Transcript Adjunctive Pharmacotherapy In Sepsis

Adjunctive Pharmacotherapy
In Sepsis
นายแพทย์ เฉลิมไทย เอกศิลป์
สถาบันสุขภาพเด็กแห่งชาติมหาราชินี
Insulin Therapy & Glycemic Control
• Hyperglycemia is common in critically-ill patients
• Associated 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
Hyperglycemia in Critically-Ill Patients
Van den Berghe G. J Clin Invest 2004; 114 : 1187-1195.
Effects of Hyperglycemia on Critically-Ill Patients
Insulin Therapy In Surgical Patients
• RCT : 1,548 Adult receiving MV in surgical-ICU
• Intensive therapy (BS 80-110 mg/dl) vs conventional gr (180-200
mg/dl)
• Result : decreased mortality and complications
• Mortality-Intensive gr vs conventional gr :4.6% vs 8%,P<0.04
• Decreased
– mortality
34%
– Blooodstream infection
46%
– Renal failure
28%
– Renal failure requiring dialysis
41%
– Critical-illness polyneuropathy
44%
– Need for prolong MV
39%
Intensive Insulin Therapy
in The Medical ICU
RCT
1,700 Critically-ill patients in Med-ICU
Intensive insulin therapy vs conventional gr
Intensive insulin
MR in hosp Overall
ICU > 3 d
Renal Failure
37.3%
43.0%
5.9%
Conventional gr
40.0%
52.5%
8.9%
P
0.33
0.009
0.04
Mechanism of Insulin Therapy
• Correct hyperglycemia
• Decrease cell apoptosis
• Anti-inflammatory action
-Suppress production :
inflammatory cytokines, superoxide
-Decrease adhesion molecule soluble :
ICAM-1, E-selectin
Insulin Therapy
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Start insulin infusion when BS>110 mg/dl
Strictly control BS: 80-110 mg/dl
Initial dose <0.05 unit/kg/hr-1 unit/kg/hr
Closely monitor BS
After ICU discharge, maintenance of BS<200
mg/dl
• Concern about hypoglycemia in pediatric
patients
• Clinical trial in pediatric patients is on going
Corticosteroid In Sepsis
• Anti-inflammatory action of high dose
corticosteroid therapy fails to decrease
mortality in sepsis and septic shock.
• Adverse drug reactions : superinfection,
hyperglycemia, GI bleeding
Adrenal Insufficiency
in Critically-Ill Patients
• Incidence ranges 0-75%
• Adrenal insufficiency is associate with
poor outcomes
• Mechanism
Inflammatory cytokines & mediators suppress
the HPA-axis and induces resistance of
glucocorticoid receptor
Adrenal Insufficiency in Critically –Ill Patients
Mechanism
Central
Hypothalamic or pituitary disease
Brain injury
Recent steroid use
Peripheral
Preexisting adrenal failure
Acute adrenal failure
Inadequate substrate
Interference ACTH action
P450 impairment
Increased clearance
Glucocorticoid receptor blockage
End-organ unresponsiveness
Other
Causes
Sepsis / inflammation
Associated with
hyperpigmentation,hypoglycemia
mild hyponatremia and hyperkalemi
Adrenal hemorrhage, autoimmune
adrenalitis
Low cholesterol
Suramin
Ketoconazole, etomidate, sepsis,
prematurity, age < 6 months
Rifampin, phenytoin, phenobarbital
Mifepristone
Cytokines decreases glucocorticoid
receptor sensitivity
Circulating inflammatory cytokine
suppress HPA axis
Felmet K and Caicillo J. .In : Fuhrman BP & Zimmerman J. Pediatric Critical Care.3rd ed. 2006 : 1462-1473.
