Acute phase proteins and other systemic responses to inflammation Dr Donald C McMillan, University Department of Surgery, Royal Infirmary, Glasgow, UK.

Non-infective diseases Infection Shock/ hypoxia SYSTEMIC INFLAMMATION MODS Pancreatitis Trauma Burn Infective diseases Non-infective diseases

Ebb and flow phases of Cuthbertson Ebb Flow Phase Pre-resuscitation phase Recovery phase Poor tissue perfusion Normal tissue perfusion Hypometabolic Hypermetabolic Decreased energy expenditure Increased energy expenditure Increased glucocorticoids Normal glucocorticoids Increased catecholamines Normal catecholamines Low insulin Increased insulin Normal glucose production Increased glucose production Mild protein breakdown Profound protein breakdown

The metabolic response to injury Cuthbertson et al. 1930

Pathophysiological changes of the systemic inflammatory response Neuroendocrine changes Fever, somnolence, fatigue and anorexia Increased adrenal secretion of cortisol, adrenaline and glucagon Haematopoietic changes Anaemia Leucocytosis Thrombocytosis Metabolic changes Loss of muscle and negative nitrogen balance Increased Lipolysis Trace metal sequestration Diuresis Hepatic changes Increased blood flow Increased acute phase protein production Gabay and Kushner, NEJM, 1999

Mediators of the metabolic response to injury Cuthberston (1930) Increased protein breakdown and REE Selye (1940’s) Corticosteroids proposed as mediator Allison (1960’s) Insulin resistance proposed as mediator Cytokines (1980’s) TNF, Il-1, Il-6 proposed as mediators Adipokines (1990’s) Leptin, adiponectin, ghrelin?

Mediators of the metabolic response to injury

SIRS (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 and the systemic inflammatory response Gabay and Kushner, 1999

C-reactive protein in patients undergoing curative surgery for colorectal cancer Crozier et al., 2004

Resting energy expenditure in injury Skeletal Trauma Major Burn Multitrauma Closed Head Injury Sepsis Elective Surgery Starvation -20 20 40 60 80 % Above Usual Requirement

Resting energy expenditure in disease % Above Usual Requirement

Energy Requirements Following Surgery Resting energy expenditure increased by 10-50% to support increased metabolic workload An additional allowance is added for activity 20 % if confined to bed 30 % if ambulatory

Surgery: Protein & Amino Acid Metabolism If there are insufficient protein reserves there is: decreased wound healing decreased immune response defective gut-mucosal barrier decreased mobility/ respiratory effort

Loss of Lean Body Mass Lean body mass= body cell mass metabolically active compartment Irreversible at some point critical mass

Protein requirements are increased to accommodate: 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

Operative measures to reduce protein loss in surgical injury Minimise the inflammatory stimulus Surgical techniques Anaesthesia Control of sepsis Environmental temperature Control of pain and anxiety Nutritional intervention If oral intake less than 60% of energy and protein requirements by 10 days

Release of Il-6, Il-1, TNF, Interferons, growth factors Injury and the systemic inflammatory response Activation of white blood cells, fibroblasts, endothelial cells Release of Il-6, Il-1, TNF, Interferons, growth factors CIRCULATION C-reactive protein Zinc Retinol Albumin Iron Alpha-tocopherol Haemoglobin Copper Carotenoids INFLAMMATORY PROCESS WHOLE BODY Resting energy expenditure Weight loss Body cell Mass QUALITY OF LIFE Fatigue Performance status HEALING

Conclusions The systemic inflammatory response plays an important role in determining protein loss in acute and chronic disease. Conclusions Acute phase proteins in particular C-reactive protein and albumin are useful in quantifying the magnitude of this response and both are associated with poor outcome