SEPSIS/septic shock/SIRS Flashcards
Give several examples of DAMPS
Heparan sulfate
Fibrinogen
Heat shock proteins
ATP
Histones
Some interleukines
DNA/RNA
Mitochondrial DNA
Defensins
Syndecans
Mitochondrial reaction oxygen species
HMBP 1 (high mobility box proteins)
Fibronectin
Hyaluronate fragments
Neutrophil elastase
Nuclear derived Surfactant prot A
Which TLR can have DAMP mediated activation
Only TLR 2, 3, 4 and 9
The ligand of TLR 5 is flagellin
TLR 7 and 8 are activated by pathogen RNA
List some acute phase proteins
CRP
fibrinogen
complement
mannan binding lectin
plasminogen
Alpha 2 macroglobulin
ferritin
Hepcidin
Ceruloplasmin
Haptoglobin
serum amyloid A
alpha 1 antitrypsin
List some negative acute phase proteins
antithrombin
albumin
transcortin
transferrin
retinol binding protein
transthyretin
List 5 actions of complement
- Bonus question: Which complement molecules account for the vast majority of them?
- Chemotaxis
- increased cytokine levels
- Increased adhesion molecule expression
- Increased TF expression
- Increased vascular permeability
- Opsonization
- Cell lysis (C5b6789) –> MAC
- Neutralization viruses
- dispose cell products after apoptosis
** C3a and C5a
List of proinflammatory cytokines
IL 1
IL 6
CXCL-8 (IL 8)
IL 12
TNF alpha
IFN gamma
bradykinin
PAF
Which cytokine has shown excellent discriminatory power for prognosing survival in critically ill dogs?
IL 6
**Values over 400pg/ml have a sensitivity/ specificity of 90/95
List 3 undesirable actions of TNF alpha
- Downregulates aPC
- Increased iNOS and COX2
- Affects electrong transport chain (ETC) complex 3 to increase ROS and NOS
List of anti-inflammatory cytokines
IL 4
IL 10
IL 13
TGFB– transforming growth factor beta
Values and reference ranges of the qSOFA score:
qSOFA one point each if:
RR > or equal to 22
SBP < or equal to 100
GCS <15
What antibiotic is recommended for first line treatement of pyelonephritis (and prostatitis) in dogs and cats?
Fluoroquinolones
Dogs: enro 10mg/kg SID
Cats: Marbo 5.5mg/kg SID
Amoxiclav is nor recommended due to poor penetration into renal parenchyma and prostate
For what causal organism of pyelonephritis are fluroquinolones not recommended?
Enterococcus —> intrinsic resistance
Penicillin + aminoglycosides
ampicillin + genta (not amikacin)
Which gene encodes for methillin resistance in microorganisms
mecA gene
It encodes for the production of modified penicillin binding protein (PBP)
What is a facultative anaerobe?
List some pathogens that are facultative anaerobes
-> pathogens that can survive in anaerobic conditions
E.Coli, Klebsiella, Pseudomonas, Staph, Streptoccus, enterococcus
List of bactericidal antibiotics
Vancomycin
fluroquinolones
penicillins
aminoglycosides
cephalosporins
metronidazole
rifampin
polymixins
Very Finely Proficient At Cell Murder, Right Paul
* Carbapenems
List of bacteriostatic antibiotics
Tetracyclins
Macrolides: erythromycin and azithromycin
Clindamycin
What are the only bactericidal that not concentration dependent
Beta lactams:
* Penicillins
* cephalosporins
* Carbapenems
Mechanism of action and 2 side effects of:
penicillins/ cephalosporins
Inhibition of the bacterial wall growth
-gastrointestinal
- hypersensitivities
Mechanism of action and 2 side effects of:
Aminoglycosides
Binding to the subunit 30s of the ribosome inhibiting protein synthesis
- nefrotoxicity
- ototoxicity
- neurotoxicity
-NMJ disease
Mechanism of action and 2 side effects of:
fluoroquinolones
Inhibition of the DNA Gyrase (in gram -) and DNA topoisomerase 4 (in gram +)
- Neurotoxicity
-Retinal toxicity in cats
- Bone marrow toxicity
Mechanism of action and 2 side effects of:
Metronidazole
Unsure mechanism but DNA damage
- Neurotoxicity
- Teratogenic
- Olfactory sensation
Mechanism of action and 2 side effects of:
Macrolides and lincosamides
Binding to the subunit 50s preventing protein synthesis
- P450 interactions,
- GI toxicity (except azithromycin)
Mechanism of action and 2 side effects of:
tetracyclins
Binding to the subunit 30s preventin protein synthesis
- oesophageal stricture
- nephrotoxic
List of ab that bind to the 50s of the ribosome
macrolides (erithro, azithromycin)
lincosamides (clindamycin)
chloramphenicol
streptogramins
Which antibiotics are water soluble and how this affects the volume of distribution (Vd)
penicillins, cephalosporins and amynoglycosides
* water soluble antibiotics have lower volume of distribution but will reach better inflammed tissues in states of oedema.
