icu endocrine issue circi and glycemic control paul marik, md, fccm, fccp division of pulmonary and...
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ICU Endocrine Issue CIRCI and Glycemic Control
Paul Marik, MD, FCCM, FCCP
Division of Pulmonary and CCM
Thomas Jefferson University
Philadelphia, PA
Slide 3
Learning Objectives
• To understand the physiology of cortisol production in stress and critical illness.
• To review the recommendations for the diagnosis and management of corticosteroid insufficiency in the ICU.
• To understand the role of insulin and glucose regulation in stress hyperglycemia.
• To appreciate the effects of intensive insulin therapy.
Slide 4
The Stress Response
• Biologic, physical, or psychologic stressors generally precipitate similar response – “general adaptation syndrome”
Selye H. A syndrome produced by diverse nocuous agents. Nature 1936;138:32
Slide 5
The HPA Axis
CRH
ACTH
IL-1TNF
IL-6LIF
IL-11
LIF
CRH GeneTranscription
POMC GeneTranscription
Vasopressin
Stress
Cortisol
TNFTGF-betaendotoxin
CRH
Cortisol
Slide 6
Cortisol & the Stress Response
• Fight & flight response
– Glucose – fuel
– Hemodynamic reserve
• Suppress activated defense mechanisms
– Prevent tissue damage
– Prevent excessive inflammation
Slide 7
Glucocorticoids
• Regulate gene transcription in every cell
• CHO-lipid-protein metabolism
• Immune function
• Cytokine synthesis and action
• Synthesis of catecholamines
• Synthesis of adrenergic receptors
• Cardiac contractility
• Vascular tone
• Membrane permeability
• Many other functions…..
Slide 8
Cortisol Synthesis in Sepsis
Cell Membrane
HDL
Pregnenolone
17OH Pregnenolone
17OH Progesterone
11-Deoxycortisol
Cortisol
Cortisol
Mitochondrion
Smooth endoplasmicreticulum
CYP11B1
CYP17
CYP21
3BHSD Isomerase
CYP11A
Cholestrol
Steroidogenicacute regulatoryprotein (StAR)
Cortisol
Nucleus
Peripheralbenzodiazepam
receptor
ACTH
ACTH HDL Receptor (SR-B1)Scavenger receptor, Class B, type 1
NH2+
NH2
C
NH
CH2
CH2
CH2
TNF
Endotoxin
TNF
Slide 9
Corticosteroid Insufficiency - CIRCI
• Severe sepsis, septic shock, and ARDS are characterized by
• relative corticosteroid insufficiency with an exaggerated
• pro-inflammatory response.
Pro-inflammatory mediators
Anti-inflammatory mediators
Homeostasis
Cortisol
NF-kBImmune dysregulation
Slide 10
CIRCI
• Adrenal insufficiency in critical illness is best described by the term critical illness-related corticosteroid insufficiency (CIRCI).
• The terms absolute or relative adrenal insufficiency are best avoided in the context of critical illness and should be replaced by the term CIRCI.
• CIRCI is a dynamic process, i.e., patients may not have CIRCI on admission to the hospital/ICU but may develop CIRCI during the course of the illness.
Slide 11
CIRCI
• CIRCI is defined as inappropriate corticosteroid activity for the severity of the patient’s illness.
• Relative cortisol insufficiency
– Suppression at any point in the HPA axis with inadequate corticosteroid release
– Drugs or destruction of components of the HPA axis by hemorrhage or necrosis
• Tissue resistance
Analogous to Type II Diabetes
Slide 12
Adrenergic receptorsCatecholamine
NF-κB
Increased pro-inflammatorymediators
CIRCI – Clinical Manifestations
Slide 13
Who to Treat?
• RCT demonstrating benefit from “moderate-dose” steroids
– General ICU patients (n=1)
– Septic shock (n=6)
– Severe sepsis (n=2)
– ALI/ARDS (n=5)
– Ventilator weaning (n=1)
– AF prophylaxis post-cardiac surgery (n=7)
• Cohort studies suggesting benefit from “moderate-dose” steroids
– Liver failure (n=2)
– Pancreatitis (n=1)
• RCT demonstrating NO benefit from “moderate-dose” steroids
– CORTICUS (n=1)
Slide 14
Indications for steroids ??
