อ.กวีศักดิ์systemic response to injury and sepsis response.pdf · systemic...
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Systemic Response to Injury and Sepsis :Systemic Response to Injury and Sepsis : Metabolic Part
ผศ.นพ.กวีศักดิ์ จิตตวัฒนรัตน
ภาควิชาศัลยศาสตร
คณะแพทยศาสตร มหาวิทยาลัยเชียงใหม
TopicTopic
• Body composition
• Basic applied biochemistryBasic applied biochemistry
• Metabolic change during stress vs starvation
• Hormonal response
Body composition
Body compositionBody composition
Body cell mass = Protein + ICWy
Lean body mass = BCM + ECWLean body mass = BCM + ECW≠Mineral + fat
Body composition changeBody composition change
Catabolic phase↓ Body cell mass & fat↑ ECF
Loss of body mass loss > 25‐30%: Inevitable with life
How can I explain this change?How can I modify this change?
Phase of responseBiochemistry changeBiochemistry changeHormonal changeI l i l hImmunological changeCellular change
Phase of metabolic responsePhase of metabolic response
Cuthbertson .Lancet 1942, 1:433–437
Phase of immunologic responsePhase of immunologic response
Early MOF Late MOFy
SIRS CARS
Attenuate responseAttenuate response
Basic biochemistryBasic biochemistry
• Carbohydrate metabolism
• Protein metabolismProtein metabolism
• Fat metabolism• Metabolic change during starvation VS stress
Ch d i t hChange during stress phase
Why body needs glucose?Why body needs glucose?
• Obligate glycolytic cell – Brain and neurons
– Immune cell
Red blood cell– Red blood cell
– Renal parenchymal cell
• Regulate TCA cycle or Kreb’s cycle – NADPH+H + NADPH+H
– Energy
Glycolysis and KetogenesisGlycolysis and KetogenesisGlucose
GlycolysisGlycolysis pathwaypathway
Pyruvate
Pyruvate Dehydrogenase complexPyruvate Dehydrogenase complex Fatty acidPyruvate Dehydrogenase complex(PDHC)
Pyruvate Dehydrogenase complex(PDHC)
Acetyl CoA
y
Acetyl‐CoA
Tricarboxylic acid cycley yKetone production
Cytosol
Mit h d iMitochrondria
Fasting ketogenesis pathwayFasting ketogenesis pathwayGlucose
GlycolysisGlycolysis pathwaypathway
Pyruvate
Pyruvate Dehydrogenase complexPyruvate Dehydrogenase complex Fatty acidPyruvate Dehydrogenase complex(PDHC)
Pyruvate Dehydrogenase complex(PDHC)
Acetyl CoA
y
Acetyl‐CoA
Tricarboxylic acid cycley yKetone production
Stress ketogenesis pathwayStress ketogenesis pathwayGlucose
GlycolysisGlycolysis pathwaypathway
Pyruvate
Pyruvate Dehydrogenase complexPyruvate Dehydrogenase complex Fatty acidPyruvate Dehydrogenase complex(PDHC)
Pyruvate Dehydrogenase complex(PDHC)
Acetyl CoA
y
Acetyl‐CoA
Tricarboxylic acid cycley yKetone production
Glycolysis pathwayy y p y
Glucose Glucose 6 P
GK
Glucose Glucose‐6‐PG6Pase
Glyceral dehyde ‐3‐P
PyruvatePyruvateIrreversible in mammal
Acetyl CoA (TCA)
Glycogenolysis pathwayGlycogen
Glucose Glucose 6 PGlucose Glucose‐6‐P
Glyceral dehyde ‐3‐P
PyruvatePyruvate
Acetyl CoA
Glycogenolysis pathway in liverGlycogen
Glucose Glucose 6 P
GK GlycogenTotal : 300‐400g
Glucose Glucose‐6‐PG6Pase
