Acute phase proteins and other Acute phase proteins and other systemic responses to inflammationsystemic responses to inflammation

Dr Donald C McMillan,Dr Donald C McMillan,University Department of Surgery,University Department of Surgery,Royal Infirmary, Glasgow, UK. Royal Infirmary, Glasgow, UK.

SYSTEMIC INFLAMMATION

MODS

SYSTEMIC INFLAMMATION

MODS

Shock/

hypoxia

Pancreatitis

BurnBurn

Infection

Infective diseases Non-infective diseases

Trauma

Ebb and flow phases of CuthbertsonEbb and flow phases of Cuthbertson

Ebb Flow Phase Pre-resuscitation phase Recovery phasePoor tissue perfusion Normal tissue perfusionHypometabolic HypermetabolicDecreased energy expenditure Increased energy expenditure Increased glucocorticoids Normal glucocorticoidsIncreased catecholamines Normal catecholaminesLow insulin Increased insulinNormal glucose production Increased glucose productionMild protein breakdown Profound protein breakdown

Cuthbertson et al. 1930

The metabolic response to injuryThe metabolic response to injury

Pathophysiological changes of thePathophysiological changes of thesystemic inflammatory responsesystemic inflammatory response

Gabay and Kushner, NEJM, 1999

Neuroendocrine changesNeuroendocrine changesFever, somnolence, fatigue and anorexiaFever, somnolence, fatigue and anorexiaIncreased adrenal secretion of cortisol, adrenaline and glucagonIncreased adrenal secretion of cortisol, adrenaline and glucagon

Haematopoietic changesHaematopoietic changesAnaemia Anaemia LeucocytosisLeucocytosisThrombocytosisThrombocytosis

Metabolic changesMetabolic changesLoss of muscle and negative nitrogen balanceLoss of muscle and negative nitrogen balanceIncreased LipolysisIncreased LipolysisTrace metal sequestrationTrace metal sequestrationDiuresisDiuresis

Hepatic changesHepatic changesIncreased blood flowIncreased blood flowIncreased acute phase protein productionIncreased acute phase protein production

Mediators of the metabolic responseMediators of the metabolic responseto injuryto injury

Cuthberston (1930) Increased protein breakdown and REECuthberston (1930) Increased protein breakdown and REE

Selye (1940’s) Corticosteroids proposed as mediatorSelye (1940’s) Corticosteroids proposed as mediator

Allison (1960’s) Insulin resistance proposed as mediatorAllison (1960’s) Insulin resistance proposed as mediator

Cytokines (1980’s) TNF, Il-1, Il-6 proposed as mediatorsCytokines (1980’s) TNF, Il-1, Il-6 proposed as mediators

Adipokines (1990’s) Leptin, adiponectin, ghrelin?Adipokines (1990’s) Leptin, adiponectin, ghrelin?

Hormonal Metabolic Chemical

Catecholamines REE pH

Glucagon Hyperglycemia Prostanoids

Corticosterioids Ketoacidosis Leukotrienes

Insulin Resistance Uremia Cytokines

Mediators of the metabolic responseMediators of the metabolic responseto injuryto injury

SIRS SIRS (Systemic Inflammatory Response Syndrome)(Systemic Inflammatory Response Syndrome)

• The systemic response to a wide range of stresses.– Temperature >38°C (100.4°) or <36°C (96.8°F).

– Heart rate >90 beats/min.

– Respiratory rate >20 breaths/min or PaCO2 <32 mmHg.

– White blood cells > 12,000 cells/ml or < 4,000

cells/ml or >10% immature (band) forms.• Note

– Two or more of the following must be present.– These changes should be represent acute alterations from baseline

in the absence of other known cause for the abnormalities.

American College of Chest Physicians/Society of Critical Care Medicine Consensus.Crit Care Med. 1992;20:864-874.

Acute phase proteins andAcute phase proteins andthe systemic inflammatory responsethe systemic inflammatory response

Gabay and Kushner, 1999

day 6day 5day 4day 3day 2day 1pre op

C-r

eact

ive

pro

tein

(m

g/l)

300

200

100

0

Crozier et al., 2004

C-reactive protein in patients undergoingC-reactive protein in patients undergoing curative surgery for colorectal cancercurative surgery for colorectal cancer

-20 0 20 40 60 80

Starvation

Elective Surgery

Sepsis

Closed Head Injury

Multitrauma

Major Burn

Skeletal Trauma

% Above Usual Requirement

Resting energy expenditure in injuryResting energy expenditure in injury

-40 -20 0 20 40 60

GI (Crohn's)

Lung (COPD)

Liver Failure

Acute Renal

Acute Renal

Cancer

Resting energy expenditure in diseaseResting energy expenditure in disease

% Above Usual Requirement

Resting energy expenditure increased by 10-50%to support increased metabolic workload

An additional allowance is added for activity20 % if confined to bed30 % if ambulatory

Energy Requirements Following Surgery

If there are insufficient protein reserves there is:

decreased wound healing

decreased immune response

defective gut-mucosal barrier

decreased mobility/ respiratory effort

Surgery: Protein & Amino Acid Metabolism

Loss of Lean Body Mass

Lean body mass= body cell massmetabolically active compartment

Irreversible at some pointcritical mass

• Immune response

• Increased metabolic activity

• Replacement of damaged cells

• Replacement of protein losses– perspiration, blood, exudates, renal, intestinal if anorexia accompanies fever/infection by muscle proteolysis

Protein requirements are increased to Protein requirements are increased to accommodate:accommodate:

Operative measures to reduce protein lossOperative measures to reduce protein lossin surgical injuryin surgical injury

Minimise the inflammatory stimulusSurgical techniquesAnaesthesiaControl of sepsisEnvironmental temperatureControl of pain and anxiety

Nutritional interventionIf oral intake less than 60% of energy and proteinrequirements by 10 days

Activation of white blood cells, fibroblasts, endothelial cells

Release of Il-6, Il-1, TNF, Interferons, growth factors

CIRCULATION

C-reactive protein Zinc RetinolAlbumin Iron Alpha-tocopherolHaemoglobin Copper Carotenoids

QUALITY OF LIFE

Fatigue Performance status

INFL

AM

MA

TO

RY

PR

OC

ESS

Injury and the systemic inflammatory responseInjury and the systemic inflammatory response

WHOLE BODY

Resting energy expenditure Weight loss Body cell Mass

HEALING

The systemic inflammatory response plays an important rolein determining protein loss in acute and chronic disease.

Acute phase proteins in particular C-reactive protein andalbumin are useful in quantifying the magnitude of this responseand both are associated with poor outcome

Conclusions