Systemic Response to Injury & Metabolic

Supportchapter 2

MUKESH KHUNT (MIKEN).

1

Keypoints

• 1. Systemic inflammation is an exaggerated immune response to either a sterile or infectious process.

• The cause of inflammatory activation needs to be addressed to resolve the dysregulated immune state.

2

Keypoints

• 2. An understanding of the signaling mechanisms and pathways underlying systemic inflammation can help guide therapeutic interventions in injured and/or septic patients.

3

Keypoints

• 3. Management of such patients is optimized with the use of evidence-based and algorithm-driven therapy.

• 4. Nutritional assessments, whether clinical or laboratory guided, and intervention should be considered at an early juncture in all surgical and critically ill patients.

4

Keypoints

• 5. Excessive feeding should be avoided in an effort to limit complications, including ventilator dependency, aspiration events, and infections.

5

Introduction

• Inflammatory response to injury– to restore tissue function– Eradicate invading microorganisms

• Local- limited duration, restores function• Major– overwhelming inflammatory response– Potential multi-organ failure– Adversely impacts patient survival

6

Clinical Spectrum of SIRS

• Infection– Identifiable source of

microbial insult

• SIRS = 2 or more:– Temp ≥38˚C or ≤36˚C– HR ≥ 90 bpm– RR ≥ 20 breaths/min or

PaCO2 ≤ 32 mmHg or mechanical ventilation

– WBC ≥ 12,000/µL or ≤ 4000/µL or ≥ 10% band forms

• Sepsis– Infection + SIRS

• Severe Sepsis– Sepsis + Organ Dysfunction

• Septic Shock– Sepsis + Cardiovascular Collapse

(requires vasopressors)

7

8

Signaling

• Humoral – inflammatory mediators in the circulation can induce fever and anorexia i.e. TNF-α

• Neural – parasympathetic vagal stimulation attenuates the inflammatory response via Ach release– Reduces HR, increases gut motility, dilates arterioles,

constricts pupils, and decreases inflammation– Reduces macrophage activation– Reduces macrophage release of pro-inflammatory

mediators (TNF-α, IL-1, IL-18)

9

CNS regulation of Inflammation

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Hormones Regulated by the Hypothalamus, Pituitary, and Autonomic System

•Hypothalamus: CRH, TRH, GHRH , LHRH

• Anterior Pituitary : ACTH, Cortisol, TSH, Thyroxine, T3, GH, Gonadotrophins , Sex hormones, Insulin-like growth factor , Somatostatin , Prolactin, Endorphins

• Posterior Pituitary : Vasopressin, Oxytocin

• Autonomic System : Norepinephrine , Epinephrine, Aldosterone

• Renin-Angiotensin System : Insulin, Glucagon , Enkephalins

11

Hormone Signaling

• Hormone classifications – polypeptide (cytokine, insulin)

– amino acid (epinephrine, serotonin, or histamine)– fatty acid (cortisol, leukotrienes)

• Pathways– Receptor Kinases – insulin

– Guanine nucleotide binding (G-protein) - prostaglandins

– Ligand Gated ion channels

12

Adrenocorticotropic Hormone

• Synthesized anterior pituitary• Regulated by circadian signals• Pattern is dramatically altered in injured patients• Elevation is proportional to injury severity• Released by: pain, anxiety, vasopressin,

angiotensin II, cholecystokinin, catecholamines, and pro-inflammatory cytokines

• ACTH signals increase glucocorticoid production

13

Glucocorticoids

• Cortisol – elevated following injury, – duration of elevation depends on severity of injury

• Potentiates hyperglycemia– Hepatic gluconeogenesis– Muscle and adipose tissue –> induces insulin

resistance– Skeletal m.–> protein degradation, lactate release– Adipose -> reduces release of TG, FFA, glycerol

14

Exogenous administration• Adrenal suppression in the acutely ill– Acute Adrenal Insufficiency– Atrophy of the adrenal glands– Weakness, n/v, fever, hypotension– Hypoglycemia, hyponatremia, hyperkalemia