*Vd improves or is altered in oedema states for water soluble drugs
Group of organisms intrinsically resistant to TMPS and clindamycin and why
- Enterococcus spp are resistant to TMPS because they absorb folic acid from their enviroment and TMPS act inhibitin folic acid synthesis.
- For clindamycin: they have the ISA gene
What is the post antibiotic effect (PAE)
Which antimicrobials do not exhibit PAE
Is the period after complete removal of the antibiotic where the concentration is below MIC but there is inhibition of bacterial growth.
*penicillins, cephalosporins, vancomycin, sulfonamides, rifampin and polymixins do not exhibit PAE
Under which conditions will aminoglycosides fail to kill microorganisms even if deemed sensitive in culture
It will fail to kill facultative anaerobes under anaerobe conditions. Aminoglycosides require aerobic movement across the cell wall to reach the targert site
What receptors does norepi act on? ( according to SACCM )
alpha 1 - vasoconstriction - post synaptic receptors
alpha 2 - -suppress norepi release from presynaptic receptors
beta 1 - inotropy, chronotropy, arrhythmogenesis
(beta 2 - smooth muscle relaxation, (vasculature. bronchodilation) )
What is the goal of having norepi activate the alpha 2 receptors
Negative feedback, to inhibit its own release when sufficient norepi has been released into the synaptic cleft, avoiding over-stimulation.
what is the second messenger system used by most adrenergic receptors, and what is the exception?
- cAMP messenger system in all receptors
Alpha 2 (decrease – Gi) medetomidine
Beta 1,2,3 (increase— Gs) norepi - alpha 1 activates phospholipase C pathyway (DAG or IP3) increases intracellular Ca,
Ex: norepi, angiotensin II, Vasopressins (V1 receptors)
How does SIRS lead to hypoalbuminemia
ALbumin is a negative acute phase protein there is an increased loss of albumin through the damage endothelium
What organs/endocrine values can be affected by SIRS (by SACCM)
Why?
- Albumin (low) -> negative acute phase prot
- blood glucose (high/low) ->
- altered CH metabolism, increased gluconeogenesis, increased BG utilization, altered counterregulatory hormones.
- Hepatobiliary markers increased:
- cholestasis, altered hepatic perfusion, cytokine stimulation.
- renal disease: Low GFR, and altered perfusion, increased UPC
What is the definition of SHOCK
Inadequate cellular energy production and/or utilization
During resuscitation, what is the ideal PAOP/ wedge pressure to aim for, according to SACCM?
10 - 12mmHg
What is the normal relationship of SvO2 vs ScvO2 ?
SvO2 is mixed venous oxygen saturation –> measured in the pulmonary artery
ScvO2 is central venous oxygen saturation –> measured in the cranial or proximal vena cava
SvO2 is higher by 2-3% as the caval blood is low in O2 due to high metabolic rate of the brain.
* in shock Svo2 might be lower due to increased splachnic oxygen extraction
SIRS Criteria in dogs
In dogs 2/4 to be SIRS +
HR> 120
RR> 20
T < 37.2 >39.2
WBC <6 or >16 and bands >2-3%
2 comon biomarkers of sepsis in people
procalcitonin
CRP
T/F For bacteriostatic antibiotics, once bacterial growth is inhibited, the antimicrobial then relies on the immune system to remove the pathogen
TRUE
What are the most common pathogens encountered in septic abdominal effusion?
