อ.กวีศักดิ์systemic response to injury and sepsis response.pdf · systemic...

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


Pyruvate



Acetyl CoA

y

Acetyl‐CoA


Stress ketogenesis pathwayStress ketogenesis pathwayGlucose


Pyruvate



Acetyl CoA

y

Acetyl‐CoA


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


PyruvatePyruvate

Acetyl CoA

Glycogenolysis pathway in liverGlycogen

Glucose Glucose 6 P

GK GlycogenTotal : 300‐400g


Liver : 75‐100gMuscle: 200‐250g


PyruvatePyruvate

Acetyl CoA

Glycogenolysis pathway in muscleGlycogen

Glucose Glucose 6 P

GK GlycogenTotal : 300‐400g


Liver : 75‐100gMuscle: 200‐250g


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



Pyruvate LactatePyruvate Lactate

Acetyl CoA

Gluconeogenesis – Alanine‐Glucose cycle

GlycogenAlanine ‐Glucose cycle

Glucose Glucose 6 P

6‐P‐GluconateGK

y



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


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)


ANS etc+ve

Triglyceride Glycerol + Fatty acid

ANS etc

Triglyceride y y

Lipolysis

Triglyceride metabolism ‐ Stress

Lipoprotein lipaseBlood vessel TNF‐α‐ ve


TNF α

(VLDL, chylomicron)


Cathecholamine +ve

Triglyceride Glycerol + Fatty acid

CortisolGlucagon etc

Triglyceride y y

Lipolysis

Triglyceride metabolism – insulin

Lipoprotein lipaseBlood vesselI li

+ve


Insulin

(VLDL, chylomicron)


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%


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


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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อ.กวีศักดิ์systemic response to injury and sepsis response.pdf · systemic...

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