• ARDS
– Progressive disease after 48 hours management
– PaO2/FiO2 < 150
• Septic shock:
– Norepi > 0.05 -0.1 ug/kg/min within 12 hours of onset
• Cirrhosis/liver failure
• Prevent post-extubation stridor
– -ve cuff leak test
• CABG
• Failure to wean?
• Pancreatitis?
• Head injury/SAH?
Slide 15
The clinical benefit of corticosteroids depends upon the dose, the duration of therapy, and
weaning strategy*
*Old Chinese proverb
Slide 16
Dosing Strategy
• The dose of glucocorticoid should be sufficient to down-regulate the pro-inflammatory response without causing immune-paresis and interfering with wound healing.
• The duration of glucocorticoid therapy should be guided by the duration of CIRCI and the associated duration of systemic inflammation.
• Myopathy and an increased risk of superinfections are more common in patients receiving in excess of 350 mg hydrocortisone equivalents per day.
• While suppressing an exaggerated pro-inflammatory response, a dose of 200-350 mg hydrocortisone/day maintains helper T-cell responsiveness and innate immunity.
Slide 17
Crit Care Med. 2008;36:1937-1949.
Slide 18
Recommendations
• Dysfunction of the HPA axis in critical illness is best described by the term critical illness-related corticosteroid insufficiency (CIRCI).
• The terms absolute and relative adrenal insufficiency are best avoided in the context of critical illness.
• At this time, adrenal insufficiency in critical illness is best diagnosed by a delta cortisol (after 250 ug cosyntropin) of <9 ug/dL or a random total cortisol of <10 ug/dL. (2B)
• The use of free cortisol measurements cannot be recommended for routine use at this time. Although the free cortisol assay has advantages over the total serum cortisol, this test is not readily available. Furthermore, the normal range of the free cortisol in critically ill patients is currently unclear. (2B)
Slide 19
Recommendations
• The ACTH stimulation test should not be used to identify those patients with septic shock or ARDS who should receive GCs. (2B)
• Hydrocortisone should be considered in the management strategy of patients with septic shock, particularly those patients who have responded poorly to fluid resuscitation and vasopressor agents. (2B)
• Moderate-dose GC should be considered in the management strategy of patients with early severe ARDS (PaO2/FiO2 <200) and before day 14 in patients with unresolving ARDS. The role of GC in acute lung injury and less severe ARDS is less clear. (2B)
Slide 20
Recommendations
• In patients with septic shock, intravenous hydrocortisone should be given in a dose of 200 mg/day in four divided doses or as a continuous infusion at 10 mg/hour (240 mg/day). The optimal dosing regimen in patients with early severe ARDS is 1 mg/kg/day methylprednisolone as a continuous infusion. (1B)
• The optimal duration of GC treatment in patients with septic and early ARDS is unclear. However, based on published studies and pathological data, patients with septic shock should be treated for ≥7days before tapering, assuming there is no recurrence or signs of sepsis or shock. Patients with early ARDS should be treated for ≥14 days before tapering. (2B)
Slide 21
Recommendations
• GC treatment should be tapered slowly and not stopped abruptly. (2B)
• Treatment with fludrocortisone (50 ug orally once daily) is considered optional. (2B)
• Dexamethasone is not recommended for treatment of septic shock or ARDS.