• Immunosuppression– Thymic involution, decreased T-killer and NK fcn, graft vs

host rxns, delayed hypersensitivity responses, inability of monocyte intracellular killing, inhibition of superoxide reactivity and chemotaxis in neutrophils

– Down regulates pro-inflammatory cytokine production (TNF-α, IL-1, IL-6)

– Increases anti-inflammatory mediator IL-10– Useful in septic shock, surgical trauma, and CABG

15

Macrophage Inhibitory Factor

• Glucocorticoid antagonist • produced by anterior pituitary & T-

lymphocytes• Reverses immunosuppressive effects of

glucocorticoids• Potentiates G- and G+ septic shock• Experimentally improves survival

16

Growth Hormone

• During stress -> protein synth, fat mobilization, and skeletal cartilage growth

• 2˚ to release of insulin-like growth factor (IGF1)• Injury reduces IGF1 levels• IGF1 inhibited by pro-inflammatory cytokines– TNF-α, IL-1α, IL-6

• GH admin to pediatric burn patients shows improvement in their clinical course

17

Catecholamines

• Severe injury activates the adrenergic system• Norepi and Epi immed. increase 3-4 fold and

remain elevated 24-48hrs after injury• Epinephrine– hepatic glycogenolysis, gluconeogenesis, lipolysis,

and ketogenesis– Decreases insulin and glucagon secretion– Peripheral- lipolysis, insulin resistance in skeletal

m.– = stress induced hyperglycemia

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Epinephrine – other effects

• Increase secretion of T3, T4, and renin• Reduces release of aldosterone• Enhances leukocyte demargination and

lymphocytosis

19

Aldosterone

• Synthesized, stored, released from the adrenal zona glomerulosa

• Maintains intravascular volume– Conserves sodium– Eliminates potassium and hydrogen ions– Acts on the early distal convoluted tubules

• Deficiency- hypotension, hyperkalemia• Excess- edema, HTN, hypokalemia, metab alkalosis

20

Insulin

• Stress inhibited release + peripheral insulin resistance = hyperglycemia

• Injury has 2 phases of insulin release– Within hours- release is suppressed– Later- normal/xs insulin production with

peripheral insulin resistance• Activated lymphocytes have insulin receptors -

> enhanced Tcell proliferation and cytotoxicity• Tight control of glucose levels esp. in diabetics

significantly reduces mortality after injury21

Acute Phase Proteins

• Nonspecific markers• Produced by hepatocytes• Response to injury, infection, inflammation• Induced by IL-6• C-reactive protein best reflects inflammation– No diurnal variation, not affected by feeding– Affected only by preexisting hepatic failure– Accuracy surpasses that of ESR

22

Inflammatory Mediators

• Heat Shock Proteins• Reactive Oxygen Metabolites• Eicosanoids• Fatty Acid Metabolites• Kallikrein-Kinin System• Serotonin• Histamine• Cytokines

23

Heat Shock Proteins

• Induced by hypoxia, trauma, heavy metals, and hemorrhage

• Intracellularly modify and transport proteins– Steroids

• Requires gene induction by a transcription factor

• ACTH sensitive• Production seems to decline with age

24

Reactive Oxygen Species• Short-lived• Cause tissue injury by oxidation of unsaturated fatty

acids within cell membranes• Produced by anaerobic glucose oxidation and

reduction to superoxide anion in leukocytes• Further metabolized to hydrogen peroxide and

hydroxyl radicals• Cells are protected by oxygen scavengers –

glutathione and catalases• In ischemia- production of oxygen metabolites are

activated but nonfunctional due to no oxygen supply. After reperfusion, large amounts are produced causing injury

25

Eicosanoids

Phospholipids

Arachadonic Acid

Cyclic endoperoxidases(PGG2, PGH2)

Hydroperoxyeicosatetraenoic acid(HPETE)

ProstaglandinsPGD2, PGE2, PGF2α, PGI2

ThromboxaneTXA2

Hydroxyeicosatetraenoic Acid HETE

Leukotrienes

Cyclooxygenase 1 & 2 Lipoxygenase

Phospholipase A2 CorticosteroidsGlucocorticoids(Cortisol)

