DR. RAJIV MEDICAL LECTURES

The metabolic response to injury (MRI) and critical illness is a complex and adaptive process aimed at ensuring survival. Understanding these responses helps in managing critically ill patients more effectively.

Introduction to metabolic response to injury

The Metabolic Changes after injury and in Critical Illness are the metabolic alterations that occur in response to severe physiological stressors like surgery, trauma, and sepsis.
This review reiterates current knowledge regarding the metabolic responses to trauma and sepsis.
Response to trauma and critical Illness includes various neuroendocrine, metabolic, and immunological changes.
The response to injury is graded:the more severe the injury, the greater the response .

MORE STRESS → MORE REACTIONS → GREATER CATABOLIC EFFECTS.

Mediators of metabolic response to injury

Stress hormones and cytokines have a role in these reactions.
The traumatised tissues release proinflammatory mediators like TNF-α and IL 1 and 6.
The direct effect of proinflammatory mediators on the hypothalamus, is well-known.
However, many new studies have stressed, on the, nuclear factor kappa B (or NF-kB) in this regard.
These changes and effects function to restore homeostasis after any injury including surgery and critical illness.  
Understanding metabolism in critical illness dates back to Cuthbertson’s description of “ebb and flow model in 1930.

Several days after injury, the immediate, “ebb” phase of low energy expenditure is replaced by the high energy expenditure phase, or “flow” phase.
The characteristic response that occurs in critically ill patients are protein and fat consumption and protection of body fluids and electrolytes.
The oxygen and energy requirement increases proportionate to the severity of trauma.

The knowledge of changes in amino acid, lipid, and carbohydrate metabolism in surgical patients is important in determining metabolic and nutritional support.
The main metabolic change in response to injury is the reduction of the normal anabolic effect of insulin, i.e. the development of insulin resistance.
Free fatty acids are primary sources of energy after trauma and in critical illness.

Surgical stress and trauma result in a reduction in protein synthesis and moderate protein degradation.
Severe trauma, burns and sepsis result in even more protein degradation.
The aim of glucose administration to surgical patients during fasting is to reduce proteolysis and to prevent loss of muscle mass.
In major stress such as sepsis and trauma, it is important both to reduce the catabolic response and to obtain a balanced metabolism in the shortest possible time with minimum loss. For these reasons, the sound knowledge of metabolic response to trauma is essential in managing these situations and patients should be treated accordingly.

Interactions

Many complex interactions involving the neuroendocrine, cytokines, and metabolic pathways drive the post-traumatic tissue response. 
For example:
1. ACTH release, by the pituitary: The proinflammatory cytokines enhance ACTH release resulting in rise of cortisol levels, in an effort to limit the proinflammatory stress response.
2. Cortisol acts synergistically with interleukin-6 to promote the synthesis of hepatic acute phase proteins like C-reactive protein and ceruloplasmin.
3. Hyperglycemia  aggravates the inflammatory response via substrate overflow into the mitochondria, leading to the formation of excess free oxygen radicals and altering the gene expression to enhance cytokine production.

At the molecular level there are changes in mRNA expression in leukocytes following the exposure to bacterial endotoxin.
An important player in this scenario is a transcription factor : Nuclear Factor Kappa B.
It is held in the cytoplasm in an inactive state by specific inhibitors.
The activation of the nuclear factor kappa B is primarily initiated by bacterial endotoxins such as lipopolysaccharide and proinflammatory cytokines such as tumor necrosis factor and interleukin-1.
After activation, the nuclear factor kappa B moves into the nucleus and activates the transcription of specific genes.

The nuclear factor kappa B plays a central role in inflammation, stress response, cell differentiation and apoptotic cell death.
The metabolic response to trauma and critical illness in humans has been categorized into 3 phases:
1) The Ebb phase of decreased metabolic rate or early shock phase,
2) The Flow phase of hypermetabolic state, and
3) The Recovery or anabolic or adaptive phase.

Metabolic response :Ebb’ and ‘Flow’ phase

The natural response to moderate injury ensures survival in the absence of medical aid.
There are three main responses:

Sir David Cuthbertson described the “ebb” and the “flow” model of post-traumatic metabolic alterations, 93 years ago, in 1930.
He postulated that the characteristic response that consumes protein and fat and preserves body fluid and electrolytes occurs primarily during the early phase or ebb phase and a hyper-metabolic flow phase follows the ebb phase.

The early, “ebb” phase of low energy expenditure is replaced by the high energy expenditure phase, or “flow” phase, several days after injury.
These two phases combine to produce the first inflammatory response to injury, known as SIRS that is “SYSTEMIC INFLAMMATORY RESPONSE SYNDROME” or the “acute phase reaction.”