Stress Hyperglycemia
Role of Intensive Insulin Therapy
Slide 23
The Stress Response
• Cortisol
• Epinephrine
• Norepinephrine
• Glucagon
• Growth Hormone
• Prolactin
Gluconeogenesis + Glycolysis = Stress Hyperglycemia
Slide 24
Stress Hyperglycemia
• Definition
– Blood glucose >200 mg/dL (15%-20%)
– Blood glucose >110 mg/dL (75%-97%)
• Etiology
– Increased release of counter-regulatory hormones
– Increased hepatic gluconeogenesis
– Decreased insulin release
– Insulin resistance
Slide 25
Hyperglycemia and Insulin
ROS, NADPH oxidase
TNF, IL-8,IL-6
TF, PAI-1
• CATABOLIC
ROS, NADPH oxidase
TNF, IL-6
TF, PAI-1
NO synthase
• ANABOLIC
GlucosePro-inflammatory
InsulinAnti-inflammatory
Slide 26
Insulin-Mediated Glucose Uptake:Muscle and Adipose Tissue
Slide 27
Once Upon a Time…
by Greet Van den Berghe
Slide 28
Intensive Insulin Therapy
• Prospective unblinded RCT of 1,538 adult SICU patients
– 70% cardiothoracic
• Conventional
– titrate glucose to 180-200 mg/dL
• Intensive
– titrate glucose to 80-110 mg/dL
• Primary outcome
– in-hospital mortality
• Secondary outcome
– ICU mortality, days to weaning from MV, ICU and hospital LOS, new kidney injury, incidence of bacteremia
Van den Berghe G et al. N Engl J Med. 2001;345:1359-1367.
Slide 29
Intensive Insulin Therapy
Van den Berghe G et al. N Engl J Med. 2001;345:1359-1367.
Slide 30
Intensive Insulin Therapy in Critically Ill Patients
• ↓ Bloodstream infections by 46%
• ↓ ARF requiring dialysis or CRRT by 41%
• ↓ Critical illness polyneuropathy by 44%
• ↓ RBC transfusions by 50%
• Greater number of ventilator-free days
• Shorter ICU LOS
• Episodes of hypoglycemia (<40 mg/dL)
– 5.1% (IIT) vs. 0.8% (conventional) p <0.001
– No adverse consequencesVan den Berghe G et al. N Engl J
Med. 2001;345:1359-1367.
Slide 31
Van den Berghe G et al. Crit Care Med. 2003;31:359-366.
▲ BG > 150 mg/dL
● BG 110-150 mg/dL
■ BG < 110 mg/dL
Outcome of Intensive Insulin Therapy
Slide 32
Mechanisms of Reduced Morbidity and Mortality with Insulin
• Lower glucose
– Improved macrophage/monocyte function
– Decreased superoxide function and improved mitochondrial function (liver, neurons)
• Higher insulin
– Anti-inflammatory effects
– Anabolic effects
– Improved lipid levels
– Improved endothelial function
Van den Berghe G. J Clin Invest. 2004;114:1187-1195.
Slide 33
Insulin Improves Dyslipidemia
• Abnormal serum lipid profiles in critically ill
– ↑ triglyceride levels, ↓↓ HDL and LDL.
• IIT results in almost complete reversal of hypertriglyceridemia, ↑ HDL and LDL.
• Lipid effects may explain beneficial effect on mortality and organ failure in prolonged critical illness.
Mesotten D et al. J Clin Endocrinol Metab. 2004;89:219-226.
Slide 34
Intensive Insulin Therapy and Outcome in ICU Practice
• 1,600 mixed ICU patients at Stamford Hospital, CT, “before and after” design
– 800 on conventional therapy
– 800 IIT (BG <140 mg/dL)
• Less strict glucose control employed to avoid inadvertent hypoglycemia
• ~ BG 131 mg/dL in IIT vs. 152 mg/dL in conventional
Krinsley JS. Mayo Clin Proc. 2004;79:992-1000.
Slide 35
The Fairy Tale Continues…..
Slide 36
Intensive Insulin Therapy
• Prospective unblinded RCT of 1,200 adult MICU patients staying >3 days
• Conventional
– titrate glucose to 180-200 mg/dL
• Intensive
– titrate glucose to 80-110 mg/dL
• Primary outcome
– in-hospital mortality
• Secondary outcome
– ICU mortality, days to weaning from MV, ICU and Hospital LOS, new kidney injury, incidence of bacteremia
Van den Berghe G et al. N Engl J Med. 2006;354:449-461.