Liver : 75‐100gMuscle: 200‐250g
Glyceral dehyde ‐3‐P
PyruvatePyruvate
Acetyl CoA
Glycogenolysis pathway in muscleGlycogen
Glucose Glucose 6 P
GK GlycogenTotal : 300‐400g
Glucose Glucose‐6‐PG6Pase
Liver : 75‐100gMuscle: 200‐250g
Glyceral dehyde ‐3‐P
PyruvatePyruvate
Acetyl CoA
Pentose monophosphate shuntGlycogen
Glucose Glucose 6 P
6‐P‐Gluconate
Glucose Glucose‐6‐P NADP
Glyceral dehyde ‐3‐PNADPH+H+
PyruvatePyruvate
Acetyl CoA
Gluconeogenesis – Cori cycleGlycogen
Cori cycle
Glucose Glucose 6 P
6‐P‐GluconateGK
y
Glucose Glucose‐6‐PG6Pase
Glyceral dehyde ‐3‐P
Pyruvate LactatePyruvate Lactate
Acetyl CoA
Gluconeogenesis – Alanine‐Glucose cycle
GlycogenAlanine ‐Glucose cycle
Glucose Glucose 6 P
6‐P‐GluconateGK
y
Glucose Glucose‐6‐PG6Pase
Glyceral dehyde ‐3‐P
Pyruvate AlaninePyruvate Alanine
Acetyl CoAGlutamine
GlutamineGlutamine
BCAA
Alanine
TriglycerideTriglyceride
Glycerol Fatty acidsy y
Gluconeogenesis – Triglyceride
GlycogenFatty acid and Ketone could not produce new glucose
Glucose Glucose 6 P
6‐P‐GluconateGK
y p g
Glucose Glucose‐6‐PG6Pase
Glycerokinase (Liver/kidney)
Glyceraldehyde ‐3‐P Glycerol
PyruvatePyruvate
Acetyl CoA Fatty acid, Ketone
Triglyceride metabolism – Normal
Lipoprotein lipaseBlood vessel
Triglyceride (VLDL chylomicron) Glycerol + Fatty acid(VLDL, chylomicron)
Triglyceride lipaseAdipose tissue
Triglyceride Glycerol + Fatty acidTriglyceride y y
Triglyceride metabolism ‐ Fasting
Lipoprotein lipaseBlood vessel LiverKid
Albumin
Triglyceride (VLDL chylomicron) Glycerol + Fatty acid
Kidney
(VLDL, chylomicron)
Triglyceride lipaseAdipose tissue
ANS etc+ve
Triglyceride Glycerol + Fatty acid
ANS etc
Triglyceride y y
Lipolysis
Triglyceride metabolism ‐ Stress
Lipoprotein lipaseBlood vessel TNF‐α‐ ve
Triglyceride (VLDL chylomicron) Glycerol + Fatty acid
TNF α
(VLDL, chylomicron)
Triglyceride lipaseAdipose tissue
Cathecholamine +ve
Triglyceride Glycerol + Fatty acid
CortisolGlucagon etc
Triglyceride y y
Lipolysis
Triglyceride metabolism – insulin
Lipoprotein lipaseBlood vesselI li
+ve
Triglyceride (VLDL chylomicron) Glycerol + Fatty acid
Insulin
(VLDL, chylomicron)
Triglyceride lipaseAdipose tissue
Insulin‐ve
Triglyceride Glycerol + Fatty acidTriglyceride y y
TGDHTGDHLipogenesis
Fat transporter systemFat transporter system
Stress condition
Impair long chain fatty acid metabolism in stress
CPT I, CPT II = Carnitine palmitoyl transferases I and II
Starvation VS Stress
Early Fasting Man (70kg)
Muscle LiverBrain
Glycogen 75g RBCProtien75g
Gluconeogenesis
WBCKidney
G180g
20%Fat stores GluconeogenesisMuscle
Triglyceride160 L&P 36g
20%
Oxidation160 g
‐ G 16g
L&P 36g
HeartKidneyM l
‐ FA 160g120g
Muscle
Late Fasting Man (70kg) KidneyGluconeogenesis
L&P 44g (55%)
Muscle LiverBrain
Gluconeogenesis
50%
Glycogen 75g RBCProtien20g
Gluconeogenesis
WBCKidney
G80g
45%Fat stores GluconeogenesisMuscle
Triglyceride180 L&P 36g (45%)
45%50%
Oxidation180 g
‐ G 18g
L&P 36g (45%)
Brain58gUrine10g
HeartKidney
‐ FA 180g135g