26

Eicosanoids

• Secreted by nucleated cells (not lymphocytes)• Induced by hypoxic injury, direct tissue injury,

endotoxin, norepinephrine, vasopressin, ang II, bradykinin, serotonin, ACh, cytokines, histamine

• Diverse systemic effects• Adverse effects include acute lung injury,

pancreatitis, renal failure• NSAIDs acetylate COX which reduce prostaglandin

levels

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Eicosanoid Effects• Pancreas – glucagon secretion-

PGD2, PGE2• Liver – glucagon stimulated

glucose production- PGE2• Adipose – lipolysis- PGE2• Bone – resorption- PGE2, PGF2α,

PGI2• Parathyroid – PTH secretion-

PGE2• Pulmonary –

Bronchoconstriction- PGF2α, TXA2, LTC4, LTD4, LTE4

• Immune – suppress lymphocytes- PGE2

• Hematologic – platelet aggregation- TXA2– Capillary leakage- PGE2, LT– PMN adherence and activation-

LT• Pituitary

– Prolactin- PGE1– LH- PGE1, PGE2, 5-HETE– TSH- PGA1, PGB1, PGE1, PGE1α– GH- PGE1

• Renal – renin secretion- PGE2, PGI2

• GI – cytoprotective- PGE2

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Fatty Acid Metabolites

• Omega 6 FA – precursors of inflammatory mediators (LT, PG, platelet activating, factor)– found in enteral nutrition formulas

• Substituting Omega 3 FA attenuate the inflammatory response– Reduces TNFα, IL6, PGE2– Reduces the metabolic rater, normalizes glucose

metabolism, attenuates weight loss, improves nitrogen balance, reduces endotoxin induced acute lung injury, minimizes reperfusion injury to the myocardium, small intestine, and skeletal muscles.

29

Kallikrein-Kinin System

• Bradykinins are potent vasodilators• Stimulated by hypoxic and ischemic injury– Hemorrhage, sepsis, endotoxemia, tissue injury– Magnitude proportional to severity of injury

• Produced by kininogen degradation by kallikrein• Kinins increase capillary permeability (edema), pain,

inhibit gluconeogenesis, renal vasodilation, incr bronchoconstriction

• In clinical trials, bradykinin antagonists help reverse G- sepsis, but do not improve survival

30

Serotonin

• Present in intestinal chromaffin cells & platelets

• Vasoconstriction, bronchoconstriction, platelet aggregation

• Myocardial chronotrope and ionotrope• Unclear role in inflammation

31

Histamine

• Stored in neurons, skin, gastric mucosa, mast cells, basophils, and platelets

• H1 – bronchoconstriction, increases intestinal motility and myocardial contractility

• H2 – inhibits histamine release• H1/H2 – hypotension, decreased venous

return/peripheral blood pooling, increased capillary permeability, myocardial failure.

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Cytokines

• Most potent mediators of inflammation• Local- eradicate microorganisms, promote wound

healing• Overwhelming response- hemodynamic instability

(septic shock) or metabolic derangements (muscle wasting)

• Uncontrolled- end-organ failure, death• Self-regulatory production of anti-inflammatory

cytokines, but inappropriate release may render the patient immunocompromised and susceptible to infection 33

Tumor Necrosis Factor α

• Secreted from monocytes, macrophages, Tcells• Responds early, T ½ < 20min• Potent evocation of cytokine cascade• Induces muscle catabolism/cachexia, coagulation,

PGE2, PAF, glucocorticoids, eicosanoids• Circulating TNF receptors compete with cellular

receptors and may act as a counter regulatory system to prevent excessive TNF-α activity

34

Interleukin-1

• Released by activated macrophages, endothelial cells• IL1α- cell membrane associated• IL1β- circulation• Synergistic with TNF- α• T ½ = 6 min• Induces febrile response by stimulating PG activity in the

anterior hypothalamus• Release of β-endorphins after surgery reduce perception

of pain

35

Interleukin-2

• Promotes T-lymphocyte proliferation, Ig production, gut barrier integrity

• T ½ < 10 min• Major injury or perioperative blood

transfusions reduce IL-2 activity leading to a transient immunocompromised state

• Regulates lymphocyte apoptosis

36

Interleukin-4

• Produced by type 2 T Helper lymphocytes• Important in antibody-mediated switching and

antigen presentation• Induces class switching to promote IgE & IgG4– Important in allergic and antihelmintic responses

