METABOLIC RESPONSE TO TRAUMA

Sudarsan Agarwalsushiagarwal@gmail.com

Pinnamaneni Medical College Vijayawada

JOHN HUNTER (1794)

• “Treatise on the Blood, Inflammation and gunshot wounds”

• “Impressions are capable of producing or increasing natural actions and are then called stimuli, but they are capable of producing too much action as well as depraved, unnatural or what we call diseased action.”

Basic Concepts in Homeostasis

1. Homeostasis is the foundation of normal physiology.

2. Stress-free peri-operative care helps to restore homeostasis following elective surgery.

3. Resuscitation, surgical intervention & critical care can return the severely injured patient to a

situation in which homeostasis becomes possible once again.

• As a consequence of modern understanding to metabolic response to injury, elective surgery practice seeks to reduce the need for a homeostatic response by minimizing the primary insult

(as for e.g – Minimal access surgery )

Response Components

• Physiological Consequences• Metabolic Manifestations • Clinical Manifestations• Laboratory Changes

Response Components

PHYSIOLOGICAL• Increased Cardiac Output• Increased Ventilation• Increased Membrane Transport• Weight loss• Wound Healing

METABOLIC• Hypermetabolism• Acclerated Gluconeogenesis• Enhanced Protein breakdown• Increased Fat oxidation

Response Components

CLINICAL• Fever• Tachycardia• Tachypnea• Presence of wound or Inflammation • Anorexia

LABORATORY• Leucocytosis/Leucopenia• Hyperglycemia• Elevated CRP/Altered acute phase reactants• Hepatic/Renal dysfunction

Graded Nature of the injury response

• Metabolic response to injury is Graded and evolves with time

Mediators of injury response

• Neuro endocrine ( Hormonal )• Metabolic and Cytokine axes

Hormonal

Neuro-endocrine response to injury/critical illness

The Neuro-endocrine response to severe injury/critical illness is biphasic

1. Acute phase characterized by an actively secreting pituitary & elevated counter regulatory hormones (cortisol, glucagon, adrenaline).Changes are thought to be beneficial for short-term survival.

2. Chronic phase associated with hypothalamic s uppression & low serum levels of the respective target organ hormones. Changes contribute chronic wasting.

Purpose of Neuro- endocrine changes following injury

The constellation of Neuro-endocrine changes following injury acts to 1. Provide essential substrates for survival2. Postpone anabolism3. Optimise host defense

These changes may be helpful in the short term, but may be harmful in the long-term, especially to the severely injured patient who would otherwise not have survived without medical intervention

Proinflammatory cytokines1. Il 1, Il 6, TNF alfa2. NO3. Endothelin 1

Cytokine antagonist• Interleukin receptor antagonist, TNF soluble

receptors are released within hours of injury

Physiological response to injury

The natural response to injury includes 1. Immobility2. Anorexia3. Catabolism

• In 1930, Sir David Cuthherstson derived the metabolic response to injury in humans into “ebb “ and “flow” phases

Metabolic changes after major trauma(Cuthbertson, Lancet, 1942)

EBB (Untreated shock)• Dec body temp• Dec O2 consumption• Lactic acidosis• Inc stress hormones• Dec Insulin• Hyperglycemia• Gluconeogenesis• Inc substrate consumption• Hepatic Acute phase response• Immune activation

FLOW PHASE• Inc body temp• Inc O2 consumption• Negative Nitrogen bal• Inc stress hormone• Normal to Inc Insulin• Hyperglycemia• Gluconeogenesis• Proteinolysis (autocannabalism)• Lipolysis• Immunosuppression

Ebb and Flow

Phase Duration Role Physiological Hormones

Ebb <24 hrs Maintenance of blood volume, catecholamines

Dec BMR, Dec temp, Dec O2 consump, vasoconst, Inc CO, Inc heart rate, acute phase proteins

Catechol, Cortisol, aldosterone

Flow

Catabolic 3 – 10 days

Maintenance of energy

Inc BMR, inc Temp, inc O2 consump, -ve N2 balance

Inc. Insulin, Glucagon, Cortisol, Catechol but insulin resistance

Anabolic (MOORE)