• Diagnosis is so difficult, no consensus
• Cortisol level in critically ill patients
vary from the healthy normal level to
20 times
Clinical Manifestration of Adrenal Insufficiency
1. Symptoms
อ่อนเพลีย
เบื่ออาหาร คลื่นไส้ อาเจียน
ปวดท้อง
ปวดกล้ามเนื้อหรือข้อ
วิงเวียน
กระหายเกลือ
ปวดหัว
ความจาเสื่อม
ซึมเศร้า
3. Laboratory Findings
Hyponatremia
Hyperkalemia
Hypoglycemia
Eosinophilia
Elevated Serum TSH
2. Signs
Hyperpigmentation
Postural hypotension
Tachypnea
Decreased body hair
Vitiligo
Hypopituitarism
Amenorrhea
Intolerance of cold
4. ลักษณะคลินิกที่สาคัญ
Hemodynamic instability
hyper > hypodynamic
Ongoing inflammation without infection
Multiorgan dysfunction
Hypoglycemia
Cooper MS and Stewart PM. N Engl J Med 2003; 348: 727-34.
Diagnosis of Adrenal Insufficiency
ACTH stimulation
< 2 yr : 125 mcg
> 2 yr : 250 mcg
Pizarro CF. Crit Care Med 2005; 33: 855-859.
Treatment with low dose steroid in
patients with septic shock
• 300 adults with septic shock
• Hydrocortisone(200mg/day)+fludrocortisone (50 mcg/day) vs
placebo
• ACTH stimulation test to identify cases with adrenal insufficienc
• 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.
Systematic review, Meta-analysis
16 RCTs, n=2,063
Result
Low dose corticosteroid
decreased mortality
more rapid for shock reversal
no difference of adverse drug events :
hyperglycemia,superinfection and GI bleeding
High dose corticosteroid did not decreased the
mortality
Annane D. BMJ 2004;329:480-489.
The Effect of Steroids on Survival and Shock
during Sepsis Depends on the Dose
• Meta-Analysis : 14 RCTs
• 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.
!! Confusion !!
Mechanism of Low Dose Corticosteroid
• Cortisol substitution
• Anti-inflammation
Decrease
IL-6,IL-8,soluble E-selectin
neutrophil activation
• 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.
Indications for Corticosteroid
in Septic Shock
1.Catecholamine resistance septic shock
with adrenal insufficiency
2.Catecholamine resistance septic shock
suspected adrenal insufficiency :
purpura fulminans, steroid use,
diseases of hypothalamic-pituitary- adrenal
prolonged critically -illness
3.Catecholamine resistance septic shock ???
Felmet K and Caicillo J.In : Fuhrman BP & Zimmerman J. Pediatric Critical Care.3rd ed.2006 : 1462-1473.
Parker MM.Crit Care Med 2004 ; 32 (Suppl.) :S591-S594.
Incidence of Adrenal Insufficiency in
Pediatric Patients with Septic Shock
• Septic shock 44 %
• Catecholamine resistance
septic shock 80-100 %
Pizarro CF. Crit Care Med 2005; 33: 855-859.
Indications for Corticosteroid
in Septic Shock
1.Catecholamine resistance septic shock
with adrenal insufficiency
2.Catecholamine resistance septic shock
suspected adrenal insufficiency :
purpura fulminans, steroid use,
diseases of hypothalamic-pituitary- adrenal
prolonged critically -illness
3.Catecholamine resistance septic shock
Felmet K and Caicillo J.In : Fuhrman BP & Zimmerman J. Pediatric Critical Care.3rd ed.2006 : 1462-1473.
Parker MM.Crit Care Med 2004 ; 32 (Suppl.) :S591-S594.
Which are the appropriate adjunctive
pharmacotherapies for this patients ?
Corticosteroid In Septic Shock
• Hydrocortisone 1 mg/ kg/ day IV q 8 hr
• Fludrocostisone 1 mcg/ kg/ day oral OD
• Duration of treatment : 5 -7 days and taper on
4 – 6 subsequent days
• Monitor hemodynamic status
• Stop vasopressor use
Annane D. BMJ 2004;329:480-489.