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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.
The Stress ResponseThe Stress Response
Activation of the hypothalamic-pituitary (HPA) axis
Activation of the sympatho-adrenal system
Activation of subset of vagal and sacral parasympathetic efferents to GUT
The Stress ResponseThe Stress Response
Activation of HPA axis• Cortisol
Epinephrine
Norepinephrine
Glucagon
Growth hormone
Prolactin
The Stress ResponseThe Stress Response
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.
The Neuro-endocrine Response to The Neuro-endocrine Response to Prolonged Critical IllnessProlonged Critical Illness
Nocturnal profileNocturnal profile
Normal
Acute illness
Chronic 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 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
0.8 g0.8 g proteinprotein/kg//kg/dayday
1.0 g1.0 g proteinprotein/kg//kg/dayday
1.5 g1.5 g proteinprotein/kg//kg/dayday
2.0 g2.0 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
Intensive Insulin Therapy in Critically Ill Intensive Insulin Therapy in Critically Ill PatientsPatients
200g Dextrose
Intensive Insulin Therapy in Critically Ill Intensive Insulin Therapy in Critically Ill PatientsPatients
Intensive Insulin Therapy in Critically Ill Intensive Insulin Therapy in Critically Ill PatientsPatients
Van den Berghe G. J Clin End Metab. 2004;89:219.
Intensive Insulin Therapy in Critically Ill Intensive Insulin Therapy in Critically Ill PatientsPatients
Van den Berghe G. J Clin End Metab. 2004;89:219.
Intensive Insulin Therapy in Critically Ill Intensive Insulin Therapy in Critically Ill PatientsPatients
Van den Berghe G. J Clin End Metab. 2004;89:219.
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
The Neuro-endocrine Response to The Neuro-endocrine Response to Prolonged Critical IllnessProlonged Critical Illness
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.