E coli
Enterococcus
Clostridium
Staphylococcus
Enterobacter
Others: Streptococcus, Klebsiella, Proteus, Pastereulla
T/F If infections occur up to 3 days after discharge or within 30 days of a surgical procedure, they are attributed to the admitting hospital
TRUE
Examples of organisms that have been implied in nosocomial infections
Serratia marcescens, Salmonella species, Clostridium perfringens, Acinetobacter baumannii, Escherichia coli, Clostridium difficile, Salmonella enterica, Klebsiella
T/F Nosocomial infections derived from endogenous flora may occur in patients receiving chemotherapy, glucocorticoid therapy, or antimicrobial therapy.
TRUE
Extrinsic risk factors for nosocomial infections
o Prolonged length of hospital stay, mechanical ventilation, and indwelling devices (i.e., intravascular or urinary catheters and nasogastric or endotracheal tubes).
o The most significant risk factors in the ICU are trauma, especially when associated with open fractures and antimicrobial use.
Intrinsic risk factors for nosocomial infections
o Include patient demographics (e.g., age, gender), comorbidities, and severity of underlying illness, which is the most widely reported risk factor.
o Patient-specific risk factors are related to general health and immune status, respiratory status, neurologic status, and fluid status.
What is a zoonosis?
A disease that normally exists in animals but that can infect humans.
A comprehensive literature review has identified 1415 species of infectious organism known to be pathogenic to humans and out of these ______ are zoonotic
61%
How can zoonosis be transmitted?
o 35% by direct contact
o 61% by indirect contact
o 22% by vectors
o 6% the transmission route is unknown.
Name emerging nosocomial infectious agents in dogs and cats
o MRSA
o Methicillin-resistant Staphylococcus pseudintermedius and S. schleiferi
o C. difficile
o Vancomycin resistant Enterococcus faecium (VRE) not yet implicated in nosocomial infections - Europe has revealed VRE carriage in healthy dogs.
Clostridium difficile associated disease (CDAD)
o Occurs as a result of intestinal colonization and toxin production by toxigenic strains.
o A diagnosis of CDAD is made after detection of an enterotoxin, designated Toxin A, and a cytotoxin, designated Toxin B, in fecal specimens.
o Some animals are known to carry toxigenic strains of C. difficile without toxin production, so demonstration of the organism in feces by anaerobic culture is not confirmatory.
What are the main 3 strategies to prevent and control nosocomial infections?
o Methods are needed to prevent cross-contamination and to control potential sources of pathogenic microorganisms that can be transmitted from patient to patient or from hospital personnel to patient.
o Guidelines are needed to direct the appropriate use of prophylactic, empiric, and therapeutic antimicrobial use.
o Strategies to limit the emergence or spread of MDR pathogens should be developed and targeted against organisms known to be prevalent in individual institutions.
What are the 5 basic properties of vitamins?
o Is not a fat, protein or carbohydrate but is an organic substance
o Included in an animal’s diet
o Small amounts are necessary for an animal’s normal physiologic function
o The animal will develop a deficiency syndrome without it
o There are insufficient quantities synthesized to support normal homeostasis.
Where can vitamin C be found?
o Vegetables and many fruits (tomatoes, cauliflower, berries and citrus fruits)
o Organ meat (liver & kidney)
T/F Vitamin C is the most potent water soluble antioxidant and the last stable of all vitamins
TRUE
Forms of vitamin C
o L-isomer of ascorbic acid (reduced form), biologically active
o D- isomer, not active
Vitamin C is very susceptible to destruction through oxidation, which is accelerated by ____ and ______
Heat and light
Can dogs and cats synthesize vitamin C?
Yes, in the liver, using glucose, trace minerals and an enzyme known as L-gulonolactone oxidase.
Most dogs synthesize approx 36mg of vitamin C/kg/day
Other species (guinea pigs, fish…) lack the enzyme therefore they cannot synthesize it.
T/F There is evidence that dogs suffering from disease, stress or anorexia have decreased ability to synthesize vitamin C
TRUE
Normal serum ascorbic acid values?
1mg/100mL
Maximum limits have not been identified
Vitamin C functions
o A lot of roles as it acts as electron donor
o Collagen synthesis
o Metabolism of: steroid (cortisol), tyrosine, folate, iron, carnitine
o Regulates immune funcition
o Antioxidant
o Required for the C1 hydroxylation of vD3 to the active form.
o Important role in gene transcription
o Metalloenzymes that synthesize NE and vasopressin require vitamin C as cofactor.