• Anti-inflammatory- downregulates IL-1, TNF-α, IL-6, IL-8 and oxygen radical production

• Increases macrophage susceptibility to anti-inflammatory effects of glucocorticoids

37

Interleukin-5

• Released from T lymphocytes, eosinophils, mast cells and basophils

• Promotes eosinophil proliferation and airway inflammation

38

Interleukin-6

• Induced by IL-1 and TNF-α• Levels are detectable within 60 min of injury, peak 4-6

hours, and persist up to 10 days• Levels are proportional to extent of tissue injury• Pro-inflammatory– Mediates hepatic acute phase response during injury and

convalescence – Induces and prolongs neutrophil activity

• Anti-inflammatory– Attenuate TNF-α and IL-1 activity– Promote release of circulating TNF- α receptors & IL-1

antagonists39

Interleukin-8

• Released from monocytes, macrophages, T lymphocytes

• Activity similar to IL-6• Chemoattractant for PMNs, basophils,

eosinophils, and lymphocytes, activates PMNs• Proposed biomarker for risk of multiple organ

failure

40

Interleukin-10

• Anti-inflammatory• Released from T lymphocytes• Down-regulates TNF-α activity• Also attenuates IL-18 mRNA in monocytes• Studies in animal sepsis and ARDS models

suggest induced IL-10 decreases the systemic inflammatory response and reduces mortality

41

Interleukin-12

• Promotes differentiation of type 1 T Helper cells

• Promotes PMN and coagulation activation• In primate studies, IL-12 induces inflammatory

responses independent of TNF-α and IL-1• In animal studies of fecal peritonitis and burns,

IL-12 administration increases survival, whereas IL-12 neutralization increases mortality

42

Interleukin-13

• Similar to IL-4, overall anti-inflammatory• Modulates macrophage function• Unlike IL-4, has no effect on T lymphocytes• Inhibits NO production • Inhibits pro-inflammatory cytokines• Attenuates leukocyte interaction with

activated endothelial surfaces

43

Interleukin-15

• Derived from macrophages• Shares receptor components with IL-2, and

shares promoting lymphocyte activation/prolif.

• In neutrophils, it induces IL-8 and nuclear factor кB -> enhanced phagocytosis against fungal infections

44

Interleukin-18

• Formerly IFN-γ-inducing factor• Produced by macrophages• Pro-inflammatory, similar to IL-12• Increased levels are pronounced (especially in

G- sepsis) and can last up to 21 days

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Interferons

• Helper T lymphocytes activated by bacterial antigens, IL-2, IL-12, or IL-18 produce IFN-γ

• IFN-γ can induce IL-2, IL-12, or IL-18• Detectable in circulation by 6 hrs and remain

elevated for up to 8 days• Activate circulating and tissue macrophages• Induces acute lung inflammation by activating

alveolar macrophages after surgery or trauma

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Granulocyte-Macrophage Colony-Stimulating Factor

• Delays apoptosis of macrophages and PMNs• Promotes the maturation and recruitment of

PMNs in inflammation and perhaps wound healing

• May contribute to organ injury such as ARDS• Peri-operative GM-CSF undergoing major

oncologic procedures and burn patients demonstrate enhances neutrophil counts and fcn

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High Mobility Group Box 1

• DNA transcription factor• Expressed 24-48 hrs after injury• Associated with weight loss, food aversion,

shock, SIRS and Sepsis• Peak levels are associated with ARDS and

death

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Cell Signaling Pathways

• Heat Shock Proteins– produced in response to ischemia/injury– HS Factors are activated upon injury, undergo

conformational changes, translocate into the nucleus, and bind HSP promoter regions

