Endocrine_resident Icu Course

8/20/2019 Endocrine_resident Icu Course

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Endocrine Issues in CriticalEndocrine Issues in Critical


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ObjectivesObjectives

Stress responsePathophysiology of stress hyperglycemia

mmunomo u a ng proper es o g ucose an nsu n

Cortisol physiology and biosynthesis

HPA and the stress response

Adrenal physiology in sepsis

Steroid replacement in sepsis


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The Stress ResponseThe Stress Response

o og c, p ys ca , or psyc o og c stressors genera yo og c, p ys ca , or psyc o og c stressors genera y

precipitate similar responseprecipitate similar response – –“ eneral ada tation s ndrome”“ eneral ada tation s ndrome”

Selye H. A syndrome produced by diverse nocuous

agents. Nature. 1936;138:32.


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ct vat on o t e ypot a am c-p tu tary

(HPA) axis

-

system

parasympathetic efferents to GUT


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Activation of HPA axis• Cortisol

Epinephrine

Norepinephrine

Glucagon

Growth hormone


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Cardiac out ut increases

Respiration increases

Gluconeogenesis and catabolism• fuel for brain, heart, muscles

Endocrine programs of pleasure, growth, and

reproduction shut down


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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


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Glucagon and EpinephrineGlucagon and Epinephrine

--


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Glucagon and EpinephrineGlucagon and Epinephrine

--


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Metabolic Consequence of the StressMetabolic Consequence of the Stress

Gluconeogenesis

Gylogenolysis

Proteolysis

Lipolysis

Insulin Resistance

HYPERGLYCEMIAHYPERGLYCEMIA


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Critical illnessCritical illness--state characterized by astate characterized by a


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Acute Stress Acute Stress--Open CholecystectomyOpen Cholecystectomy


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The NeuroThe Neuro--endocrine Response toendocrine Response to

Van den Berghe G. J Clin End Metab.

1998;83:1827.


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Nocturnal profileNocturnal profile

Normal

Acute illness

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


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Changes in the GH Axis During CriticalChanges in the GH Axis During Critical

Acute Acute ChronicChronic

Loss of pulsatile GH

secretionInc. pulsatile GH

secretion

ow - , -

Inc GHBP• recover of GH resistance

Low IGF-1, IGFBP-3• Dec anabolism

Dec. GHBP• GH resistance

• Cytokine mediated

• ? Post-receptor JAK2 kinases


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Stress HyperglycemiaStress Hyperglycemia

e n on

• 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


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Insulin Mediated Glucose UptakeInsulin Mediated Glucose Uptake


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Postulated Mechanism of Insulin ResistancePostulated Mechanism of Insulin Resistance


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Hyperglycemia and InsulinHyperglycemia and Insulin

Pro-inflammatory Anti-inflammatory

ucose nsu n

ROS, NADPH oxidase• Oxidative injury

TNF, IL-8,IL-6

ROS, NADPH oxidase ICAM-1, MCP-1

TNF, IL-6 TF, PAI-1CATABOLIC

TF, PAI-1 NO synthase ANABOLIC


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Protein Catabolism and Nitrogen Balance inProtein Catabolism and NitrogenProtein Catabolism and Nitrogen Balance inBalance in

Acute Renal Failure Acute cute Renal Renal Failure ailure

d a y )

/ g / d a y d a y ) )

2.5

0.0

2.52.5

0.00.0Level of protein administrationLevelLevel of of protein administrationprotein administration

B a l a n c e (

B a l a n c e (

B a l a n c e (

-2.5

-5.0

--2.52.5

--5.05.0

N i t r o g e n

t

N i t r o g e n

N i t r o g e n

-7.5--7.57.5

..

0.8 g0.8 g proteinprotein /kg/ /kg/ dayday


1.51.5 g roteinprotein /k / /kg/ daday N e N e N e -10.0

-12.5

--10.010.0

--12.512.5


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

Macias WLMacias WL etet al.al.

JPEN 20:56,1996JPEN 20:56,1996


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Glucose ToxicityGlucose Toxicity


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Conventional - 78% abnormal Intensive - 1% abnormal

Hepatocyte


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Conventional Intensive Conventional Intensive


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ROS

ICAM-1

MCP-1 PAI-1


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>150 mg/dl

110 -150 mg/dl

< 110 mg/dl


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•

NEJM findings – -

benefit in all patients

– -

incidence of severe hypoglycemia (BS < 50)


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Intensive Insulin Therapy in Critically IllIntensive Insulin Therapy in Critically Ill


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200g Dextrose


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Van den Berghe G. J Clin End Metab.

2004;89:219.


