Metabolic Response to Injury


Metabolic Response to Fasting

  1. Substrate Metabolism
    • Basal metabolic needs require 22 – 25 kcal/kg/day (200 lb person expends ~ 2000 kcal/day)
    • Energy is derived from lipid, carbohydrate, and protein sources
    • In short term fasting, the principal fuel sources are muscle protein and body fat
    • Obligate glycolytic cells (neurons, WBCs, RBCs, renal medulla) require 180 gm glucose/24 hr

    1. Glucose Metabolism
      • During acute starvation, 100 - 150 gm of glucose can be mobilized from hepatic glycogen stores (~ 16 hours supply of glucose)
      • skeletal muscle also stores glycogen, but cannot directly release free glucose into the circulation (lacks glucose-6-phosphatase)
      • Falling glucose levels result in ↓ insulin, ↑ glucagon, ↑ epinephrine, ↑ cortisol
        • ↑ glucagon, ↑ epinephrine   → ↑ glycogenolysis
        • ↑ glucagon, ↑ cortisol   → ↑ gluconeogenesis
      • Primary gluconeogenic precursors used by the liver are lactate, glycerol, and amino acids (alanine, glutamine)
      • Lactate metabolism:
        • Released by skeletal muscle after breakdown of endogenous glycogen stores and after glycolysis of transported glucose
        • Released by RBCs and WBCs after anaerobic glycolysis
        • Converted into glucose in the liver by the Cori cycle (provides up to 40% of plasma glucose during starvation)

    2. Protein Metabolism
      • Amount of glucose made from lactate and glycerol is not sufficient to maintain glucose homeostasis
      • 75 gm of protein must be broken-down daily during fasting to provide gluconeogenic precursors to the liver
        • Mobilized protein is primarily from skeletal muscle, but loss of protein from other organs does occur
      • Proteolysis results from ↓ insulin, ↑ cortisol
      • Urinary nitrogen excretion is increased within the initial 5 days of fasting
      • After 5 days, rate of proteolysis decreases to 15 - 20 gm/day
      • Reduction in proteolysis occurs as the nervous system and other glucose-utilizing tissues adapt to ketone oxidation as the major energy source

    3. Lipid Metabolism
      • 160 grams/day of triglycerides are mobilized from adipose tissue in the form of free fatty acids (FFAs) and glycerol
      • FFA release is stimulated by ↓ insulin, ↑ glucagon, ↑ epinephrine
      • FFAs are converted into ketone bodies in the liver
      • FFAs, ketone bodies are used as an energy source by the heart, kidney, muscle, liver
      • Lipid stores provide up to 40% of the caloric expenditure during starvation

  2. Extended Starvation
    • Basal calorie requirement decreases to 1500 kcal/day
    • Reduction in resting energy expenditure is a consequence of decreased sympathetic nervous system activity and reduced skeletal muscle activity
    • Liver glycogen stores are depleted
    • Diminished use of muscle protein as a gluconeogenic precursor (15 - 20 gm/day)
    • Gluconeogenesis from amino acids now takes place mainly in the kidneys
    • Brain is using ketones
    • Ketones meet 70% of body’s energy requirements

    Metabolic changes in Fasting
    Metabolic Changes During Fasting

Metabolic Response to Injury

  1. Overview
    • Metabolic consequences of injury differ in many fundamental ways from those of simple starvation
    • Sustained activities of hormones in conjunction with immune cell activation provides the signals that differentiate injury metabolism from starvation
    • In starvation, the body responds by conserving energy and protein; during injury, there is an obligate increase in energy expenditure and nitrogen excretion
    • Inability to down-regulate the body’s energy expenditure and nitrogen losses may rapidly deplete energy stores
    • Post-injury metabolic environment precludes the efficient oxidation of fat and ketone production, thereby promoting the continued erosion of protein pools
    • If unchecked, this net protein catabolism results in critical organ failure

