Acute phase proteins and other
systemic responses to inflammation
Dr Donald C McMillan,
University Department of Surgery,
Royal Infirmary, Glasgow, UK.
Shock/
hypoxia
Infection
SYSTEMIC
INFLAMMATION
Pancreatitis
MODS
Trauma
Infective diseases
Burn
Non-infective diseases
Ebb and flow phases of Cuthbertson
Ebb
Flow Phase
Pre-resuscitation phase
Poor tissue perfusion
Hypometabolic
Decreased energy expenditure
Increased glucocorticoids
Increased catecholamines
Low insulin
Normal glucose production
Mild protein breakdown
Recovery phase
Normal tissue perfusion
Hypermetabolic
Increased energy expenditure
Normal glucocorticoids
Normal catecholamines
Increased insulin
Increased glucose production
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
Hormonal
Metabolic
Chemical
 Catecholamines
 REE
 pH
 Glucagon
Hyperglycemia
Prostanoids
 Corticosterioids
Ketoacidosis
Leukotrienes
Insulin Resistance
Uremia
Cytokines
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
0
20
40
% Above Usual Requirement
60
80
Resting energy expenditure in disease
Cancer
Acute Renal
Acute Renal
Liver Failure
Lung (COPD)
GI (Crohn's)
-40
-20
0
20
% Above Usual Requirement
40
60
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
Injury and the systemic inflammatory response
Activation of white blood cells, fibroblasts, endothelial cells
CIRCULATION
C-reactive protein
Albumin
Haemoglobin
Zinc
Iron
Copper
Retinol
Alpha-tocopherol
Carotenoids
WHOLE BODY
Resting energy expenditure
Weight loss
QUALITY OF LIFE
Fatigue
Performance status
HEALING
Body cell Mass
INFLAMMATORY PROCESS
Release of Il-6, Il-1, TNF, Interferons, growth factors
Conclusions
The systemic inflammatory response plays an important role
in determining protein loss in acute and chronic disease.
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