Endocrine Issues in Critical Illness - Penn Medicine · The NeuroThe Neuro--endocrine Response to endocrine Response to Prolonged Critical IllnessProlonged Critical Illness Nocturnal

Endocrine Issues in Critical Endocrine Issues in Critical IllnessIllnessIllnessIllness

ObjectivesObjectives

Be able to identify the following:Be able to identify the following:Stress responsePathophysiology of stress hyperglycemiaI d l ti ti f l d i liImmunomodulating properties of glucose and insulinCortisol physiology and biosynthesisHPA and the stress responseEvaluation of HPA in the critically illEvaluation of HPA in the critically illAdrenal physiology in sepsisSteroid replacement in sepsis

The Stress ResponseThe Stress Response

Bi l i h i l h l i t llBi l i h i l h l i t llBiologic, physical, or psychologic stressors generally Biologic, physical, or psychologic stressors generally precipitate similar response precipitate similar response ––“general adaptation syndrome”“general adaptation syndrome”g p yg p y

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


A i i f h h h l i i iActivation of the hypothalamic-pituitary (HPA) axis

Activation of the sympatho adrenalActivation of the sympatho-adrenal system

Activation of subset of vagal and sacralActivation of subset of vagal and sacral parasympathetic efferents to GUT


Activation of HPA axis• Cortisol

Epinephrine

Norepinephrine

Glucagong

Growth hormone

ProlactinProlactin


Cardiac output increasesp

Respiration increases

Blood flow directed to brain and skeletal muscleBlood 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 MediatedMediated -- GluconeogenesisGluconeogenesisMediated Mediated -- GluconeogenesisGluconeogenesis

Glucagon and Epinephrine Glucagon and Epinephrine MediatedMediated -- GylcolysisGylcolysisMediated Mediated -- GylcolysisGylcolysis

Metabolic Consequence of the Stress Metabolic Consequence of the Stress ResponseResponseResponseResponse

Gluconeogenesis

Gylogenolysis

Proteolysis

LipolysisInsulin Resistance

HYPERGLYCEMIAHYPERGLYCEMIA

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

Acute StressAcute Stress--Open CholecystectomyOpen Cholecystectomy

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

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


Nocturnal profileNocturnal profile

NormalAcute illnessChronic critical illnessChronic critical illness

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

Changes in the GH Axis During Critical Changes in the GH Axis During Critical IllnessIllnessIllnessIllness

Acute Acute ChronicChronicLoss of pulsatile GH secretionL IGF 1 IGFBP 3

Inc. pulsatile GH secretion• Mobilization fuel Low IGF-1, IGFBP-3

Inc GHBP• recovery of GH resistance

• Mobilization fuel

Low IGF-1, IGFBP-3• Dec anabolism y

Dec. GHBP• GH resistance• Cytokine mediated• ? Post-receptor JAK2 kinases

Stress HyperglycemiaStress Hyperglycemia

D fi itiDefinition• 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 Sepsisin Sepsisin Sepsis

Hyperglycemia and InsulinHyperglycemia and Insulin

Pro-inflammatory Anti-inflammatoryGl I liGlucose Insulin

ROS, NADPH oxidase• Oxidative injury

TNF, IL-8,IL-6

ROS, NADPH oxidaseICAM-1, MCP-1TNF, IL-6

TF, PAI-1CATABOLIC

TF, PAI-1NO synthase

ANABOLIC

Protein Catabolism and Nitrogen Balance inProtein Catabolism and NitrogenProtein Catabolism and Nitrogen Balance inBalance ingAcute Renal FailureAcuteAcute RenalRenal FailureFailure

g/da

y)g/g/

day

day ))

2.5

0.0

2.52.5

0.00.0 Level of protein administrationLevelLevel ofof protein administrationprotein administration

Bal

ance

(gB

alan

ce (g

Bal

ance

(g

-2.5

-5.0

--2.52.5

--5.05.0 0 5 g0 5 g proteinprotein/kg//kg/dayday

tNitr

ogen

tt Nitr

ogen

Nitr

ogen

5.0

-7.5--7.57.5

0.5 g0.5 g proteinprotein/kg//kg/dayday0.8 g0.8 g proteinprotein/kg//kg/dayday1.0 g1.0 g proteinprotein/kg//kg/dayday1.5 g1.5 g proteinprotein/kg//kg/dayday

NetNet

Net -10.0

-12.5

--10.010.0

--12.512.50 10 20 30 40 50 600 10 20 30 400 10 20 30 40 50 6050 60

gg pp gg yy2.0 g2.0 g proteinprotein/kg//kg/dayday

Non-protein kcal/kg/dayNonNon--protein protein kcal/kg/kcal/kg/dayday0 10 20 30 40 50 600 10 20 30 40 0 10 20 30 40 50 6050 60

