Endocrine

Endocrine Issues in Critical Endocrine Issues in Critical IllnessIllness

Paul Marik, MD, FCCM, FCCPPaul Marik, MD, FCCM, FCCPProfessor of Medicine

Chief, Div. Pulmonary & CCMThomas Jefferson University

Philadelphia PA

ObjectivesObjectives

Be able to identify the following:Stress responsePathophysiology of stress hyperglycemiaImmunomodulating properties of glucose and insulinBenefits of tight glycemic controlCortisol physiology and biosynthesisHPA and the stress responseEvaluation of HPA in the critically illAdrenal physiology in sepsisSteroid replacement in sepsis

The Stress ResponseThe Stress Response

Biologic, physical, or psychologic stressors generally Biologic, physical, or psychologic stressors generally precipitate similar response –precipitate similar response –

“ “general adaptation syndrome”general adaptation syndrome”

Selye H. A syndrome produced by diverse nocuous agents. Nature. 1936;138:32.


Activation of the hypothalamic-pituitary (HPA) axis

Activation of the sympatho-adrenal system

Activation of subset of vagal and sacral parasympathetic efferents to GUT


Activation of HPA axis• Cortisol

Epinephrine

Norepinephrine

Glucagon

Growth hormone

Prolactin


Cardiac output increases

Respiration increases

Blood flow directed to brain and skeletal muscle

Gluconeogenesis and catabolism• fuel for brain, heart, muscles

Endocrine programs of pleasure, growth, and reproduction shut down

Glucocorticoids and the Stress ResponseGlucocorticoids and the Stress Response

Increase blood glucose↑ hepatic gluconeogenesis

↓ adipose tissue glucose uptake

Lipolysis - FFA release

Prototeolysis - AA release

Synthesis of catecholamines

Synthesis of adrenergic and angiotensin II receptors

Cardiac contractility

Vascular tone

Glucagon and Epinephrine Glucagon and Epinephrine Mediated - GluconeogenesisMediated - Gluconeogenesis

Glucagon and Epinephrine Glucagon and Epinephrine Mediated - GylcolysisMediated - Gylcolysis

Metabolic Consequence of the Stress Metabolic Consequence of the Stress ResponseResponse

Gluconeogenesis

Gylogenolysis

Proteolysis

Lipolysis

HYPERGLYCEMIAHYPERGLYCEMIA

Critical illness-state characterized by a Critical illness-state characterized by a pathologically prolonged stress responsepathologically prolonged stress response

Acute Stress-Open CholecystectomyAcute Stress-Open Cholecystectomy

The Neuro-endocrine Response to The Neuro-endocrine Response to Prolonged Critical IllnessProlonged Critical Illness

Van den Berghe G. J Clin End Metab. 1998;83:1827.


Nocturnal profileNocturnal profile

Normal

Acute illness

Chronic critical illness


Changes in the GH Axis During Critical Changes in the GH Axis During Critical IllnessIllness

Loss of pulsatile GH secretion

Low IGF-1, IGFBP-3

Inc GHBP• recovery of GH resistance

Inc. pulsatile GH secretion• Mobilization fuel

Low IGF-1, IGFBP-3• Dec anabolism

Dec. GHBP• GH resistance

• Cytokine mediated

• ? Post-receptor JAK2 kinases

Acute Acute ChronicChronic

Stress HyperglycemiaStress Hyperglycemia

Definition• Blood glucose > 200 mg/dl (15 - 20%)• Blood glucose > 110mg/dl (75 - 97%)

Etiology• Increased release of counter-regulatory hormones

- increased hepatic gluconeogenesis

• Decreased insulin release• Insulin resistance

Insulin Mediated Glucose UptakeInsulin Mediated Glucose Uptake

Postulated Mechanism of Insulin Resistance Postulated Mechanism of Insulin Resistance in Sepsisin Sepsis