T/F Humans with sepsis have very low vitamin C levels compared to healthy controls
TRUE
o People with vitamin C deficiency have a higher incidence of multiple organ failure and death.
Providing nutrition increases vitamin C?
o Human hospitalized patients receiving full RER with enteral / parenteral nutrition had low plasma vitC, especially septic patients (90% hypovitaminosis C).
Clinical signs of hypovitaminosis C?
o Similar as critical illness itself: hypotension, excessive inflammation, capillary leakiness, microcirculatory dysfunction, oxidative organ injury and impaired immune defense and wound healing
Antioxidant activity of vitamin C
o Donates an e-, generating ascorbic radical that scavenges ROS and prevents damage to cellular proteins.
o Can reactivate other ROS scavengers like glutathione and alpha-tocopherol.
o Acts on the enzyme nicotinamide adenine dinucleotide oxidase (NOX), a key player in the activation and production of additional ROS, especially those that damage the vascular endothelium.
o Helps with microcirculatory perfusion -> prevents superoxide from oxidizing tetrahjydrobiopterin -> causes a decrease in NO thus in microvascular perfusion.
Vitamin C and vasopressor synthesis
o It is the rate limiting step in the synthesis of LDOPA, precursor to dopamine.
o Increases production of tyrosine hydroxylase to further increase dopamine production
o Potentially modulates alpha / beta adrenergic receptors by binding to them and augmenting their activation from E.
o Synthesis of ADH requires the enzyme PAM, for which vitamin C is a cofactor.
T/F RBCs have a high concentration of vitamin C
FALSE - WBCs
Roles of vitamin C in leukocytes
o Facilitate chemotaxis
o Support lymphocyte proliferation
o Help with oxidative neutrophilic destruction of bacteria
o Stimulates the reticuloendothelial system and antibody formation
Does vitamin C have strong bactericidal activity?
No. It has strong bacteriostatic activity and can significantly inhibit bacterial replication.
How can vitamin C help improve microcirculatory flow?
o Inhibits NF-KappaB activation -> down regulates TNF alpha induced production of intracellular adhesion molecules (ICAMs)
o This decreases stickiness and sluggishness of the WBCs and improves microcirculatory flow.
T/F Vitamin C inhibits apoptosis and protects endothelial progenitor cells
TRUE
What happens if we give vitamin C to a patient that does not need it?
o Liver downregulates endogenous production of vitamin C
o Supraphysiologic amounts can be deleterious to liver and kidney, especially if administered chronically.
o Potential to form calcium oxalate urolithiasis in predisposed individuals as vitamin C is metabolized to oxalate.
o Can cause diarrhea and potential allergic reaction in mouth at high doses.
Do dogs and cats require vitamin C in their diet?
No
Is there any data regarding doses, tolerance and toxicity?
o No, doses are not evidence based.
o Intakes of 0.5 and 0.3 g of ascorbic acid per day in cats and dogs respectively, did not find adverse effects
T/F Tissue levels of vitamin C decrease with any kind of stress and this stimulates the biosynthesis of the vitamin in those animals with this ability
TRUE
Recommendations for daily antioxidant fortification rates of vitamin C?
Dogs - 60mg for a 13.6kg
Cats - 12mg for 2.7kg
Vitamin D contains a group of ________________ that function to ____________ GI absorption of calcium, magnesium and phosphate, as well as other biological effects
o fat-soluble seco steroids
o increase
How can vitamin D be obtained?
o Through dietary intake
o Irradiation of the body in some species
Where is vitamin D2 derived from?
From the plant steroid ergosterol
Where is vitamin D3 derived from?
o AKA - cholecalciferol
o Made from animal products via the precursor 7-dehydrocholesterol, synthesized in the body.
Which form is more active, vitamin D2 or D3?
o Both are equally bioactive in domestic animals
o They are the 2 most prominent forms of vitamin D
Vitamin D metabolism
o Ingestion of vit D
o The vitamin D binding protein (VDBP) transports it to the liver
o In the liver: hydroxylation to 25-hydroxy-vitD (aka calcidiol)
o Travels to the kidney -> 1-alpha hydroxylase will convert calcidiol in calcitriol (25-hydroxy-vitD) in the renal epithelial cells.
o Travels to intestine, bones or elsewhere where it does its functions.