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

Glucose ToxicityGlucose Toxicity

Conventional - 78% abnormal Intensive - 1% abnormal

Hepatocyte

C CConventional Intensive Conventional Intensive

ROSROSICAM-1MCP-1PAI-1

>150 mg/dl

110 -150 mg/dl

< 110 mg/dl

Intensive Insulin TxIntensive Insulin Tx

• More recent studies have not confirmedMore recent studies have not confirmed NEJM findings

Keeping BS 80 110 may not have mortality– Keeping BS 80-110 may not have mortality benefit in all patients

– Keeping BS 80-110 is associated with highKeeping BS 80 110 is associated with high incidence of severe hypoglycemia (BS < 50)

Intensive Insulin Therapy in Critically Ill Intensive Insulin Therapy in Critically Ill PatientsPatientsPatientsPatients


200g Dextrose





Van den Berghe G. J Clin End Metab.2004;89:219.



Regimen 1: 1L 30% sorbital and 1L 5% glucoseRegimen 2: 1L 50% and 1L 5% glucose

insulin only BG > 270 mg/dlR i 3 1L 50% d 1L 5% l

25

Regimen 3: 1L 50% and 1L 5% glucose insulin to keep BG 72 - 144 mg/dl

15

20

Regimen 1Regimen 2

0

5

10Regimen 2Regimen 3

Urea Production (g/24hr)

JPEN. 2002;26:271.

7Nitrogen gramsNitrogen grams

5

6

2

3

4 ControlInsulin

0

1

2

JPEN. 1994;18:214.

Hyperglycemia: TEN versus TPNHyperglycemia: TEN versus TPN

230Glucose mg/dl

Trauma meta-analysis

TEN (n = 92) versus TPN 170190210

( )(n = 102)

Similar ATI, ISS, BEE, 110130150

organ injuries

Goal: 0.2 - 0.25 g N/kg/d507090

110

50B MID END

TPN TEN

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

Physiologic Effects of Enteral and Physiologic Effects of Enteral and Parenteral Feeding on PancreaticobiliaryParenteral Feeding on PancreaticobiliaryParenteral Feeding on Pancreaticobiliary Parenteral Feeding on Pancreaticobiliary

Secretion in HumansSecretion in Humans

Glucose Insulin

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

Placebo GH pFinnsh StudyFinnsh Study (n = 242)

20% 39% < 0.001

Multi-national study (n = 280) 18% 44% < 0.001(n = 280)

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

THE GOOD THE BADGlycemic control• BS < 110-150• Insulin?

High glucose load

High caloric intakeInsulin?

Early enteral nutritionSlowly absorbed CHO

Poor glycemic control

Rapidly absorbed CHOSlowly absorbed CHOPermissive underfeeding

p y

GH

TPNunderfeedingOmega 3 FA

TPN

Low omega 3FA

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

CortisolCortisol

The HypothalamicThe Hypothalamic--PituitaryPituitary--Adrenal AxisAdrenal Axis

HypothalamusSTRESS

CRH

Hypothalamus

CRH

Pituitary

ACTHCortisol

ACTH

Adrenal

GREGRE

Steroid Hormone Receptor TraffickingSteroid Hormone Receptor TraffickingThrough the Nuclear CompartmentThrough the Nuclear CompartmentThrough the Nuclear CompartmentThrough 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 CellsSteroidogenesis 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.

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

25

15

20

10

15

0

5

0BL POD1 POD2 POD3 POD4

Total % free Free

Clin Chem Lab Med. 2003;41:146.

“Normal” Stress Response“Normal” Stress Response

ACTH > 40 pg/dlACTH > 40 pg/dlACTH 40 pg/dlACTH 40 pg/dlCortisol level > 20 ug/dlCortisol level > 20 ug/dlCBGCBG Free cortisol Glucocorticoid receptorGlucocorticoid receptor Androgen synthesis Aldosterone synthesisdoste o e sy t es s

Cortisol and the Stress ResponseCortisol and the Stress Response

S ti t dFight 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 HemorrhageHemorrhageHemorrhageHemorrhage

Endocrinology. 1990;127:766.

Evaluation of Adrenal FunctionEvaluation of Adrenal Function

“G ld St d d”“G ld St d d” St C ti lSt C ti l“Gold Standard” “Gold Standard” -- Stress CortisolStress CortisolWhen stress is not adequate: • Provocative testing• Provocative testing

- Insulin hypoglycemia, metyrapone test • CRH stimulation test • ACTH (corticotropin) stimulation test ( p )

- Standard - 250 ug- Low dose - 1 ug

Standard ACTH TestStandard ACTH Test

Baseline cortisol 250 ug cosyntropin1 hour level• 1 hour < 18 ug/dl (AI)• < 9 ug/dl - “Occult 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• serum levels 1000 x1000 x maximal normal stress levels

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

Severely stressed patients may not increase levels further.CORTICUS Trial suggests ACTH stimulation does not have predictive value in critical illness

Problems with Classic ACTH TestProblems with Classic ACTH Test

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

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

h h4 hour 12 hour

Acad Emerg Med. 2001;8:1.