– Attenuate inflammatory response• Ligand Gated Ion Channels– When activated by a ligand, a rapid influx of ions

cross the cell membrane. i.e. neurotransmitters

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Cell Signaling Pathways

• G-protein receptors– Largest family of signaling receptors– Adjacent effector protein activated receptor– Second messengers – cAMP or calcium– Can result in gene transcription or activation of

phospholipase C• Tyrosine Kinases– When activated, receptors dimerize, phosphorylate, and

recruit secondary signaling molecules – Used in gene transcription and cell proliferation– i.e. insulin, PGDF, IGF-1

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Cell Signaling Pathways

• Janus Kinase/Signal Transduction and Activator of Transcription (JAK-STAT)– IL-6, IL-10, IL-12, IL-13, IFN-γ– Ligand binds to the receptor, receptor dimerizes,

enzymatic activation via phosphorylation propagates through the JAK domain and recruits STAT to the cytosolic receptor portion.

– STAT dimerizes and translocates into the nucleus as a transcription factor

– Suppressors of cytokine signaling (SOCS) block JAK-STAT

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APOPTOSIS

• normal function of cellular disposal w/o activating the immune/inflammatory system

• 2 receptors– TNFR-1 : inflammation, apoptosis, circulatory shock– TNFR-2 : no inflammation or shock

• CD95 (Fas) receptor similar structure to TNFR-1– Initiates apoptosis

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Cell Mediated Inflammation• Platelets– Source of eicosanoids and vasoactive mediators– Clot is a chemoattractant for PMNs/monocytes– Modulate PMN endothelium adherence– Migration occurs within 3 hrs of injury

• Mediated by serotonin, PAF, PGE2• Eosinophils– Migrate to parasitic infection and allergen challenge to

release cytotoxic granules– Reside in the GI, lung, and GU tissues– Activated by IL-3, GM-CSF, IL-5, PAF, and anaphylatoxins

C3a and C5a

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Cell Mediated Inflammation

• Lymphocytes– T-helpers produce IL-3, TNF-α, GM-CSF

• TH1: IFN-γ, IL-2, IL-12• TH2: IL-4, IL-5, IL-6, IL-9, IL-10, IL-13• Severe infection – shift toward more TH2

• Mast Cells– First responders to injury– Produce histamine, cytokines, eicosanoids, proteases,

chemokines, TNF-α (stored in granules)– Cause vasodilation, capillary leakage, and recruit immunocytes

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Cell Mediated Inflammation

• Monocytes– Downregulation of receptor TNFR is clinically and

experimentally correlated with CHF, nonsurvival in sepsis

• Neutrophils– Modulate acute inflammation– Maturation is stimulated by G-CSF– Rolling (L-selectin (fast), P-selectin (slow)– Adhesion/transmigration – ICAM 1, 2, PECAM 1, VCAM 1,

CD18

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Endothelium-Mediated Injury

• Neutrophil-Endothelium Interaction– Increased vascular permeability – facilitate oxygen

delivery and immunocyte migration– Accumulation of neutrophils at injury sites can

cause cytotoxicity to vital organs– Ischemia-reperfusion injury potentiates this

response by releasing oxygen metabolites and lysosomal enz.

– Neutrophils – rolling 10-20min (p-selectin), >20min

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Nitric Oxide

• Derived from endothelial surfaces responding to Ach, hypoxia, endotoxin, cellular injury, or shear stresses of circulating blood

• T ½ = seconds• Reduces microthrombosis, mediates protein

synthesis in hepatocytes• Formed from oxidation of L-arginine via NOS

(+calmodulin, Ca2+, NADPH)

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Prostacyclin (PGI2)

• Endothelium derived in response to shear stress and hypoxia

• Vasodilator• Platelet deactivation (increases cAMP)• Clinically used to reduce pulmonary

hypertension (especially pediatric)

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Endothelins

• Produced as a response to a variety of factors – injury, anoxia, thrombin, IL-1, vasopressin

• ET-1 is a potent vasoconstrictor, 10x more potent than angiotensin II

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Platelet Activating Factor

• Phospholipid component of cell membranes, constitutively expressed at low levels