Low energy ‘Ebb’ phase

The initial “ebb” phase develops approximately 12 hours after trauma or surgical stress and lasts for 24–48 hours.
In this phase, decreased oxygen consumption and reduced temperatures lower the body’s total energy needs and divert energy toward immune responses.
The resuscitation ameliorates the ebb phase, but does not completely abolish it.
In ebb phase is marked by hypovolaemia, hypothermia, decreased basal metabolic rate, reduced cardiac output, and lactic acidosis.

The main hormones, modulating the ebb phase are catecholamines, cortisol, and aldosterone due to the activation of the renin-angiotensin system (or RAS).
The magnitude of this neuroendocrine response depends on the severity of the injury.

In this phase, decreased oxygen consumption, and reduced temperature, lower the body’s total energy needs, and divert energy toward adaptive immune responses or CARS (that is Compensatory Anti-inflammatory Response Syndrome). The main purpose of the ebb phase is to conserve both the circulating blood volume and the energy stores for recovery and repair.

Hypermetabolic ‘Flow’ phase

In an ongoing insult, the low energy ebb phase, evolves into, a high energy ‘flow phase’.
The “flow” phase is marked by, an increase in, baseline energy expenditure that can progress to a chronic “hyper-metabolism,”
In this phase, there is mobilization of body energy stores for recovery and, subsequent repair and re-placement of lost or damaged tissue.

One of the primary mechanisms underlying this hyper-metabolism is the activation of toll-like receptors on innate immune cells like leukocytes by antigens from contaminating micro-organisms, such as endotoxins.
Activated leukocytes produce proinflammatory cytokines that mobilize amino acids in the muscles and peripheral fat to the liver to make acute phase proteins such as C-reactive protein instead of regular proteins such as albumin and transferrin.

The flow phase is characterized by tissue edema (due to vasodilatation and increased capillary leakage), increased basal metabolic rate (or hypermetabolism), increased cardiac output, raised body temperature, leukocytosis, increased oxygen consumption, and increased gluconeogenesis.
The flow phase has been subdivided into an initial catabolic phase, lasting approximately 3–10 days, followed by an anabolic phase, which may last for weeks if the insult is ex-tensive and pro-longed following a serious injury.
If the primary injury or illness is severe and pro-longed, the Helper T Cells induce counter-regulatory or adaptive responses, known as compensatory anti-inflammatory response syndrome (or “CARS”) leading to repair and recovery which may continue for weeks.

SIRS

The ebb and flow phase together produce the first inflammatory response to injury, known as Systemic Inflammatory Response Syndrome (SIRS) or the Acute Phase Reaction.
The activation of toll-like receptors on leukocytes by Damage-Associated Molecular Pattern molecules (DAMPS) is one of the primary mechanisms underlying the hypermetabolic flow phase.
The damage-associated molecular pattern molecules are molecules released by damaged or dying native cells. These are recognized by the leukocytes as antigens from contaminating microorganisms, such as endotoxin.
These activated leukocytes produce proinflammatory cytokines (signalling molecules) such as TNF-α and IL 1 and 6.
These signalling molecules cause the liver to convert of amino acids in lean body mass and peripheral fat to acute phase proteins (e.g.  C-reactive protein) instead of regular proteins such as albumin and transferrin.
These proteins can then play additional roles as structural components for wound healing.
Glutamine is the preferred energy source for immune cells because it is used to synthesize the antioxidant glutathione.The most obvious change in critical illness is the breakdown of proteins forming the lean body mass.

CARS

If the primary injury is severe enough, above mentioned counter regulatory responses lead to an overcompensation into immunosuppression, which has become known as Compensatory Anti-inflammatory Response Syndrome (CARS).
The hyperimmune (SIRS) and immunosuppressive (CARS) effects maintain the balance between fighting the infection and limiting the collateral host damage, however these effects can accentuate to chronic immunosuppression.

If there is a prolonged survive of patients with organ dysfunction in ICU, a catabolic condition called persistent inflammation, immunosuppression, and catabolism syndrome supervenes in 30% to 50% of patients.
Such patients are refractory to nutrition replacement and so are particularly difficult to manage.
This nutritional deficit leads to severe immunosuppression of the host as insufficient fuel is available for protective immune responses.

The most prominent clinical effect of inflammatory responses is anemia, as IL-1 and TNF cause reduction in blood iron and zinc content.
Treatments aimed at reducing the progress of flow phase by blocking proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6), have not been beneficial to ICU patients in clinical trials.