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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
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 3
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 4
The HPA Axis
Stress
CRH Gene
Transcription
CRH
IL-1
TNF
CRH
LIF
Vasopressin
IL-6
LIF
IL-11
POMC Gene
Transcription
Cortisol
TNF
TGF-beta
endotoxin
ACTH
Cortisol
Slide 5
Cortisol & the Stress Response
• Fight & flight response
– Glucose – fuel
• Suppress activated defense
mechanisms
– Prevent tissue damage
– Hemodynamic reserve
– Prevent excessive
inflammation
Slide 6
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 7
Cortisol Synthesis in Sepsis
HDL
ACTH
Cortisol
HDL Receptor (SR-B1)
Scavenger receptor, Class B, type 1
Cell Membrane
CH2
CH2
CH2
NH
Endotoxin
NH2+
C
Cortisol
NH2
Cholestrol
Steroidogenic
acute regulatory
protein (StAR)
ACTH
T
Mitochondrion
N
F
Smooth endoplasmic
reticulum
Peripheral
benzodiazepam
receptor
Cortisol
CYP11A
CYP11B1
Pregnenolone
CYP17
17OH Pregnenolone
11-Deoxycortisol
CYP21
3BHSD Isomerase
Nucleus
Slide 8
17OH Progesterone
T
N
F
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
Immune dysregulation
Cortisol
Homeostasis
Slide 9
NF-kB
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 10
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 11
CIRCI – Clinical Manifestations
Adrenergic
receptors
Catecholamine
NF-κB
Increased
pro-inflammatory
mediators
Slide 12
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 13
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 14
The clinical benefit of
corticosteroids depends upon the
dose, the duration of therapy, and
weaning strategy*
*Old Chinese proverb
Slide 15
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 16
Crit Care Med. 2008;36:1937-1949.
Slide 17
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 18
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 19
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 20
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.
Slide 21
Stress Hyperglycemia
Role of Intensive Insulin Therapy
The Stress Response
• Cortisol
• Epinephrine
• Norepinephrine
• Glucagon
• Growth Hormone
• Prolactin
Gluconeogenesis + Glycolysis = Stress Hyperglycemia
Slide 23
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 24
Hyperglycemia and Insulin
Glucose
Pro-inflammatory
Insulin
Anti-inflammatory
 ROS, NADPH oxidase
 ROS, NADPH oxidase
  TNF, IL-8,IL-6
  TNF, IL-6
  TF, PAI-1
  TF, PAI-1
• CATABOLIC
  NO synthase
• ANABOLIC
Slide 25
Insulin-Mediated Glucose Uptake:
Muscle and Adipose Tissue
Slide 26
Once Upon a Time…
by Greet Van den Berghe
Slide 27
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
Van den Berghe G et al. N Engl J Med.
2001;345:1359-1367.
– ICU mortality, days to weaning from MV, ICU and hospital LOS,
new kidney injury, incidence of bacteremia
Slide 28
Intensive Insulin Therapy
Van den Berghe G et al. N Engl J Med. 2001;345:1359-1367.
Slide 29
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 consequences
Slide 30
Van den Berghe G et al. N Engl J
Med. 2001;345:1359-1367.
Outcome of Intensive Insulin Therapy
▲ BG > 150 mg/dL
● BG 110-150 mg/dL
■ BG < 110 mg/dL
Van den Berghe G et al. Crit Care
Med. 2003;31:359-366.
Slide 31
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
Van den Berghe G. J Clin Invest.
2004;114:1187-1195.
– Improved lipid levels
– Improved endothelial function
Slide 32
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 33
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 34
The Fairy Tale Continues…..
Slide 35
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
Van den Berghe G et al. N Engl J Med.
2006;354:449-461.
– in-hospital mortality
• Secondary outcome
– ICU mortality, days to weaning from MV, ICU and Hospital LOS,
new kidney injury, incidence of bacteremia
Slide 36
Intensive Insulin Therapy
Van den Berghe G et al. N Engl J Med. 2006;354:449-461.
Slide 37
Intensive Insulin Therapy
80% calories by parenteral nutrition
Van den Berghe G et al. N Engl J Med. 2006;354:449-461.
Slide 38
Intensive Insulin Therapy
IIT – 18.7% hypoglycemia
Van den Berghe G et al. N Engl J Med. 2006;354:449-461.
Slide 39
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%
Hypoglycemia increases risk of DEATH
Van den Berghe G et al. N Engl J Med. 2006;354:449-461.
Slide 40
Intensive Insulin Therapy
Clinical Trials: Update
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 (80110 mg/dL)
– 241 conventional (180200 mg/dL)
N Engl J Med. 2008;358:125-139.
Slide 42
VISEP Trial: Stopped in Late 2005
Conventional
Intensive Insulin
n= 241
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 43
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
Slide 44
http://clinicaltrials.gov
GLUCONTROL
Group A
Group B
n=538 (IIT)
n=553 (CV)
Mortality rate
12.27%
9.76%
0.186
Death among
patients with
hypoglycemia
(<40 mg/dL)
18.3%
11.6%
0.0002
Slide 45
p value
Ann Intern Med.
2007;146:233-243.
Slide 46
Intensive Intraoperative Insulin Rx
Ann Intern Med. 2007; 146:233-243.
Slide 47
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
Slide 48
Case Studies with Questions
The following are case studies that can be used for review
of this presentation.
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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 50
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
Slide 51
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Conclusion
• This concludes this presentation.
Slide 53