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Regimen 1: 1L 30% sorbital and 1L 5% glucose

Regimen 2: 1L 50% and 1L 5% glucoseinsulin only BG > 270 mg/dl

25

eg men : an g ucoseinsulin to keep BG 72 - 144 mg/dl

15

20

Regim en 1

0

5

10

Regim en 3

Urea Production (g/24hr )


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JPEN. 2002;26:271.


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7 Nitrogen gramsNitrogen grams

5

6

3

4Control

Insulin

0

1

JPEN. 1994;18:214.


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Hyperglycemia: TEN versus TPNHyperglycemia: TEN versus TPN

230

Glucose mg/dl

Trauma meta-analysisTEN n = 92 versus TPN 170

190

210

(n = 102)

Similar ATI, ISS, BEE,130

150

organ injuries

Goal: 0.2 - 0.25 g N/kg/d 7090

B MID END

TPN TEN

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


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Physiologic Effects of Enteral andPhysiologic Effects of Enteral and

Secretion in HumansSecretion in Humans

Glucose Insulin

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


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Placebo GH p

(n = 242)20% 39% < 0.001

Multi-national study

18% 44% < 0.001

Glucose greater in GH group, p < 0.001

Nitrogen retention greater in GH group, p = 0.002


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Glucose Control in the ICUGlucose Control in the ICU

THE GOOD THE BAD

Glycemic control• BS < 110-150

•

High glucose load

High caloric intake

Early enteral nutrition Poor glycemic control

Ra idl absorbed CHOw y

PermissiveGH

Omega 3 FA Low omega 3FA


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Adrenal Insufficiency in the Adrenal Insufficiency in the


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CortisolCortisol


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The HypothalamicThe Hypothalamic--PituitaryPituitary--Adrenal Axis Adrenal Axis

STRESS

Pituitary

Cortisol

Adrenal


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GREGRE

S ffS ff


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Steroid Hormone Receptor TraffickingSteroid Hormone Receptor Trafficking

HSP90

FKBP51

FKBP52

Dynein


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845 genes 1125 genes


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Synthesis of CortisolSynthesis of Cortisol

80% exogenous

20% endogenous

HDL S b t t Ch l t l fHDL S b t t Ch l t l f


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HDL as Substrate Cholesterol forHDL as Substrate Cholesterol for

Life Sciences. 1998;62:1387.


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


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Th NTh N d i R td i R t


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J Clin End Met. 1995;80:1238.

F S C ti l D i th P tF S C ti l D i th P t


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Free Serum Cortisol During the PostFree Serum Cortisol During the Post--opop

25

20

10

5

BL POD1 POD2 POD3 POD4

Total % free Free

Clin Chem Lab Med. 2003;41:146.


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“ Normal” Stress Response“ Normal” Stress Response

>>

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

Free cortisol

Glucocorticoid rece tor

Androgen synthesis

Aldosterone s nthesis


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Cortisol and the Stress ResponseCortisol and the Stress Response

Fight and flight response• Glucose – fuel

• Hemodynamic reserve

uppress ac va edefense mechanisms• Prevent tissue damage

• Prevent excessive inflammation

Adrenalectomy and Survival FollowingAdrenalectomy and Survival Following


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Adrenalectomy and Survival Following Adrenalectomy and Survival Following

Endocrinology. 1990;127:766.


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Evaluation of Adrenal FunctionEvaluation of Adrenal Function

o an aro an ar -- ress or soress or so

When stress is not adequate:

- Insulin hypoglycemia, metyrapone test

• CRH stimulation test

• ACTH corticotro in stimulation test

- Standard - 250 ug

- Low dose - 1 ug


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Standard ACTH TestStandard ACTH Test

Baseline cortisol

250 ug cosyntropin

1 hour level

• 1 hour < 18 ug/dl (AI)• - “ ”

Annane - “Non responder”

C CC C


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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•

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

nonstressed atients

Severely stressed patients may not increase levels

further.

CORTICUS Trial suggests ACTH stimulation does not

have predictive value in critical illness

P bl ith Cl i ACTH T tP bl ith Cl i ACTH T t


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Problems with Classic ACTH TestProblems with Classic ACTH Test

~ 50% of healthy volunteers and stressed patients~ 50% of healthy volunteers and stressed patientswithout evidence of HPA disease will have awithout evidence of HPA disease will have a cortisolcortisol

< 9ug/dl.< 9ug/dl.


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4 hour 12 hour

Acad Emerg Med. 2001;8:1.

LL d C ti t i T td C ti t i T t


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LowLow--dose Corticotropin Testdose Corticotropin Test

H

A C T

J Clin End Metab. 1999;84:3648.