Hyperglycemia and InsulinHyperglycemia and Insulin

ROS, NADPH oxidase• Oxidative injury

TNF, IL-8,IL-6 TF, PAI-1CATABOLIC

ROS, NADPH oxidase ICAM-1, MCP-1 TNF, IL-6 TF, PAI-1 NO synthaseANABOLIC

Pro-inflammatory Anti-inflammatory

Glucose Insulin

Protein Catabolism and Nitrogen Balance inAcute Renal Failure

Protein Catabolism and NitrogenProtein Catabolism and Nitrogen Balance inBalance inAcuteAcute RenalRenal FailureFailure

Non-protein kcal/kg/dayNonNon--protein protein kcal/kg/kcal/kg/dayday

Net

Nitr

ogen

Bal

ance

(g/

day

)N

etN

etN

itrog

enN

itrog

enB

alan

ce (g

/B

alan

ce (g

/da

yda

y))

2.5

0.0

-2.5

-5.0

-7.5

-10.0

-12.5

2.52.5

0.00.0

--2.52.5

--5.05.0

--7.57.5

--10.010.0

--12.512.50 10 20 30 40 50 600 10 20 30 40 0 10 20 30 40 50 6050 60

0.5 g0.5 g proteinprotein/kg//kg/dayday





Level of protein administrationLevelLevel ofof protein administrationprotein administration

Macias WLMacias WL etet al.al.JPEN 20:56,1996JPEN 20:56,1996

Glucose ToxicityGlucose Toxicity

Conventional - 78% abnormal Intensive - 1% abnormal

Hepatocyte

Conventional Intensive Conventional Intensive

ROS

ICAM-1

MCP-1

PAI-1

< 110 mg/dl

110 -150 mg/dl

>150 mg/dl

Intensive Insulin Therapy in Critically Ill Intensive Insulin Therapy in Critically Ill PatientsPatients


200g Dextrose








0

5

10

15

20

25

Urea Production (g/24hr)

Regimen 1

Regimen 2

Regimen 3

Regimen 1: 1L 30% sorbital and 1L 5% glucoseRegimen 2: 1L 50% and 1L 5% glucose insulin only BG > 270 mg/dlRegimen 3: 1L 50% and 1L 5% glucose

insulin to keep BG 72 - 144 mg/dl

JPEN. 2002;26:271.

0

1

2

3

4

5

6

7

Control

Insulin

Nitrogen gramsNitrogen grams

JPEN. 1994;18:214.

Trauma meta-analysis

TEN (n = 92) versus TPN (n = 102)

Similar ATI, ISS, BEE, organ injuries

Goal: 0.2 - 0.25 g N/kg/d507090

110130150170190210230

B MID END

TPN TEN

Hyperglycemia: TEN versus TPNHyperglycemia: TEN versus TPN

Glucose mg/dl

Moore FA, et al. Ann Surg. 1992;216:172.

Physiologic Effects of Enteral and Parenteral Physiologic Effects of Enteral and Parenteral Feeding on Pancreaticobiliary Secretion in Feeding on Pancreaticobiliary Secretion in

HumansHumans

Glucose Insulin

O’Keefe SJ, et al. Am J Physiol. 2003;284:G27.

Placebo GH p

Finnsh Study

(n = 242)20% 39% < 0.001

Multi-national study (n = 280)

18% 44% < 0.001

Glucose greater in GH group, p < 0.001 Nitrogen retention greater in GH group, p = 0.002

Glucose Control in the ICUGlucose Control in the ICU

Tight glycemic control• insulin

Early enteral nutrition

Slowly absorbed CHO

Permissive underfeeding

Omega 3 FA

High glucose load

High caloric intake

Poor glycemic control

Rapidly absorbed CHO

GH

TPN

Low omega 3FA

THE GOOD THE BAD

Adrenal Insufficiency in the Adrenal Insufficiency in the Critically IllCritically Ill

CortisolCortisol

The Hypothalamic-Pituitary-Adrenal AxisThe Hypothalamic-Pituitary-Adrenal Axis

CRH

ACTHCortisol

Hypothalamus

Pituitary

Adrenal

STRESS

GREGRE

Steroid Hormone Receptor TraffickingSteroid Hormone Receptor Trafficking Through the Nuclear Compartment Through the Nuclear Compartment

HSP90FKBP51FKBP52Dynein

845 genes 1125 genes

Synthesis of CortisolSynthesis of Cortisol

80% exogenous20% endogenous

HDL as Substrate Cholesterol for HDL as Substrate Cholesterol for Steroidogenesis by Bovine Adrenal CellsSteroidogenesis by Bovine Adrenal Cells

Life Sciences. 1998;62:1387.