Slide 37
Intensive Insulin Therapy
Van den Berghe G et al. N Engl J Med. 2006;354:449-461.
Slide 38
Intensive Insulin Therapy
Van den Berghe G et al. N Engl J Med. 2006;354:449-461.
80% calories by parenteral nutrition80% calories by parenteral nutrition
Slide 39
Intensive Insulin Therapy
IIT – 18.7% hypoglycemiaIIT – 18.7% hypoglycemiaVan den Berghe G et al. N Engl J Med. 2006;354:449-461.
Slide 40
Intensive Insulin Therapy
Conventional Intensive
Hospital Mortality - ITT 40% 37.3%
Hypoglycemia - ITT 3.1% 18.7%
Hospital Mortality - hypoglycemia
73.3% 61.9%
Mortality at day 3 2.8% 3.9%
Van den Berghe G et al. N Engl J Med. 2006;354:449-461.
Hypoglycemia increases risk of DEATHHypoglycemia increases risk of DEATH
Intensive Insulin Therapy Clinical Trials: Update
Slide 42
German Competence Network Sepsis (SepNet)
• Prospective, randomized, multicenter study of intensive vs. conventional insulin therapy on outcome in patients with severe sepsis/septic shock
• April 2003 - December 2005
• 488 patients (planned 600):
– 247 intensive insulin (80 110 mg/dL)
– 241 conventional (180 200 mg/dL)
N Engl J Med. 2008;358:125-139.
Slide 43
VISEP Trial: Stopped in Late 2005
Conventional
n= 241
Intensive Insulin
n=247
Male 61.9% 49.8%
Mean age, year 64.9% 63.8%
Hypoglycemia 4.1% 17*
Serious adverse events 5.2% 10.9%#
28-day mortality 26% 24.7%
90-day mortality 35.4% 39.7%
* p=<0.001; # p<0.01
Slide 44
GLUCONTROL
• Prospective, multicenter RCT of adult patients
• 7 countries, 21 ICUs in 19 centers
• Intervention:
– Intensive: titrate glucose to 80-110 mg/dL
– Conventional: titrate glucose to 140-180 mg/dL
• Planning:
– 3,500 patients required to detect 4% ↓ in mortality
– Interim analysis each 100 ICU deaths
• Study stopped on May 29, 2006
– Safety concern
http://clinicaltrials.gov
Slide 45
GLUCONTROL
Group A
n=538 (IIT)
Group B
n=553 (CV)p value
Mortality rate 12.27% 9.76% 0.186
Death among patients with hypoglycemia (<40 mg/dL)
18.3% 11.6% 0.0002
Slide 46
Ann Intern Med. 2007;146:233-243.
Slide 47
Intensive Intraoperative Insulin Rx
Ann Intern Med. 2007; 146:233-243.
Slide 48
Tight Glycemic Control – Unanswered Questions
• Ideal goal?
– 80 -110 mg/dL
– 100 -140 mg/dL
– 110 -150 mg/dL
• Elective surgical (cardiac) vs. medical
• Only in patients on TPN?
• Less tight first 3 days?
• How to measure blood glucose?
– Accuracy of “Accuchecks”
– Q12 simultaneous lab glucose measurements
Case Studies with Questions
The following are case studies that can be used for review of this presentation.
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Slide 50
Case Presentation
• A 56-year-old gentleman status post-coronary artery bypass surgery develops a ventilator-associated pneumonia with bacteremia. Despite fluid resuscitation, he remains hemodynamically unstable. His urine output has decreased.
• He is currently receiving 20 μg/min of norepinephrine, 2.4 units/hour of vasopressin, and 5 μg/min of dobutamine.
Slide 51
Case Presentation
• His vital signs are notable for:
– A CVP of 12
– BP of 90/30 mm Hg
– SpO2 of 91% on an FIO2 of 80%
– Temperature of 40 degrees Celsius
• His laboratory data are notable for:
– WBC: 17,000/mm3
– Random cortisol: 9 μg/dL
– Glucose: 217 mg/dL
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Slide 53
Conclusion
• This concludes this presentation.