KidneyMuscle
Stress and trauma (70kg) KidneyGluconeogenesis
L&P 180g (50%)
Muscle LiverWound
Gluconeogenesis
Glycogen 75g RBCProtien250g
Gluconeogenesis
WBCKidney
G360g
Fat stores GluconeogenesisMuscle
Triglyceride170
50%
L&P 180g (50%)Oxidation170 g
‐ G 17g
L&P 180g (50%)
HeartKidneyM l
‐ FA 170g130g
Muscle
Cause of injury Accumulate 10 days N loss (g)Cause of injury Accumulate 10 days N loss (g)
Major burnM lti l i j
170150Multiple injury
PeritonitisB f t
150136115Bone fracture
Major surgeryMi
1155024Minor surgery 24
Ad lt 1 it l L b d 0 04 0 05%Adult : 1 g nitrogen loss = Lean body mass 0.04‐0.05%
25‐30% LBM loss Dead25 30% LBM loss Dead
Mortality N loss threshold =500‐750 gy g
Hormonal response
Membrane receptorsMembrane receptors
Cytosol receptorCytosol receptor
Need time to action
Axis ClassificationAxis Classification
HPT
Pituitary
Effector
CRH – ACTH – Adrenal axisCRH – ACTH – Adrenal axis
Cortisol /GlucocorticoidCortisol /Glucocorticoid
• Effect of cortisol– Increase blood sugar due to synergistic to glucagon g y g g gand catecholamine
– Amino acids release from skeletal muscleAmino acids release from skeletal muscle
– Fat mobilization from adipose tissue
i l i– Hepatic gluconeogenesis
– Insulin resistance
– Decrease inflammatory response (↓TNF‐α, IL‐1, IL‐6 and ↑IL‐10 )
TRH – TSH –thyroid axisthyroid axis
↑ glucose uptake↑glucose oxidation
↑cellular metabolism ↑oxygen consumption
Thyroid metabolism in acute and chronic patients
Euthyroid sick syndrome
Cortisol,Dopamine‐ve
, p
‐ve
ProinflammationProinflammation
GHRH – GH – IGF 1GHRH – GH – IGF‐1
• GHRH Hyperglycemia• GHRH • Autonomic stimulation • thyroxine
• Hyperglycemia• Hyperlipidemia• Somatostatin
• AVP • ACTH• Glucagons
• Beta adrenergic stimulation
• Sex hormone
GHGH+
IGF 1
+
IGF‐1
Effect of GHEffect of GH
i ff• Direct effect– ↑ lipolysis– ↑ protein synthesis– Water and sodium retention Positive
Nit• Indirect effect via IGF‐1
↑ glycogenesis
NitrogenBalance
– ↑ glycogenesis– ↑ lipolysis↑ t i th i– ↑ protein synthesis
• GH and IGF‐1 decrease in injured pts
ProlactinProlactin
• CRH
• TRH
• LHRH
• GnRH Prolactin+• GHRH
• Serotonin
• Dopamine Prolactin+ ‐
• VIP
Immunostimulation :lymphocyte proliferation , IL‐2 , IFN‐γImmunostimulation :lymphocyte proliferation , IL 2 , IFN γSuppress sex hormone : amenorhea
Increase in injured patients
VasopressinVasopressin
(ADH)
CatecholaminesCatecholamines
• epinephrine(Epi) norepinephrine(NE)– Glycogenolysis – T3,T4 – Gluconeogenesis
– Lipolysis– parathyroid hormone
– renin– Ketogenesis– ↓ insulin
– Neutrophilia& lymphocytosis
– ↑ glucagon
Renin – Angiotensin – AldosteroneRenin Angiotensin Aldosterone
ACTH
Refill phenomenon
InsulinInsulin• Effect
– Glycogenesis
• Two phase after injury– Phase I : Insulin deficiency
– Lipogenesis
– Proteogenesis
– Phase II : Insulin resistance
• Improve immune function p
Ti ht t lAnabolic hormone Tight control blood sugar
GlucagonGlucagon
• Action– Glycolysis
– Gluconeogenesis