• Released by PMNs, platelets, mast cells, monocytes during acute inflammation

• Further activates PMNs and platelets• Increases vascular permeability• PAF antagonists reduce ischemia/reperfusion

injury

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SURGICAL METABOLISM

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Metabolism During Fasting

• Comparable to changes seen in acute injury

• Requires 25-40 kcal/kg/day of carbs, protein, fat

• Normal adult body contains 300-400g carbs (glycogen) – 75-100g hepatic, 200-250g muscle (not available systemically due to deficiency of G6P)

Mass (kg)

Energy (Kcal)

Days Available

Water 49 0 0

Protein 6 24,000 13

Glycogen

0.2 800 0.4

Fat 15 140,000

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Total 70.2 164,800

91.4

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Metabolism During Fasting

• A healthy 70kg adult will use 180 g /d of glucose to support obligate glycolytic cells (neurons, RBCs, PMNs, renal medulla, skeletal m.)

• Glucagon, Norepi, vasopressin, AngII promote utilization of glycogen stores

• Glucagon, Epi, and cortisol promote gluconeogenesis

• Precursors include lactate (sk.m., rbc, pmn), glycerol, and aa (ala, glutamine)

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Metabolism of Simple Starvation

• Lactate is not sufficient for glucose demands• Protein must be degraded (75 g/d) for hepatic

gluconeogenesis• Proteolysis from decreased insulin and

increased cortisol• Elevated urinary nitrogen (7 -> 30 g/d)

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Metabolism of Prolonged Starvation

• Proteolysis is reduced to 20g/d and urinary nitrogen excretion stabilizes to 2-5g/d

• Organs (myocardium, brain, renal cortex, sk.m) adapt to ketone bodies in 2-24 days

• Kidneys utilize glutamine and glutamate in gluconeogenesis

• Adipose stores provide up to 40% calories (approx 160 g FFA and glycerol)– Stimulated by reduced insulin and increased glucagon and

catecholamines

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Metabolism Following Injury

• Magnitude of expenditure is proportional to the severity of injury

• Changes in – Lipid Absorption– Lipid Oxidation– Carbohydrate metabolism

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Lipid Absorption• Oxidation of 1g fat = 9 kcal energy• Dietary lipids require pancreatic lipase and phospholipase to

hydrolyze TG into FFA and monoglycerides within the duodenum

• After gut absorption, enterocytes resynthesize TG from monoglycerides + fatty acyl-CoA

• Long chain TG (>12 carbons) enter the circulation as chylomicrons. Shorter FA chains directly enter portal circulation and are transported via albumin

• Under stress, hepatocytes utilize FFA as fuel• Systemically TG and chylomicrons are used from hydrolysis

with lipoprotein lipase (suppressed by trauma and sepsis)

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Fatty Acid Oxidation

• FFA + acyl-CoA = LCT are transported across the mitochondrial inner membrane via the carnitine shuttle

• Medium-chain TG (MCT) 6-12 carbons long, freely cross the mitochondrial membrane

• Fatty acyl-CoA undergoes β-oxidation to acetyl-CoA to enter TCA cycle for oxidation to ATP, CO2, and water

• Excess acetyl-CoA is used for ketogenesis

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Carbohydrate Metabolism

• Carbohydrates + pancreatic intestinal enzymes yield dimeric units (sucrase, lactase, maltase)

• Intestinal brush border disaccharidases break them into simple hexose units which are transported into the intestinal mucosa

• Glucose and galactose are absorbed via a sodium dependent active transport pump

• Fructose absorption via facilitated diffusion

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Carbohydrate Metabolism

• 1g carbohydrate = 4 kcal energy• IV/parenteral nutrition 3.4 kcal/g dextrose• In surgical patients dextrose administration is

to minimize muscle wasting• Glucose can be utilized in a variety of

pathways – phosphorylation to G6P then glycogenesis or glycogenolysis, pyruvic acid pathway, or pentose shunt

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Protein and Amino Acid Metabolism

• Average adult protein intake 80-120 g/day– every 6 g protein yields 1 g nitrogen– 1g protein = 4 kcal energy

