1. Adjunctive Pharmacotherapy In Sepsis นายแพทย์ เฉลิมไทย เอก ศิลป์ สถาบันสุขภาพเด็กแห่งชาติ มหาราชินี

2. Insulin Therapy & Glycemic Control Hyperglycemia is common in critically-ill patientsHyperglycemia is common in critically-ill patients Associated with increased risk of death and substantial morbidity such asAssociated with increased risk of death and substantial morbidity such as critical-illness polyneuropathy skeletal-muscle wasting and need for prolonged mechanical ventilation increased susceptibility to infections Organs failure

3. Hyperglycemia in Critically-Ill Patients Van den Berghe G. J Clin Invest 2004; 114 : 1187-1195.

4. Effects of Hyperglycemia on Critically-Ill Patients

5. Insulin Therapy In Surgical Patients RCT : 1,548 Adult receiving MV in surgical-ICURCT : 1,548 Adult receiving MV in surgical-ICU Intensive therapy (BS 80-110 mg/dl) vs conventional gr (180-200 mg/dl)Intensive therapy (BS 80-110 mg/dl) vs conventional gr (180-200 mg/dl) Result : decreased mortality and complicationsResult : decreased mortality and complications Mortality-Intensive gr vs conventional gr :4.6% vs 8%,P<0.04Mortality-Intensive gr vs conventional gr :4.6% vs 8%,P<0.04 DecreasedDecreased –mortality 34% –Blooodstream infection 46% –Renal failure 28% –Renal failure requiring dialysis 41% –Critical-illness polyneuropathy 44% – Need for prolong MV 39% GREET VAN DEN BERGHE. N Engl J Med2001;345:1359-67

6. Intensive Insulin Therapy in The Medical ICU - RCT 1,700 Critically-ill patients in Med-ICU Intensive insulin therapy vs conventional gr

7. Intensive insulin Conventional gr P MR in hosp Overall 37.3% 40.0% 0.33 ICU > 3 d 0.009 ICU > 3 d 43.0% 52.5% 0.009 Renal Failure 0.04 Renal Failure 5.9% 8.9% 0.04

9. Mechanism of Insulin Therapy Correct hyperglycemia Correct hyperglycemia Decrease cell apoptosis Decrease cell apoptosis Anti-inflammatory action Anti-inflammatory action -Suppress production : -Suppress production : inflammatory cytokines, superoxide -Decrease adhesion molecule soluble : -Decrease adhesion molecule soluble : ICAM-1, E-selectin

10. Insulin Therapy Start insulin infusion when BS>110 mg/dlStart insulin infusion when BS>110 mg/dl Strictly control BS: 80-110 mg/dlStrictly control BS: 80-110 mg/dl Initial dose <0.05 unit/kg/hr-1 unit/kg/hrInitial dose <0.05 unit/kg/hr-1 unit/kg/hr Closely monitor BSClosely monitor BS After ICU discharge, maintenance of BS<200 mg/dlAfter ICU discharge, maintenance of BS<200 mg/dl Concern about hypoglycemia in pediatric patientsConcern about hypoglycemia in pediatric patients Clinical trial in pediatric patients is on goingClinical trial in pediatric patients is on going

11. Corticosteroid In Sepsis Anti-inflammatory action of high dose corticosteroid therapy fails to decrease mortality in sepsis and septic shock.Anti-inflammatory action of high dose corticosteroid therapy fails to decrease mortality in sepsis and septic shock. Adverse drug reactions : superinfection, hyperglycemia, GI bleedingAdverse drug reactions : superinfection, hyperglycemia, GI bleeding

12. Adrenal Insufficiency in Critically-Ill Patients Incidence ranges 0-75%Incidence ranges 0-75% Adrenal insufficiency is associate with poor outcomesAdrenal insufficiency is associate with poor outcomes MechanismMechanism Inflammatory cytokines & mediators suppress the HPA-axis and induces resistance of glucocorticoid receptor

13. Adrenal Insufficiency in Critically –Ill Patients MechanismCauses Central Hypothalamic or pituitary disease Brain injury Brain injury Recent steroid use Recent steroid use Peripheral Preexisting adrenal failure Preexisting adrenal failure Acute adrenal failure Acute adrenal failure Inadequate substrate Inadequate substrate Interference ACTH action Interference ACTH action P450 impairment P450 impairment Increased clearance Increased clearance Glucocorticoid receptor blockage Glucocorticoid receptor blockage End-organ unresponsiveness End-organ unresponsiveness Associated with hyperpigmentation,hypoglycemia mild hyponatremia and hyperkalemia mild hyponatremia and hyperkalemia Adrenal hemorrhage, autoimmune adrenalitis Low cholesterol Suramin Ketoconazole, etomidate, sepsis, prematurity, age < 6 months Rifampin, phenytoin, phenobarbital Mifepristone Cytokines decreases glucocorticoid receptor sensitivity Other Sepsis / inflammation Circulating inflammatory cytokine suppress HPA axis Felmet K and Caicillo J..In : Fuhrman BP & Zimmerman J. Pediatric Critical Care.3 rd ed. 2006 : 1462-1473.