Vitamin D functions
o Involved with the metabolism/maintenance of calcium, phosphorus levels
o Support bone density
o Regulates parathyroid gland, immune function, skin, cancer prevention
o Foreign chemical metabolism and cellular development / differentiation
o In essence, it functions as a hormone.
Regulation of 1,25(OH2)D3
o Tightly regulated by PTH based on calcium and phosphorus levels
o Stress -> PTH activates renal mitochondrial-1-alpha-hydroxylases -> removes the 1-OH-group, inactivates renal and extra renal hydroxylates that remove the 24 and 34 OH groups, and therefore converts 1,25(OH)2D3 to inactive metabolites.
o Calcitonin counteracts PTH and vitamin D to lower blood calcium via decreased osteoclast activity in bones and increased excretion of Ca and Ph in the kidney.
T/F Dogs and cats have a nutritional requirement for vitamin D even when sunlight is available
TRUE
T/F Vitamin D3 is produced enough in the skin of dogs and cats through UV radiation
FALSE - It is not produced in the skin of dogs and cats in sufficient amounts to prevent osteomalacia.
T/F Calcidiol and calcitriol have the same potency to bind vitamin D receptors
FALSE - Calcitriol is 500 times more potent than calcidiol binding VDRs
What are the effectors of of calcitriol?
o Primary - intestines
o Acts also through receptors in bone, kidneys, cardiovascular, hepatic, reproductive, respiratory, immune and CNS
What are the 3 main effects of calcitriol binding the VDRs?
o Hormone secretion (PTH and renin inhibition, insulin and fibroblast growth factor-23 stimulation).
o Cellular proliferation and differentiation (inhibits angiogenesis).
o Immune function (both innate and adaptive).
In the ICU, up to ______ of critically ill humans suffer from low vitamin D
82%
How can we measure vitamin D?
o Easier than vitamin C and thiamine
o Calcidiol as surrogate of vitamin D status -> is stable, readily assayable and has longer t1/2 than calcitriol.
o Only 0.003% of serum calcidiol is free, 12% is bound to albumin and 88% is bound to vitamin D binding protein.
o When measuring calcidiol in patients with hypoalbuminemia, serum levels might be decreased by up to 30%.
T/F Hypovitaminosis D has not yet been identified in critically ill dogs and cats
FALSE - Hypovitaminosis D as well as dysregulations in Ca have been identified in CI.
Is the hypovitaminosis D of CI same as osteomalacia?
No, the abnormalities of hypovitaminosis D are acute and short-term, but prolonged deficiencies could lead to bone abnormalities.
Other than decreased intake, what else could influence vitamin D levels?
o Endocrine disease
o Intesintal malabsorption/maldigestion
o Hepatic insufficiency
o Renal disease
o Drugs
Clinical hypovitaminosis D?
o Hypertension, renal dysfunction, vascular damage and cardiac hyperthrophy -> suspected due to stimulation of renin when vita levels are low.
o Can lead to diabetes, cardiovascular disease, neoplasia and autoimmune disease in humans.
o Increased PTH and low vitamin D -> increased risk of heart failure in people
o Inconsistently associated with all-cause mortality and may be a predictor in survival in a variety of illnesses.
o Low levels -> inconsistently linked to increased infection, incidence of ARDS and disease severity.
o Hospitalized cats and CI or septic dogs with low 25(OH)D levels -> higher 30 day mortality.
T/F Vitamin D modulates the inflammatory response to invading pathogens by inducing or suppressing gene expression after binding to VDRs
TRUE
How can calcitriol help the immune system?
o Stimulates VDRs on neutrophils, monocytes, lymphocytes, NKs and epithelial cells
o That leads to the production of antimicrobial and anti-endotoxins peptides like B-defensins and cathelicidins
o Cathelicidins -> forme pores in bacterial cell membranes and enhance chemotaxis of other immune cells -> stimulates phagocytosis and release of ROS.
o Cathelicidins -> also interferes with biofilm formation and have activity against Pseudomonas, Salmonella, E. coli, Listeria, Staphylococcus and Enterococcus.
o Fungi and mycobacteria in the skin, respiratory, GI and urinary tract -> destroyed by cathelicidins -> prevention of hospital acquired infections?