– Lipolysis & ketogenesis75% of blood sugar
↑ blood sugar
Catabolic hormoneCatabolic hormone
Hyperosmolarity Glycosuria osmotic diuresis dehydration
Insulin resistance ( l i i )
HYPERGLYCEMIA
(glucose toxicity)
HYPERGLYCEMIA(acute severe in hospitalized patient)
Impaired wound healing (collagenSk l t l l healing (collagen glycosylation)
Immune
Skeletal muscle proteolysis
dysregulation
MacrophagesOxidative stress
(proinflammatory)
p g
Neutrophils
I l b li(p y)
Immunoglobulins
Complement
Glycemic Control in SepsisGlycemic Control in Sepsis
• Hyperglycemia alters macrophage function
• Hyperglycemia is proinflammatoryHyperglycemia is proinflammatory• NF kappa B activated with modest hyperglycemia
(Diabetes 1999)(Diabetes 1999)
• Hyperglycemia activates TNF through oxidant stress (inhibited via antioxidants) (JBC 2000)( ) ( )
• Hyperglycemia induces oxidative stress via PKC (Diabetes 2003)
Tight control of blood sugarTight control of blood sugar
Glucose and Insulin after Preop. and Postop. Gl I f i T tGlucose Infusion Tests
25
200
240
20
25GlucoseIRI
160
00
15GLUCOSE p
80
12010
(mmol/L) IRI
mU/L
405
005 30 60 90 5 30 60 90
PREOPERATIVE POSTOPERATIVE
MINUTES GITest
PREOPERATIVE POSTOPERATIVE
Giddings et al. Ann Surg 1977;186:681‐686
Reduction in Insulin Sensitivity afterDifferent Surgical Procedures
100
80
100 % reduction
60
40
0
20
0Lap Chol Hernia Op Chol Colorectal
A. Thorell, J. Nygren, O. Ljungqvist. Curr Op Clin Nutr Met Care 1999
Intensive Insulin Therapy in Critically Ill P ti tPatients
1548 patients with critical illness
783Control
(BS=180 200 mg%)
765Intensive Rx
(BS 80 110 mg%)(BS=180‐200 mg%) (BS=80‐110 mg%)
MR =20.2% MR =10.6%
Greet Van den Berghe, et al. NEJM 2001; 345:1359‐67
Intensive insulin therapy in critically ill patients
Van den Berghe G et al, NEJM 2001
Possible mechanismPossible mechanism
• Hyperglycemic effects– Glucose transporterp
• Insulin effect
GLUT 1 – BBB, GI, Kidney except Liver muscleGLUT 2 Beta cell of pancreasGLUT 2 – Beta cell of pancreasGLUT 3 – Most tissueGLUT 4 Muscle (Correlate to insulin resistance)GLUT 4 – Muscle (Correlate to insulin resistance)GLUT 5 – Fructose transporter
Possible mechanismPossible mechanism
• Hyperglycemic effects– ↑ GLUT 1,3 Transporter in critically ill pts↑ , p y p
– ↓ GLUT 4 Transporter ↑ insulin resistance
↑ Glucose ↑Glucose flux via GLUT 1 3– ↑ Glucose ↑Glucose flux via GLUT 1,3 receptors
• Insulin effect
↑ expression of GLUT 4 ↓ insulin resistance↑ expression of GLUT 4 ↓ insulin resistance
Anabolic effect of insulin
SummarySummary
• Body composition : Changing of body compositionp
• Basic applied biochemistry : CHO, Protein, Fat
M b li h d i i• Metabolic change during stress vs starvation
• Hormonal response and modulate of response p pcould be improve outcome of treatment.
Bundle of treatments are important to flight the injured or septic patientsthe injured or septic patients
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