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HD

LD

J Clin End Metab. 1995;80:1243.

Di i f HPA F ilDi i f HPA F il


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Diagnosis of HPA FailureDiagnosis of HPA Failure

ClinicalClinicalHighHigh--dose (250 ug) cosyntropin stimulation testdose (250 ug) cosyntropin stimulation test

Low-dose (1ug) cosyntropin stimulation test

Urinary cortisol (free)

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

Salivary cortisol (free)

Free cortisol index

Free cortisol

IntraIntra--nuclear cortisolnuclear cortisol

Gene productGene product

Adrenal Insufficiency in the Critically IllAdrenal Insufficiency in the Critically Ill


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Adrenal Insufficiency in the Critically Ill Adrenal Insufficiency in the Critically Ill

AdrenergicNF-KB

– –

Catecholamine

Increased

Proinflammatorye a ors

Cli i l Di i f HPA F ilCli i l Di i f HPA F il


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Clinical Diagnosis of HPA FailureClinical Diagnosis of HPA Failure

Hemodynamic instabilityHemodynamic instability

Fever

Unexplained confusionEosinophilia

Hypoglycemia


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Reversible Adrenal InsufficiencyReversible Adrenal Insufficiency

Sepsis and the HPA AxisSepsis and the HPA Axis


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Sepsis and the HPA AxisSepsis and the HPA Axis

Decreased glucocorticoid

receptor synthesis and

affinit

TNF and Cortisol ProductionTNF and Cortisol Production


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TNF and Cortisol ProductionTNF and Cortisol Production

250

Cortisol nmol/l

200

100

150

50

0

BL ACTH ACTH + TNF

0.1

ACTH TNF

1.0

ACTH + TNF

10 ng/ml

Endocrinology. 1991;128:623.


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. o

LDL

HDL


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9

7

8

4

5 Control

TNF

IL-1

2

3 IL-6

0Cell Protein, mg Cell APO-A1

u m cell rotein

Arterioscler Thromb. 1994;14:8.


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Cortisol Synthesis in SepsisCortisol Synthesis in Sepsis


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Cortisol Synthesis in SepsisCortisol Synthesis in Sepsis

TNF

Endotoxin

TNF

ACTH Response During Septic Shock andACTH Response During Septic Shock and


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ACTH Response During Septic Shock and ACTH Response During Septic Shock and

13 of 20 patients BL < 25 mg/dl

30

35

i s o

l m g / d l

25

C o r

15

20

Shock

Recovery

BL 60 min

10

Intensive Care Med. 1996;22:894.


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failure

Paul Marik & GaryZaloga

Hydrocortisone Infusion in PatientsHydrocortisone Infusion in Patients


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yy

n = 46 Placeboy ro-

cortisone

P value

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

Duration10 4 0.007

Hosp LOS 21 13 0.03

Hosp Mortality 7 (30%) 0 0.009

AJRCCM. 2005;171:242.


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Study DescriptionStudy Description


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Design• an om ze , ou e- n , p ace o-contro e tr a

• 19 ICUs France, 1995 - 1999

Po ulation – Se tic 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

u rocor sone q or ma c ng p ace o



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• 250 ug corticotropin test

• Responders

–

• Non-responders (occult adrenal insufficiency)

– increase cortisol < 9 ug/dl

n -po n s• 28-day mortality

• Time to vasopressor withdrawal

Hydrocortisone Increases Survival inHydrocortisone Increases Survival in


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yy

30% RRR of death30% RRR of death100100

SurvivalSurvival (%)(%)

8080

n = 299n = 299

6060 Treatment

2020

4040Placebo

00 77 1414 2121 2828

00

p = 0.0096

Time (days)Time (days)


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• , ,

• RCT design• erences w nnane

– Did not include fludrocortisone – Enrolled patients up to 3 days following onset

of sepsis

– Steroids dosed for 11 days with 6 day taper

NEJM 2008; 358 : 111-124


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•

response to exogenous steroid

vasopressor sparing effect

• xogenous s ero a m n s ra on oes no

have mortality benefit

• Steroid group had higher incidence of

infection and recurrent severe sepsis/shock

NEJM 2008; 358 : 111-124


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AJRCCM. 2003;167:512.


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ConclusionsConclusions


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ConclusionsConclusions

Adrenal insufficiency (AI) common in ICU patients,espec a y ose w seps s.

mediated by cytokines, endotoxin, low HDL, etc.

Role for treatment with re lacement doses ofhydrocortisone (50 - 100 mg q8) remains uncertain.

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Endocrine_resident Icu Course