  2. Energy Balance
    • In 1930, Sir David Cuthherston divided the metabolic response to injury into Ebb and Flow phases
    • Ernest Moore added the Recovery (or Anabolic) phase to this model

    Ebb and Flow Phases in the Metabolic Response to Injury
    1. Ebb Phase
      • Occurs in the first 24 hours after injury
      • Associated with:
        • Hemodynamic instability or reductions in effective circulating volume
        • Decreased energy expenditure and oxygen consumption
      • In severe injury, without resuscitation, the patient will die

    2. Flow Phase
      • Initiated by compensatory mechanisms resulting from volume repletion and cessation of initial injury conditions
      • characterized by:
        • Increased metabolic rate and oxygen consumption
        • Fever
        • Gluconeogenesis
        • Restoration of blood volume
        • Generation of acute-phase reactants, immunoreactive proteins, and coagulation factors
      • Energy and protein substrates are directed to preserve critical organ function and repair damaged tissues
      • ↑ energy expenditure and ↑ oxygen consumption varies directly with the severity of the injury
      • ↑ energy expenditure results from ↑ activity of the sympathetic nervous system and ↑ concentrations of circulating catecholamines
      • Cortisol excess does not enhance energy expenditure

    3. Early Anabolic Phase
      • Occurs within 3 to 8 days after elective surgery, weeks after sepsis, or months after severe burn injuries
      • Corticoid-withdrawal phase
      • Characterized by a sharp decrease in nitrogen excretion, indicating a positive nitrogen balance with net protein synthesis
      • Results in synthesis of tissue repair and anabolic factors such as IGF-1
      • Clinical manifestations include diuresis of retained water and renewed interest in oral nutrition
      • Phase may last a few weeks to a few months, depending on the capacity to ingest adequate nutrition and the extent to which erosion of protein stores has occurred
      • Gain in weight and muscular strength is much slower than the rate of initial loss
      • Overall amount of nitrogen gain equals the amount lost during the catabolic phase

    4. Late Anabolic Phase
      • Gradual restoration of fat stores
      • Nitrogen balance becomes normal
      • Weight gain is much slower during this phase
      • Phase ends with a gradual return to the previously normal body weight

    Summary of the Ebb and Flows phases of Injury
    Summary of the Ebb and Flow Phases of Injury

  3. Carbohydrate Metabolism
    • Systemic glucose intolerance in injured patients is the norm
    • Plasma glucose levels are proportional to the severity of the injury
    • Insulin levels are elevated, indicating a state of relative insulin resistance
    • hepatic glucose production:
      • Increased by 50 to 100%
      • occurs at the expense of protein stores (alanine, glutamine)
      • Primarily under the control of glucagon and cortisol, with assistance from IL-6
      • Not suppressed by administering exogenous glucose
    • Hyperglycemia provides a ready source of substrate to tissues which do not require insulin for glucose transport
    • Wound inflammatory cells require glucose as an energy substrate

  4. Lipid Metabolism
    • FFAs are a principal source of energy after injury (50 – 80%)
    • Lipolysis is enhanced by ↑ cortisol, ↑ catechols, ↑ GH, ↑ glucagon, ↑ sympathetic nervous system activity, ↓ insulin
    • FFAs are transported by albumin to tissues requiring this fuel source (heart, skeletal muscle)
    • Increased lipolysis also results in hepatic ketogenesis
    • Many tissues can use ketones for energy, but ketogenesis is variable and is inversely proportional to the severity of injury

  5. Protein and Amino Acid Metabolism
    • Intake of protein is approximately 80 - 120 gm/day or 13 - 20 gm of nitrogen/day
    • injury is associated with ↑ proteolysis and ↑ urinary excretion of nitrogen → net loss in lean body mass is as high as 1.5% per day
    • Amino acids:
      • Not a viable long term fuel source
      • Provide substrates for gluconeogenesis
      • Used to synthesize acute phase reactants and coagulation factors
      • Release of glutamine and alanine is greater than their relative abundance in muscle, indicating their net synthesis before their release
      • Glutamine is a major energy source for lymphocytes, fibroblasts, and the GI tract
    • Skeletal muscle is depleted while visceral tissues are relatively preserved
    • After severe injury, negative nitrogen balance may persist for weeks or months
    • Insulin resistance, cortisol excess, and cytokines exert a synergistic effect on skeletal muscle breakdown