14. Diagnosis is so difficult, no consensusDiagnosis is so difficult, no consensus Cortisol level in critically ill patients vary from the healthy normal level to 20 timesCortisol level in critically ill patients vary from the healthy normal level to 20 times

15. Clinical Manifestration of Adrenal Insufficiency 1. Symptoms อ่อนเพลีย เบื่ออาหาร คลื่นไส้ อาเจียน ปวดท้องปวดกล้ามเนื้อหรือข้อวิงเวียนกระหายเกลือปวดหัวความจำเสื่อมซึมเศร้า 3. Laboratory Findings HyponatremiaHyperkalemiaHypoglycemiaEosinophilia Elevated Serum TSH 2. Signs Hyperpigmentation Postural hypotension Tachypnea Decreased body hair VitiligoHypopituitarism Amenorrhea Amenorrhea Intolerance of cold Intolerance of cold 4. ลักษณะคลินิกที่สำคัญ 4. ลักษณะคลินิกที่สำคัญ Hemodynamic instability hyper > hypodynamic hyper > hypodynamic Ongoing inflammation without infection Ongoing inflammation without infection Multiorgan dysfunction Hypoglycemia Cooper MS and Stewart PM. N Engl J Med 2003; 348: 727-34.

16. Diagnosis of Adrenal Insufficiency Diagnosis of Adrenal Insufficiency Pizarro CF. Crit Care Med 2005; 33: 855-859. ACTH stimulation < 2 yr : 125 mcg > 2 yr : 250 mcg

17. Treatment with low dose steroid in patients with septic shock 300 adults with septic shock300 adults with septic shock Hydrocortisone(200mg/day)+fludrocortisone (50 mcg/day) vs placeboHydrocortisone(200mg/day)+fludrocortisone (50 mcg/day) vs placebo ACTH stimulation test to identify cases with adrenal insufficiencyACTH stimulation test to identify cases with adrenal insufficiency Result :Result : –reduced mortality rate in patients with septic shock and adrenal insufficiency –Adrenal insufficiency -mortality in steroid gr vs placebo :53% vs 63%, p=0.02 Annane D.JAMA 2002;288:862-71.

18. Systematic review, Meta-analysis 16 RCTs, n=2,063 Result Low dose corticosteroid decreased mortality decreased mortality more rapid for shock reversal more rapid for shock reversal no difference of adverse drug events : no difference of adverse drug events : hyperglycemia,superinfection and GI bleeding hyperglycemia,superinfection and GI bleeding High dose corticosteroid did not decreased the mortality Annane D. BMJ 2004;329:480-489 Annane D. BMJ 2004;329:480-489.

19. The Effect of Steroids on Survival and Shock during Sepsis Depends on the Dose Meta-Analysis : 14 RCTsMeta-Analysis : 14 RCTs Results :Results : – Low dose corticosteroid increased survival rate and shock reversal – The treatment effects of steroids on mortality or shock reversal did not statistically significantly differ on the present of adrenal insufficiency or not Minneci PC.Ann Intern Med. 2004;141:47-56.

20. !! Confusion !!

21. Mechanism of Low Dose Corticosteroid Cortisol substitution Cortisol substitution Anti-inflammation Anti-inflammationDecrease IL-6,IL-8,soluble E-selectin neutrophil activation Increase vascular tone via Increase vascular tone via inhibit inducible nitric oxide synthase enhance adrenergic receptor expression stimulate guanylate cyclase KehD. Am J Respir Crit Care Med 2003 ; 167 : 512 - 520.

22. Indications for Corticosteroid in Septic Shock Felmet K and Caicillo J.In : Fuhrman BP & Zimmerman J. Pediatric Critical Care.3 rd ed.2006 : 1462-1473. Parker MM.Crit Care Med 2004 ; 32 (Suppl.) :S591-S594. 1.Catecholamine resistance septic shock with adrenal insufficiency with adrenal insufficiency 2.Catecholamine resistance septic shock suspected adrenal insufficiency : suspected adrenal insufficiency : purpura fulminans, steroid use, purpura fulminans, steroid use, diseases of hypothalamic-pituitary- adrenal prolonged critically -illness diseases of hypothalamic-pituitary- adrenal prolonged critically -illness 3.Catecholamine resistance septic shock ???

23. Incidence of Adrenal Insufficiency in Pediatric Patients with Septic Shock Septic shock 44 %Septic shock 44 % Catecholamine resistance septic shock 80-100 %Catecholamine resistance septic shock 80-100 % Pizarro CF. Crit Care Med 2005; 33: 855-859.

24. Indications for Corticosteroid in Septic Shock Felmet K and Caicillo J.In : Fuhrman BP & Zimmerman J. Pediatric Critical Care.3 rd ed.2006 : 1462-1473. Parker MM.Crit Care Med 2004 ; 32 (Suppl.) :S591-S594. 1.Catecholamine resistance septic shock with adrenal insufficiency with adrenal insufficiency 2.Catecholamine resistance septic shock suspected adrenal insufficiency : suspected adrenal insufficiency : purpura fulminans, steroid use, purpura fulminans, steroid use, diseases of hypothalamic-pituitary- adrenal prolonged critically -illness diseases of hypothalamic-pituitary- adrenal prolonged critically -illness 3.Catecholamine resistance septic shock

25. Which are the appropriate adjunctive pharmacotherapies for this patients ?

26. Corticosteroid In Septic Shock Hydrocortisone 1 mg/ kg/ day IV q 8 hr Hydrocortisone 1 mg/ kg/ day IV q 8 hr Fludrocostisone 1 mcg/ kg/ day oral OD Fludrocostisone 1 mcg/ kg/ day oral OD Duration of treatment : 5 -7 days and taper on 4 – 6 subsequent days Duration of treatment : 5 -7 days and taper on 4 – 6 subsequent days Monitor hemodynamic status Monitor hemodynamic status Stop vasopressor use Stop vasopressor use Annane D. BMJ 2004;329:480-489.