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2 general responses:
(a) an acute proinflammatory response resulting from
immune system recognition of ligands
(b) an anti- inflammatory response to modulate the
proinflammatory phase and return to
homeostasis
SIRS
R
E
C
OMOF
V
CARS E
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Y
The clinical features of the injury-mediated systemic
inflammatory response:
body temperature,
heart rate,
respirations,
WBC
are similar to those observed with infection
Clinical Spectrum of SIRS TABLE2-1
Infection Sepsis
Identifiable source of microbial Infection + SIRS
insult
SIRS = 2 or more:
Severe Sepsis
Temp ≥38˚C or ≤36˚C
Sepsis + Organ Dysfunction
HR ≥ 90 bpm
RR ≥ 20 breaths/min or
PaCO2 ≤ 32 mmHg or
mechanical ventilation
WBC ≥ 12,000/µL or ≤
Septic Shock
4000/µL or ≥ 10% band forms Sepsis + Cardiovascular Collapse
(requires vasopressors)
Damage-associated molecular patterns (DAMPs)
and their receptors TABLE 2-2
Epinephrine
hepatic glycogenolysis, gluconeogenesis, lipolysis,
and ketogenesis
Decreases insulin and glucagon secretion
Peripheral- lipolysis, insulin resistance in skeletal m.
= stress induced hyperglycemia
Epinephrine – other effects
Increase secretion of T3, T4, and renin
Reduces release of aldosterone
Enhances leukocyte demargination and
lymphocytosis
Aldosterone
Synthesized, stored, released from the adrenal zona
glomerulosa
Maintains intravascular volume
Conserves sodium
Eliminates potassium and hydrogen ions
Pathways
Receptor Kinases – insulin
Guanine nucleotide binding (G-protein) - prostaglandins
Arachadonic Acid
Cyclooxygenase 1 & 2 Lipoxygenase
Prostaglandins Hydroxyeicosatetraenoic
PGD2, PGE2, PGF2α, PGI2 Acid HETE
Thromboxane Leukotrienes
TXA2
Eicosanoids
Secreted by nucleated cells (not lymphocytes)
Induced by hypoxic injury, direct tissue injury,
endotoxin, norepinephrine, vasopressin, ang II,
bradykinin, serotonin, ACh, cytokines, histamine
APOPTOSIS
NECROPTOSIS
APOPTOSIS
Regulated cell death
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
Eosinophils
Primarily “Antihelmenthic”
Reside in the GI, lung, and GU tissues
Activated by IL-3, GM-CSF, IL-5, PAF, and anaphylatoxins
C3a and C5a
Cell Mediated Inflammation
Lymphocytes & T –Cell Immunity
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
Cell Mediated Inflammation
Monocytes
mononuclear phagocytes that circulate in the bloodstream
and can differentiate into macrophages, osteoclasts, and
dendritic cells on migrating into tissues.
Macrophages are the main effector cells of the immune
response to infection and injury, primarily through
mechanisms that include phagocytosis of microbial
pathogens, release of inflammatory mediators, and clearance
of apoptotic cells
Cell Mediated Injury
Neutrophils:
1st responders to sites of infection and injury
potent mediators of acute inflammation.
Carbohydrate metabolism
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)
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
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
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
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
Renal-Failure
Lower fluid volume, K, phos, and Mg
Essential aa, high calorie : nitrogen ratio, no vitamins
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
Etc.
Total Parenteral Nutrition
Central parenteral nutrition, aka TPN
Requires access to a large diameter vein
Dextrose content is high (15-25%)
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
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)
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
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
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
The End
Thank you..