LowLow--dose Corticotropin Testdose Corticotropin Test

TH

AC

T

J Clin End Metab. 1999;84:3648.

HD

18 ug/dl18 ug/dl

LD

J Clin End Metab. 1995;80:1243.

Diagnosis of HPA FailureDiagnosis of HPA FailureClinicalClinicalHighHigh--dose (250 ug) cosyntropin stimulation testdose (250 ug) cosyntropin stimulation testLow-dose (1ug) cosyntropin stimulation testUrinary cortisol (free)Random “stress” cortisol (total sRandom “stress” cortisol (total s--cortisol)cortisol)Salivary cortisol (free)Free cortisol indexFree cortisolIntraIntra--nuclear cortisolnuclear cortisolGene productGene product

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

Adrenergic receptors NF-KB

–– Clinical PresentationClinical Presentation

receptorsCatecholamine

Increased ProinflammatoryM di tMediators

Clinical Diagnosis of HPA FailureClinical Diagnosis of HPA Failure

HypotensionHypotensionHypotensionHypotension

Hemodynamic instabilityHemodynamic instability

Fever

Unexplained confusion

Eosinophilia

Hypoglycemia

Reversible Adrenal Insufficiency Reversible Adrenal Insufficiency of Sepsisof Sepsisof Sepsisof Sepsis

Sepsis and the HPA AxisSepsis and the HPA Axis

Decreased glucocorticoidreceptor synthesis and affinityy

TNF and Cortisol ProductionTNF and Cortisol Production

250Cortisol nmol/l

200

100

150

50

0BL ACTH ACTH + TNF

0.1ACTH TNF

1.0ACTH + TNF

10 ng/ml

Endocrinology. 1991;128:623.

T Ch lT.Chol

LDL

HDL

9

6

7

8

4

5

6

ControlTNFIL-1

1

2

3IL 1IL-6

0

1

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

Arterioscler Thromb. 1994;14:8.

Cortisol Synthesis in SepsisCortisol Synthesis in SepsisTNF

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)after Recovery (in patients with HPA failure)after Recovery (in patients with HPA failure)

13 of 20 patients BL < 25 mg/dl

30

35

tisol

mg/

dl 25

Cor

t

15

20

ShockRecovery

BL 60 min10

Intensive Care Med. 1996;22:894.

61% patients HPA61% patients HPA failure

Paul Marik & GaryZaloga

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

Hydron = 46 Placebo Hydro-cortisone P value

D MODS 16 ( 0%) 8 (3 %) 0 04Dev. MODS 16 (70%) 8 (35%) 0.04

Duration ventilation 10 4 0.007ventilation

Hosp LOS 21 13 0.03

Hosp Mortality 7 (30%) 0 0.009

AJRCCM. 2005;171:242.

Study DescriptionStudy Description

DesignR d i d d bl bli d l b t ll d t i l• Randomized, double-blind, placebo-controlled trial

• 19 ICUs France, 1995 - 1999

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

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

fl d ti PO d t hi l bfludrocortisone PO qd or matching placebo

Study DescriptionStudy Description

Adrenal assessmentAdrenal assessment• 250 ug corticotropin test• Responders

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

– increase cortisol < 9 ug/dl

E d i tEnd-points• 28-day mortality• Time to vasopressor withdrawal

Hydrocortisone Increases Survival in Hydrocortisone Increases Survival in Septic ShockSeptic Shock

30% RRR of death30% RRR of death100100

Septic ShockSeptic Shock

SurvivalSurvival (%)(%)8080

n = 299n = 299

6060 Treatment

2020

4040Placebo

00 77 1414 2121 282800

p = 0.0096

Time (days)Time (days)

CORTICUSCORTICUS

• Larger multinational EuropeanLarger, multinational, European• RCT design

Diff ith A• Differences with Annane– 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

CORTICUSCORTICUS

• ACTH stimulation is not predictive ofACTH stimulation is not predictive of response to exogenous steroid

• Exogenous steroid administration has a• Exogenous steroid administration has a vasopressor sparing effectE t id d i i t ti d t• Exogenous steroid administration does not have mortality benefit

• Steroid group had higher incidence of infection and recurrent severe sepsis/shock

NEJM 2008; 358 : 111-124

AJRCCM. 2003;167:512.

ConclusionsConclusions

Adrenal insufficiency (AI) common in ICU patients, i ll th ith iespecially those with sepsis.

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

Diagnosis of AI controversialDiagnosis of AI controversial

Role for treatment with replacement doses of phydrocortisone (50 - 100 mg q8) remains uncertain.

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Endocrine Issues in Critical Illness - Penn Medicine · The NeuroThe Neuro--endocrine Response to endocrine Response to Prolonged Critical IllnessProlonged Critical Illness Nocturnal