Nutritional Assessment and Requirements

  1. Assessing Malnutrition
    • No universal definition of what constitutes malnutrition
    • BMI is an imperfect measure of nutritional status
    • Laboratory markers such as albumin, prealbumin, and transferrin are of limited value in hospitalized patients
    • Clinically, malnutrition can be accurately diagnosed if two or more of the following criteria are present:
      • Insufficient energy intake
      • Weight loss > 5% of usual weight over 6 – 12 months
      • Loss of muscle mass (temples, quadriceps)
      • Loss of subcutaneous fat (areas with loose or hanging skin)
      • Localized or generalized edema
      • Decreased functional status
      • Weak handgrip strength

    1. Consequences of Malnutrition in the Surgical Patient
      • Increased susceptibility to infection
      • Poor wound healing
      • Increased frequency of decubitus ulcers
      • Overgrowth of bacteria in the GI tract

  2. Determination of Energy Requirements
    • Calorie and protein requirements depend on the extent of injury and degree of malnutrition present
    • 25 – 30 kcal/kg/day is a reasonable estimate of caloric needs in injured patients
    • Basal energy requirements can be measured by indirect calorimetry or estimated from the Harris-Benedict equation

    1. Indirect Calorimetry
      • Performed using a bedside metabolic cart which measures oxygen consumption and carbon dioxide production
      • Most accurate method of measuring basal energy expenditure, but it is not readily available and is labor intensive

    2. Harris-Benedict Equation
      • Less accurate than indirect calorimetry
      • Result must be multiplied by a stress factor (1.3 – 1.8) for severely injured patients

      Modified Harris Benedict Equation
  3. Substrate Requirements
    1. Glucose (Dextrose)
      • Provides the nonprotein calorie requirement (3.4 kcal/gm)

    2. Lipids
      • Serve as a source of the essential fatty acids linoleic acid and linolenic acid
      • Dense source of calories: 9 kcal/gm
      • Particularly useful in patients intolerant of high dextrose concentrations
      • Lipids are associated with immune suppression, modulation of the inflammatory response, and adverse clinical outcomes
      • optimal use of lipids remains unclear

    3. Protein
      • Not stored like carbohydrates or lipids
      • Must provide an exogenous source of 8 essential amino acids
      • protein requirements:
        • Normal daily protein requirement is 0.8 gm/kg/day
        • In fasted surgical patients, 1.0 to 1.5 gm/kg/day is sufficient
        • Severely injured patients may require up to 2.5 gm/kg/day
      • Given as 20% of total calories
      • Provides 4.0 kcal/gm

    4. Vitamins, Minerals, Trace Minerals
      • 13 essential vitamins
      • Minerals are structural components of bone (calcium, phosphorus, magnesium, zinc) or function as charged ions (sodium, chloride, potassium, calcium, magnesium)
      • Trace minerals (iron, zinc, copper, selenium) are components of metalloproteins and metalloenzymes

  4. Routes of Administration
    1. Enteral Nutrition
      • Nutritional route of choice if the gut is usable - disuse of the gut results in mucosal atrophy, altered mucosal defenses, and bacterial overgrowth
      • Fewer septic complications than parenteral nutrition
      • In trauma patients, most studies show decreased infectious complications in patients given early enteral nutrition (within first 24 – 48 hours)
      • Bowel sounds or passage of flatus or stool are not prerequisites for starting enteral feedings
      • Bowel resections, low output fistulas, or open abdomens are not contraindications
      • If gastroparesis is present, feedings should be administered distal to the pylorus
      • Feeding should begin once the patient is hemodynamically stable
      • Meeting 100% of caloric goals is not necessary to see the benefits of enteral nutrition

