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

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.

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

The HPA Axis

CRH

ACTH

IL-1TNF

IL-6LIF

IL-11

LIF

CRH GeneTranscription

POMC GeneTranscription

Vasopressin

Stress

Cortisol

TNFTGF-betaendotoxin

CRH

Cortisol

Cortisol & the Stress Response

• Fight & flight response

– Glucose – fuel

– Hemodynamic reserve

• Suppress activated defense mechanisms

– Prevent tissue damage

– Prevent excessive inflammation

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…..

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

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

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.

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

Adrenergic receptorsCatecholamine

NF-κB

Increased pro-inflammatorymediators

CIRCI – Clinical Manifestations

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)

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?

The clinical benefit of corticosteroids depends upon the dose, the duration of therapy, and

weaning strategy*

*Old Chinese proverb

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.

Crit Care Med. 2008;36:1937-1949.

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)

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)

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)

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

The Stress Response

• Cortisol

• Epinephrine

• Norepinephrine

• Glucagon

• Growth Hormone

• Prolactin

Gluconeogenesis + Glycolysis = Stress Hyperglycemia

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

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

Insulin-Mediated Glucose Uptake:Muscle and Adipose Tissue

Once Upon a Time…

by Greet Van den Berghe

Intensive Insulin Therapy

• Prospective unblinded RCT of 1,538 adult SICU patients

– 70% cardiothoracic

• Conventional

– titrate glucose to 180-200 mg/dL

• Intensive


• 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.

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.

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

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.

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.

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.

The Fairy Tale Continues…..


• Prospective unblinded RCT of 1,200 adult MICU patients staying >3 days

• Conventional


• Intensive


• Primary outcome

– in-hospital mortality

• Secondary outcome

– ICU mortality, days to weaning from MV, ICU and Hospital LOS, new kidney injury, incidence of bacteremia




80% calories by parenteral nutrition80% calories by parenteral nutrition


IIT – 18.7% hypoglycemiaIIT – 18.7% hypoglycemiaVan den Berghe G et al. N Engl J Med. 2006;354:449-461.


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 DEATHHypoglycemia increases risk of DEATH

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 (80 110 mg/dL)

– 241 conventional (180 200 mg/dL)

N Engl J Med. 2008;358:125-139.

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

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

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

Ann Intern Med. 2007;146:233-243.

Intensive Intraoperative Insulin Rx

Ann Intern Med. 2007; 146:233-243.

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.

Review Cases

Skip Case Studies

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.

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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Conclusion

• This concludes this presentation.

icu endocrine issue circi and glycemic control paul marik, md, fccm, fccp division of pulmonary and...

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pancreatitis n

aliards n

septic shock n

term circi

patients illness

severe sepsis n

context of critical

cortisol synthesis