10 – 60 days

Replacement of lost tissue

+ve Nitrogen balance Growth hormone, IGF

Ebb

• Starts at the time of injury and lasts for approximately 24-48 hours

• Main hormones in ebb phase are catecholamines, cortisol, and aldosterone

• It may be attenuated by proper resuscitation but not completely abolished

• The main physiological role of this phase is to conserve both circulating volume and energy stores for recovery and repair

Flow

• It lasts for several wks• This phase involves mobilization of body

energy stores for repair and recovery• Following resuscitation , Ebb phase evolves

into hypermetabolic flow phase, which corresponds to SIRS

Key catabolic elements of flow phase

• Hypermetabolism• Alterations in skeletal muscle protein• Alterations in Liver protein• Insulin resistance

Hypermetabolism

Majority of trauma patients demonstrate energy expenditure approximately 15-25% above predicted healthy resting values

Factors which increases this metabolism are centreal thermodysregulation, increased sympathetic activity, increased protein turnover, wound circulation abnormalities etc..

Hypermetabolism

Hyper metabolism following injury:

1. Is mainly caused by an acceleration of futile metabolic cycles2. Is limited in modern practice on account of elements of routine critical care.

Skeletal muscle wasting

1. Provides amino acids for protein synthesis in central organ/tissues2. Is mediated at a molecular level mainly by activation of the ubiquitin-protease pathway3. Can result in immobility & contribute to hypostatic pneumonia & death if prolonged and excessive

Hepatic acute phase response

• The Hepatic acute phase response represents a reprioritization of body protein metabolism towards the liver & is characterized by:

• 1. Positive reactants (CRP) : plasma concentration increases

• 2. Negative reactants (albumin) : : plasma concentration decreases

Insulin resistance

• The degree of insulin resistance is directly proportional to magnitude of the injurious process.

• Following routine upper abdominal surgery, insulin resistance may persist foe appr 2 wks

• Postop patients with insulin resistance behave in a similar manner to individuals with type 2 diabetes

• The mainstay of treatment is i.v insulin • Intensive insulin infusions are better over

conservative approach.

• Main labile energy reserve in the body is fat• Main labile protein reserve in the body is

skeletal muscle

• While fat mass can be reduced without major detriment to function, loss of protein mass results not only in skeletal muscle wasting, but also depletion of visceral protein mass

• With lean issue, each 1 g of nitrogen is contained within 6.25 g of protein, which is contained in approximately 36 g of wet weight tissue.

• Thus the loss of 1 g of nitrogen in urine is equivalent to the breakdown of 36 g of wet weight lean tissue.

• Protein turnover in the whole body is of the order of 150-200 g per day.

• A normal human ingests 70-100 g of protein per day, which is metabolized and excreted in urine as ammonia and urea(14 g N/day)

• During total starvation, urinary loss of nitrogen is rapidly attenuated by a series of adaptive changes

• Loss of body weight follows a similar course , thus accounting for the survival of hunger strikers for a period of 50-60 days

• Following major injury, and particularly in the presence of ongoing septic complications , this adaptive change fails to occur, and there is a state of auto cannibalism , resulting in continuing urinary nitrogen losses of 10-20 g/day(500 g lean tissue/day)

• As with total starvation, once loss of body protein mass has reached 30-40 % of the total, survival is unlikely

In critically ill patients with resuscitation,

• <24 hrs – Body weight increases due to extracellular water expansion by 6-10 litres.

– This can be overcome by careful intra operative management of fluid balance

• 1-10 days – Total body protein will diminish by 15% and body weight will reach negative balance as the expansion of extra cellular space resolves

– This can be overcome by blocking Neuro endocrine response with epidural analgesia and early enteral feeds

Avoidable factors that compound the response to injury

1. Continuing hemorrhage 2. Hypothermia3. Tissue edema4. Tissue under perfusion5. Starvation6. Immobility

• Volume loss: Careful limitation of intra operative administration of colloids and crystalloids so that there is no net weight gain

• Hypothermia : RCT have shown that normothermia by an upper body forced air heating cover reduces wound infection, cardiac complications and bleeding and transfusion requirements

• Tissue edema : During systemic inflammation, fluid, plasma proteins, leucocytes, macrophages and electrolytes leave the vascular space and accumulate in the tissues.

• This can diminish the alveolar diffusion of oxygen and may lead to reduced renal function

• Systemic inflammation and tissue under perfusion: the vascular endothelium controls vasomotor tone and micro vascular flow and regulates trafficking of nutrients and biologically active molecules.