• Following injury, glucocorticoids increase urinary nitrogen excretion (>30g/d), peak at 7d, persist 3-7 wks

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Nutrition in the Surgical Patient

• Nutritional assessment to determine the severity of deficiencies/excess

• Wt loss, chronic illnesses, dietary habits, quality/quantity of food, social habits, meds

• Physical exam – loss of muscle/adipose tissue, organ dysfunction

• Biochemical – Cr excretion, albumin, prealbumin, total lymphocyte count, transferrin

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Surgical Nutrition

• Support the requirements for protein synthesis• Nonprotein calorie : nitrogen ratio = 150:1• A lower rate of 80-100:1 may be beneficial in some

critically ill or hypermetabolic patients

• Basal Energy Expenditure (BEE):men = 66.47 + 13.75(W) + 5(H) – 6.76(A) kcal/d

women = 655.1 + 9.56(W) + 1.85(H) – 4.68 (A) kcal/dW= wt in kg, H= Ht in cm, A= age in

years73

Enteral Feeding

• Lesser expenses and risks than parenteral• Reduced intestinal atrophy• 44% reduction in infections over parenteral in

the critically ill• Healthy patients without malnutrition

undergoing uncomplicated surgery can tolerate 10 d of maintenance IV fluids only before significant protein catabolism begins

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Initiation of Enteral Feeding

• Immediately after adequate fluid resuscitation (UOP)

• Not absolute prerequisites: presence of bowel sounds, passage of flatus or stool

• Gastric residuals of >200ml in 4-6 hrs or abdominal distention requires cessation/lowering the rate

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Enteral Formulas

• Low-residue isotonic – caloric density 1.0kcal/ml, 1500-1800 ml/day– Provide carbs, protein, lytes, water, fat, water sol vitamins,

calorie:Nitrogen of 150:1.– No fiber bulk = minimum residue– Standard for stable patients with an intact GI tract

• Isotonic with fiber– Soluble and insoluble fiber (soy)– Delay GI transit time and reduce diarrhea– Not contraindicated in the critically ill

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Enteral Formulas

• Immune-Enhancing– Glutamine, argenine, omega-3 FA, nucleotides, beta-

carotene.– Benefits not consistent in trials– Expensive

• Calorie-Dense– 1.5-2 kcal/ml, higher osmolality (ok for intragastric

feeding)– for fluid restriction/inability to tolerate larger volumes

• High-Protein– Isotonic and nonisotonic available– calorie:Nitrogen ratio of 80-120:1

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Enteral Formulas

• Elemental– Contain predigested nutrients, small peptides– Limited complex carbs and fat (long/med chains)– Easily absorbed, but limited long term use– High osmolality = slow infusion or diluted– Expensive

• Renal-Failure– Lower fluid volume, K, phos, and Mg– Essential aa, high calorie : nitrogen ratio, no

vitamins78

Enteral Formulas

• Pulmonary-Failure– Fat content is increased to 50% of total calories– Reduces CO2 production and ventilation burden

• Hepatic-Failure– 50% of aa are branched chains (Leu, Ile, Val)– Potentially reverses encephalopathy– Controversial, no clear benefits in trials

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Enteral Access• Nasogastric Tube - requires intact mental status and laryngeal

reflexes to reduce aspiration– Difficult to place, requires radiographic confirmation– If required >30 d, convert to PEG– Problems: clogging, kinking, inadvertent removal

• Percutaneous Endoscopic Gastrostomy – – Impaired swallowing/obstruction, major facial trauma – Contraindications: ascites, coagulophathy, gastric varices, gastric

neoplasm, lack of suitable location– Tubes can be use for 12-24 mos– Requires endoscopic transillumination of abdominal wall and passage of

catheter into an insufflated stomach– Complications in 3% of cases: infection, peritonitis,

aspiration/pneumonia, leaks, dislodgement, bowel perforation, enteric fistulas, bleeding

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Percutaneous Endoscopic Gastrostomy-Jejunostomy

