive Care Medicine,2007

27 Adrenal Responsiveness to 10 ug ACTH Stimulation Test among Critically Ill Patients on Inotropic Support Admitted to PGH MORTALITY OUTCOME CIRCI 15 out of 20 75% vs. NO CIRCI 10 out of % p = RR = 2.25 (95% CI = 1.3 4) Cutillar, 2005

28 Question: Who should be given glucocorticoids?

29 Population: 300 patients with septic shock Intervention: Hydrocortisone 50 mg every 6 H plus fludrocortisone 50 mcg OD for 7 days versus Placebo Methodology: Multi-center, double blinded, placebocontrolled, randomized trial Outcome: 28 day survival Annane et al, JAMA. 2002; 288:

30 28-day mortality Population (n=299) Placebo Hydrocortisone + Fludrocortisone P All patients 61% 55% 0.09 Responders 53% 61% 0.96 Non-responders 63% 53% 0.04 Annane et al, JAMA. 2002; 288:

31 Study population 499 patients with septic shock Hydrocortisone 50 mg IV q 6H for 5 days Dose was tapered during 6-day period (n= 252) Placebo (n= 248) CIRCI n = 125 NO CIRCI n = % 28.8% 28 day mortality 36.1 % 28.7 % p = % 34.7% ICU death 40.7 % 33.3 % p = days 18 days Length ICU stay 17 days 19 days p = days 36 days Hospital days 31 days 35 days p =0.47 * Data missing for total of 4 patients CIRCI n = 108 NO CIRCI n = 136*

32 Study population 499 patients with septic shock Hydrocortisone 50 mg IV q 6H for 5 days Dose was tapered during 6-day period (n= 252) Placebo (n= 248) CIRCI n = 125 NO CIRCI n = 118 CIRCI n = 108 NO CIRCI n = 136* 76.0% 84.7% SHOCK REVERSAL 79.7% % 70.4 % 76.5 % NS p = 0.18 NS * Data missing for total of 4 patients

33 Kaplan-Meier Curves for the Time to Reversal of Shock CORTICUS TRIAL (p=0.06) (p= < 0.001) (p= < 0.001) The duration of time until the reversal of shock was significantly shorter among patients receiving hydrocortisone 3.3 days versus 5.8 days

34 28-day mortality Long course of low dose corticosteroids JAMA, June 10, 2009 Vol 301, No. 22

35 Question: Who should be given glucocorticoids? Hydrocortisone should be considered in patients with septic shock, particularly those who have responded poorly to fluid resuscitation and vasopressor agents. Strength of Recommendation: 2B Crit Care Med 2008 Vol. 36, No. 6

36 Question: Who should be given glucocorticoids? Moderate-dose GC should be considered in the management strategy of patients with early severe ARDS (PaO2/FIO2 of 200) and before day 14 in patients with unresolving ARDS. The role of GC treatment in acute lung injury and less severe ARDS (PaO2/FIO2 of 200) is less clear. Strength of Recommendation: 2B Crit Care Med 2008 Vol. 36, No. 6

37 Acute Respiratory Distress Syndrome (ARDS) Normal Alveolus Injured Alveoli during the Acute Phase Early phase: Severe inflammation Late phase: Fibrosis

38 Mortality Crit Care Med 2009 Vol. 37, No. 5

39 Mechanical Ventilation (days) Length of ICU stay (days) Crit Care Med 2009 Vol. 37, No. 5

40 MODS Score Lung Injury Score Crit Care Med 2009 Vol. 37, No. 5

41 ARDS network trial : Findings for patients randomized after Day 14 of ARDS Intensive Care Med (2008) 34:61 69

42 Question: How much steroids to give?

43 Question: How much steroids to give? Septic shock IV Hydrocortisone 200 mg/day in four divided doses OR 100 mg IV bolus, followed by a continuous infusion at 10 mg/hr (240 mg/day) Strength of Recommendation: 1B (strong recommendation with moderate quality of evidence) Crit Care Med 2008 Vol. 36, No. 6

44 Question: How much steroids to give? Early Severe ARDS Methylprednisolone 1 mg / kg / day as continuous infusion Strength of Recommendation: 1B (strong recommendation with moderate quality of evidence) Crit Care Med 2008 Vol. 36, No. 6

45 Question: How much steroids to give? Dexamethasone is NOT recommended for the treatment of septic shock and ARDS Strength of Recommendation: 1B (strong recommendation with moderate quality of evidence) Crit Care Med 2008 Vol. 36, No. 6

46 Question: For how long should we give glucocorticoids? Septic shock treat for >7 days before tapering Early Severe ARDS treat for >14 days before tapering Strength of Recommendation: 2B (weak recommendation with moderate quality of evidence) Crit Care Med 2008 Vol. 36, No. 6

47 Question: For how long should we give glucocorticoids? Glucocorticoid treatment should be tapered slowly and NOT stopped abruptly The dose should be reduced every 2 3 days in small steps Crit Care Med 2008 Vol. 36, No. 6

48 Annane et al, JAMA. 2002; 288: Annane et al, JAMA. 2010;303(4): Study population 509 patients with septic shock Intensive Insulin therapy plus Hydrocortisone Intensive Insulin therapy plus Hydrocortisone plus Fludrocortisone Conventional glucose control plus Hydrocortisone Conventional glucose control plus Hydrocortisone plus Fludrocortisone

49 Annane et al, JAMA. 2002; 288: Annane et al, JAMA. 2010;303(4): Study population 509 patients with septic shock

50 Treatment with fludrocortisone (50 mcg orally once daily) is considered optional. Strength of Recommendation: 2B Crit Care Med 2008 Vol. 36, No. 6

51 Adverse Events Myopathy Superinfections Poor wound healing Hyperglycemia among patients receiving > 300 mg of hydrocortisone equivalents per day Hemodynamic improvement Adverse effects Hydrocortisone mg per day suppress an exaggerated inflammatory response does not seem to have immunosuppressive effects The use of a continuous infusion of hydrocortisone has been reported to less variability of blood glucose concentration

52 Infection Crit Care Med 2009 Vol. 37, No. 5

53 Neuromyopathy Crit Care Med 2009 Vol. 37, No. 5

54 All Major Adverse Events Crit Care Med 2009 Vol. 37, No. 5

55 Summary / Practical Points to Remember CIRCI is a common clinical condition associated with high mortality rate Tests to diagnose CIRCI have significant limitations and should not be used as basis of treatment

56 Summary / Practical Points to Remember Corticosteroid treatment should be considered in the following patients: Septic shock refractory to fluids and vasopressor resuscitation give IV hydrocortisone Early, severe ARDS, or before day 14 of unresolving ARDS give IV methylprednisolone

57 Summary / Practical Points to Remember mortality outcome is conflicting; meta-analysis showed modest survival benefit Corticosteroid treatment only shortens the time to shock reversal

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