Scavenger Receptor, Type B, Class 1Scavenger Receptor, Type B, Class 1

Cortisol SynthesisCortisol Synthesis


J Clin End Met. 1995;80:1238.

Decreased Cortisol Binding Globulin in Decreased Cortisol Binding Globulin in “Acute” Illness“Acute” Illness

Free Serum Cortisol During the Post-op Free Serum Cortisol During the Post-op Period Determined by Mass SpectrometryPeriod Determined by Mass Spectrometry

0

5

10

15

20

25

BL POD1 POD2 POD3 POD4

Total % free Free

Clin Chem Lab Med. 2003;41:146.

Hamrahian AH, et al. N Engl J Med. 2004;350:1629.

Baseline Serum-free Cortisol and Cosyntropin-Stimulated Serum-free Cortisol Concentrations in Two Groups of Critically Ill Patients

and in Healthy Volunteers

““Normal” Stress ResponseNormal” Stress Response

ACTH > 40 pg/dlACTH > 40 pg/dl

Cortisol level > 20 ug/dlCortisol level > 20 ug/dl

CBG

Free cortisol

Glucocorticoid receptor

Androgen synthesis

Aldosterone synthesis

Cortisol and the Stress ResponseCortisol and the Stress Response

Fight and flight response• Glucose – fuel

• Hemodynamic reserve

Suppress activated defense mechanisms• Prevent tissue damage• Prevent excessive inflammation

Adrenalectomy and Survival Following Adrenalectomy and Survival Following HemorrhageHemorrhage

Endocrinology. 1990;127:766.

Evaluation of Adrenal FunctionEvaluation of Adrenal Function

““Gold Standard” - Stress CortisolGold Standard” - Stress Cortisol

When stress is not adequate: • Provocative testing

- Insulin hypoglycemia, metyrapone test

• CRH stimulation test • ACTH (corticotropin) stimulation test

- Standard - 250 ug- Low dose - 1 ug

Standard ACTH TestStandard ACTH Test

Baseline cortisol

250 ug cosyntropin

1 hour level• 1 hour < 18 ug/dl (AI) < 9 ug/dl - “Occult AI”

Annane - “Non responder”

Problems with Classic ACTH TestProblems with Classic ACTH Test

Bypasses the hypothalamus and pituitary• unphysiological compared to endogenous stressor

Produces supra-physiologic levels of ACTH • serum levels 1000 x1000 x maximal normal stress levels

Cutoff of 18 mcg/dl based on response to ACTH in nonstressed patients

Severely stressed patients may not increase levels further.

~ 50% of healthy volunteers and stressed patients ~ 50% of healthy volunteers and stressed patients without evidence of HPA disease will have a without evidence of HPA disease will have a cortisol < cortisol <

9ug/dl.9ug/dl.

Problems with Classic ACTH TestProblems with Classic ACTH Test

4 hour 12 hour

Acad Emerg Med. 2001;8:1.

Low-dose Corticotropin TestLow-dose Corticotropin Test

J Clin End Metab. 1999;84:3648.

AC

TH

LD

HD

18 ug/dl

J Clin End Metab. 1995;80:1243.