• Feeding administered past the pylorus• Cannot tolerate gastric feedings/signif

aspiration• Passes a catheter through an existing PEG past

the pylorus into the duodenum• Long term malfunction >50% due to

retrograde tube migration into the stomach, kinking, clogging

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Direct Percutaneous Endoscopic Jejunostomy

• Same technique as PEG placement but requires an enteroscope/colonscope to reach the jejunum

• Less malfunction than PEG-J • Kinking/clogging reduced by placing larger

caliber catheters

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Surgical Gastrostomy and Jejunostomy

• With complex abdominal trauma/laparatomy there may be an opportunity for placement

• Contraindication: distal obstruction, severe intestinal wall edema, radiation enteritis, inflammatory bowel disease, ascites, severe immunodeficiency, bowel ischemia

• Adverse effects: abdominal/bowel distention, cramps, pneumatosis intestinalis, small bowel necrosis

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Parenteral Nutrition

• Continuous infusion of hyperosmolar carbs, proteins, fats and other nutrients through a catheter into the SVC

• Optimal > 100-150 kcal/g nitrogens • Higher rates of infection compared to enteral• Studies with parenteral nutrition and

complete bowel rest results in increased stress hormone and inflammatory responses

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Parenteral Nutrition Rationale

• Seriously ill patients with malnutrition, sepsis or surgery/trauma when use of the GI tract for feeding is not possible– Short bowel syndrome after massive resection– Prolonged paralytic ileus (>7 days)– Severe intestinal malabsorption– Functional GI disorders – esophageal dyskinesia– Etc.

85

Total Parenteral Nutrition

• Central parenteral nutrition, aka TPN• Requires access to a large diameter vein• Dextrose content is high (15-25%)

86

Peripheral Parenteral Nutrition

• Lower osmolality• Reduced dextrose (5-10%)• Protein (3%)• Not appropriate for severe malnutrition due

to need for larger volumes of some nutrients• Shorter periods, < 2 wks

87

Parenteral Nutrition

• Dextrose 15-25%• Amino acids 3-5%• Vitamins (Vit K is not included)• Lipid emulsions to prevent essential FA

deficiency (10-15% of calories)• Prepared by the pharmacy from commercially

available kits• If prolonged – supplement trace minerals– Zinc (eczematous rash), copper (microcytic anemia),

chromium (glucose intolerance)88

Parenteral Nutrition

• Insulin supplement to insure glucose tolerance• IV fluids/electrolytes if high fluid losses• Freq. monitor fluid status, vital signs, UOP,

electrolytes, BUN, and LFTs. Glucose q6h

89

Complications• Hyperglycemia – pt with impaired glc tolerance or high

infusion rate– Tx- volume replacement, correct electrolytes, insulin– Avoid by monitoring daily fluid balance, glc, & lytes

• Overfeeding – results in CO2 retention and respiratory insufficiency

• Hepatic steatosis• Cholestasis and gallstones• Hepatic abnormalities – serum transaminase, alk phos and

bilirubin• Intestinal - atrophy from disuse, bacterial overgrowth,

reduced lymphoid tissue and IgA production, impaired gut immunity

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Special Formulations• Glutamine and Arginine– Glutamine – nonessential aa, comprises 66% of free amino

acids– During stress glu is depleted and shunted as a fuel source to

visceral organs and tumors– Inconclusive data for benefits of increased supplementation– Arginine – nonessential aa, promotes net nitrogen retention

and protein synthesis in the critically ill/injured. Benefits still under investigation.

• Omega-3 Fatty Acids– Canola or fish oil. Displaces omega-6 FAs, theoretically

reducing pro-inflammatory responses• Nucleotides– ? Increase cell proliferation, DNA synthesis, T Helper cell

function 91

The End

• Thank you..

92

References

The material in this presentation was directly adapted from:

E. Lin, S. E. Calvano, and S. F. Lowry. Chapter 1. Systemic Response to Injury and Metabolic Support. In Schwartz's Principles of Surgery, 8th ed. F. C. Brunicardi, D. K. Andersen , T. R. Billiar, D. L. Dunn, J. G. Hunter, R. E. Pollock, eds. McGraw-Hill Professional, 2004.

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