      1. Access
        1. Nasogastric Tubes
          • Used only in patients with intact mentation and protective laryngeal reflexes because of the aspiration risk
          • Contraindicated in patients with gastroparesis
          • Frequently dislodged
          • Placement requires x-ray confirmation
          • Indicated for short term use only (< 1 month)

        2. Nasoenteric Tubes
          • Difficult to position in the jejunum without fluoroscopy
          • Lower risk of aspiration compared to NG tubes
          • Easily clogged, kinked, or dislodged

        3. PEG Tubes
          • Similar risks and contraindications as nasogastric tubes
          • Ascites, coagulopathy, and inability to transilluminate the anterior stomach against the abdominal wall are contraindications
          • Serious complications occur in 3%
          • Allow bolus feedings
          • Indicated for long term use

        4. PEG-J Tubes
          • Inserted through an existing PEG tube into the jejunum

        5. Surgical Gastrostomy
          • Open or laparoscopic placement
          • Usually performed when PEG tube placement is unsuccessful or contraindicated

        6. Surgical Jejunostomy Tube
          • Often placed during complex abdominal/trauma surgery

      2. Complications of Enteral Nutrition
        • Intolerance, aspiration, metabolic abnormalities, and mechanical problems with the access
        1. Abdominal Distention, Cramps, Diarrhea
          • Associated with solute overload of hyperosmolar solution
          • Corrected by temporarily holding feedings, and then resuming at a slower rate
          • Diluting the formula may also be helpful
          • Rarely can progress to pneumatosis intestinalis and small bowel necrosis

    2. Parenteral Nutrition
      • Continuous infusion of a hyperosmolar solution containing glucose, protein, lipids, and other essential vitamins through a catheter placed into the SVC
      • Associated with more complications than enteral feeding
      • In patients without preexisting malnutrition, several studies have shown that TPN was detrimental when compared to no nutritional support in the acute setting for short durations (< 7 days)
      • No advantage to combining TPN with enteral nutrition

      1. Indications
        • GI tract is temporarily or permanently unusable (high output fistulas, prolonged ileus, short gut)
        • Failure of oral or enteral nutrition

      2. Complications
        1. Central Line Complications
          • Pneumothorax, hemothorax, subclavian artery injury
          • Line sepsis

        2. Metabolic Complications
          • Hyperglycemia, which usually can be managed by adding insulin
          • Overfeeding leads to CO2 retention, respiratory insufficiency
          • Hepatic steatosis, cholestasis, and abnormal LFTs

        3. Intestinal Atrophy
          • Mucosal atrophy, bacterial overgrowth, decreased IgA production, impaired gut immunity

    3. Immunonutrition
      • Goal is nutritional modification of the immune response and attenuation of oxidative stress and cellular injury

      1. Indications
        • Trauma, burn patients > 30% TBSA
        • ARDS, acute lung injury
        • Patients requiring mechanical ventilation
        • Patients who have undergone major GI surgery

      2. Components
        • Arginine – upregulates nitric oxide
        • Glutamine – key fuel for immune cells
        • Omega-3 fatty acids – reduces the inflammatory response
        • Anti-oxidants (vitamin C, selenium, zinc)

      3. Results
        • Morbidity and length of stay are reduced, but no benefit for mortality has been shown over standard enteral formulas
        • Potentially harmful in patients with severe sepsis









References

  1. O’Leary, 2nd ed. pgs 102 – 103
  2. Schwartz, 10th ed. Pgs 43 – 59
  3. Sabiston, 20th ed. Pgs 98 - 127
  4. Cameron, 13th ed., pgs 1451 - 1457
  5. UpToDate. Overview of Perioperative Nutrition Support. Reza Askari, MD, FACS, Kathleen S. Romanowski, MD, FACS. Oct 12, 2020. Pgs 1 – 23
  6. UpToDate. Nutrition Support in Critically Ill Patients: An Overview. David Seres, MD. July 01, 2021. Pgs 1 – 27