• Administration of activated protein C to critically ill patients has been shown to reduce organ failure and death and is thought to act, in part, via preservation of the micro circulation in vital organs

• Maintaining the normoglycemia with insulin infusion during critical illness has been proposed to protect the endothelium, probably in part, via inhibition of excessive iNOS- induced NO release , and thereby contribute to the prevention of organ failure and death

• Starvation : During starvation, the body is faced with an obligate need to generate glucose to sustain cerebral energy metabolism(100g of glucose per day)

• This is achieved in the first 24 hours by mobilizing glycogen stores and thereafter by hepatic gluconeogenesis from amino acids, glycerol and lactate.

• The energy metabolism of other tissues is sustained by mobilizing fat from adipose tissue

• Such fat metabolisation is mainly dependent on a fall in circulating insulin levels.

• Eventually , accelerated loss of lean tissue is reduced as a result of the liver converting free fatty acids into ketone bodies, which can serve as a substitute for glucose for cerebral energy metabolism.

• Provision of 2 litres of iv 5% D as iv fluids for surgical patients who are fasted provides 100g of glucose per day and has a significant protein sparing effect.

• Modern guidelines on fasting prior to anesthesia allow intake of clear fluids upto 2 hours before surgery.

• Administration of carbohydrate drink at this time reduces perioperative anxiety and thirst and decreases post operative insulin resistance

• Immobility : Has been recognized as a potent stimulus for inducing muscle wasting. Early mobilization is an essential measure to avoid muscle wasting

A prospective approach to prevent unnecessary aspects of the surgical stress response 1. Minimal access techniques 2. Blockade of afferent painful stimuli (epidural anesthesia)3. Minimal periods of starvation4. Early mobilization

Therapeutic implications

The catabolic response to injury is always a major concern in postoperative care. Three types of interventions were tried to reduce this. These are:

–Nutritional –Hormonal –Biologic

Nutritional :

Three important aspects of nutrition have to be considered • Route of administration (enteral/parenteral): enteral

nutrition is preferred. It improves the protein balance & clinical outcome

• Timing (early versus late feeding): – enteral nutrition is started as early as possible. Early is superior

in its effects on catabolic & hyper metabolic response to injury. – A slower rate of fluid resuscitation after trauma hemorrhage

leads to a faster restoration of the depressed cell-mediated immunity. Whereas rapid fluid resuscitation produces a prolonged depression of immune responses.

Composition of feeding(nutritional supplements): commonly tried are• Glutamine (both for enteral & parenteral

nutrition)• Branched chain amino acids – leucine,

isoleucine & valine• Arginine can stimulate GH & IGF-1 release and

is a substrate for NO production. At high doses it promotes wound healing

• Unsaturated fatty acids: They can modulate cytokine biology. Anti inflammatory effect of fish oil is due to n-3 polyunsaturated fatty acids.

• Fats rich in n-6 polyunsaturated fatty acids enhance IL-1 production & tissue response to cytokines.

• Fats rich in n-3 polyunsaturated fatty acids have the opposite effect.

• Monounsaturated fatty acids decrease tissue responsiveness to cytokine. IL-6 production is enhanced by total unsaturated fatty acid intake.

• Dietary nucleotides: may improve cell-mediated immunity. A combination of arginine, n-3 polyunsaturated fatty acids & nucleotides has been used as “immune enhancing “diet.

Hormonal treatment:

• Anabolic hormones –GH, IGF-1 & insulin promote positive nitrogen balance.

• GH supplementation improves wound healing & decreases postoperative wound infection rate.

• IGF-1 mediates most of the metabolic effects of GH. Exogenous IGF-1 reduces gut mucosal atrophy in trauma.

• Both GH & IGF-1 are powerful modulators of the effector function of phagocytic cells.

Biologic treatment:

• Various strategies have been tried, which include antibodies to endotoxin, TNF or IL-6.

• But most patients with sepsis have elevated levels of cytokines & other mediators.

• So this can be given as “prophylaxis” for patients with high risk, for example, those undergoing major surgical procedures.

• Genetic alterations can occur during injury & infection. Hence in the future, gene therapy will have a role in the management of trauma patients who are critically ill.