Diagnosis of HPA FailureDiagnosis of HPA Failure

ClinicalClinical

High-dose (250 ug) cosyntropin stimulation testHigh-dose (250 ug) cosyntropin stimulation test

Low-dose (1ug) cosyntropin stimulation test

Urinary cortisol (free)

Random “stress” cortisol (total s-cortisol)Random “stress” cortisol (total s-cortisol)

Salivary cortisol (free)

Free cortisol index

Free cortisol

Intra-nuclear cortisolIntra-nuclear cortisol

Gene productGene product

Adrenergic receptorsCatecholamine

NF-B

Increased ProinflammatoryMediators

Adrenal Insufficiency in the Critically IllAdrenal Insufficiency in the Critically Ill– Clinical Presentation– Clinical Presentation

Clinical Diagnosis of HPA FailureClinical Diagnosis of HPA Failure

HypotensionHypotension

Hemodynamic instabilityHemodynamic instability

Fever

Unexplained confusion

Eosinophilia

Hypoglycemia

Reversible Adrenal Insufficiency Reversible Adrenal Insufficiency of Sepsisof Sepsis

Sepsis and the HPA AxisSepsis and the HPA Axis

IL-1IL-6

TNFCorticostatin++ IL-1EndotoxinTGF-betaACTH-variants

Other??

CRH

ACTH

Decreased glucocorticoidreceptor synthesis and affinity

TNF and Cortisol ProductionTNF and Cortisol Production

0

50

100

150

200

250

BL ACTH ACTH + TNF0.1

ACTH TNF1.0

ACTH + TNF10 ng/ml

Cortisol nmol/l

Endocrinology. 1991;128:623.

T.Chol

HDL

LDL

0

1

2

3

4

5

6

7

8

9

Cell Protein, mg Cell APO-A1ug/ mg cell protein

ControlTNFIL-1IL-6

Arterioscler Thromb. 1994;14:8.

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

Cortisol Synthesis in SepsisCortisol Synthesis in Sepsis

TNF

Endotoxin

TNF

ACTH Response During Septic Shock and ACTH Response During Septic Shock and after Recovery (in patients with HPA failure)after Recovery (in patients with HPA failure)

BL 60 min

Cor

tisol

mg/

dl

10

15

20

25

30

35

ShockRecovery

13 of 20 patients BL < 25 mg/dl

Intensive Care Med. 1996;22:894.

Paul Marik & GaryZaloga

61% patients HPA failure

Study DescriptionStudy Description

Design• Randomized, double-blind, placebo-controlled trial• 19 ICUs France, 1995 - 1999

Population – Septic Shock• Focus of infection + HR >90/min + fever/hypothermia• SBP < 90 mm Hg for 1 hour despite fluid /pressors• Randomization within 8 hours shock

Treatment Arms• Randomization to hydrocortisone 50mg IV q 6 + 50 ug fludrocortisone

PO qd or matching placebo

Study DescriptionStudy Description

Adrenal assessment• 250 ug corticotropin test• Responders

– cortisol > 9 ug/dl

• Non-responders (occult adrenal insufficiency) cortisol 9 ug/dl

End-points• 28-day mortality• Time to vasopressor withdrawal

30% RRR of death30% RRR of death

Time (days)Time (days)

SurvivalSurvival (%)(%)

00 77 1414 2121 282800

2020

4040

6060

8080

100100

Placebo

Treatment

p = 0.0096

n = 299n = 299

Hydrocortisone Increases Survival in Hydrocortisone Increases Survival in Septic ShockSeptic Shock

Hydrocortisone Infusion in Patients Hydrocortisone Infusion in Patients with Severe CAP: A RCTwith Severe CAP: A RCT

n = 46 PlaceboHydro-

cortisoneP value

Dev. MODS 16 (70%) 8 (35%) 0.04

Duration ventilation

10 4 0.007

Hosp LOS 21 13 0.03

Hosp Mortality 7 (30%) 0 0.009

AJRCCM. 2005;171:242.

AJRCCM. 2003;167:512.

ConclusionsConclusions

Adrenal insufficiency (AI) common in ICU patients, especially those with sepsis.

Decreased synthesis of cortisol and release of ATCH mediated by cytokines, endotoxin, low HDL, etc.

Diagnosis of AI controversial - stress cortisol useful dx test in ICU

Treatment with replacement doses of hydrocortisone (50 - 100 mg q8) improves outcome.

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Endocrine