T/F Vitamin D appears to be a key regulator of the immune response in septic patients, and helps prevent an overexubernt inflammatory response
TRUE
Mechanism on how vitamin D helps regulate immune response in sepsis
o Calcitriol modulates proliferation and differentiation of B and T cells (decreases antibody production)
o Vitamin D -> decreases the antigen-presenting ability of antigen-presenting cells that normally recognize PAMPs
o Subsequently -> decrease in proinflammatory response and production of cytokines like IL1B, IL2, TNF alpha, IFN, IL6 and IL12, and increasing production of IL10, a potent anti-inflammatory cytokine (observed in both people and dogs).
T/F Vitamin D supplementation has been shown to decrease pro-inflammatory cytokines in people with cardiovascular disease
TRUE
T/F In dogs, vitamin D blunts TNF production by leukocytes without compromising TLR4 or phagocytosis in neutrophils or monocytes
TRUE
T/F Vitamin D levels above reference rage are completely safe
FALSE - then can lead to negative health outcomes, possibly due to a pro-inflammatory state.
Thiamine is also known as vitamin?
B1
Which organisms can make thiamine endogenously?
Bacteria, fungi and plants
Essential nutrient for dogs, cats and humans
Where can thiamine be found
Whole grains, legumes and some fish and meat
Where is thiamine absorbed
In the jejunum and ileum and it can be inhibited by folate deficiency and alcohol consumption
How does thiamine exists in the body
o Free thiamine
o Various phosphorylated forms - thiamine monophosphate, thiamine diphosphate and triphosphate.
o Thiamine diphosphate, aka thiamine pyrophosphate (TPP) is the most active form. It stays within the cells and is the best marker of thiamine nutritional status.
T/F The body has great thiamine stores
FALSE - thiamine body stores are minimal
Why can thiamine deficiency develop?
o Poor nutrition
o Increased urinary excretion (diuresis)
o Acute metabolic stress
Has low thiamine been described in dogs and cats?
o Yes, when thiamine-deficient food is fed to animals or with malabsorption / maldigestion.
o Pathophysiology of vB1 deficiency in CI animals less well studied.
o Most CI animals - not eating - probably goes unrecognized most of the times.
Thiamine functions
o Breakdown of carbohydrates and aa - needed for glucose metabolism.
o Production of ATP and build blocks for cellular function.
o Maintains normal neuronal and neuromuscular function.
o TPP is a cofactor in oxidative decarboxylation in 3 mitochondrial complexes.
o TPP - necessary for protection agains oxidative damage in tissues through maintenance of NADP+ -> stimulates the activity of glutathione peroxidase, decreasing oxidative stress.
o Necessary for synthesis of Ach and myelin, passive transport of Na and maintenance of normal levels of neurotransmitters (glutamate, aspartate and GABA)
T/F Mitochondrial dysfunction is an important feature of many types of CI and could be exacerbated by thiamine deficiency
TRUE
T/F Thiamine deficiency can lead to type B lactic acidosis due to inability to perform aerobic metabolism
True
How can we measure thiamine levels
o Not simple to measure, difficult in a clinical setting.
o Published ranges vary considerably.
Around ____ of human ICU patients with sepsis are thiamine deficient upon admission, and it increased to _____ within 72h of admission
10%
20%
How can we suspect thiamine deficiency?
o History / disease process
o Clinical signs
o An elevated lactate without evidence of hypoperfusion
o Unexplained neurological signs
o +/- response to thiamine supplementation
Clinical signs of thiamine deficiency
o Acute -> neurological signs
o Chronic -> 3 stages
* First: lethargy, V and decreased appetite
* Second: Neuro signs - ataxia, decreased CP, paraparesis, nystagmus, delayed PLR, blindness, recumbency and eventually seizures. Cats - also, neck ventroflexion and respiratory difficulties. Bradyarrhythmias may occur. * Third: rapid worsening and death
MRI changes consistent with thiamine deficiency
Bilateral brainstem lesion
Thiamine deficiency treatment
o Clinical improvement seen fast, Neuro signs might take longer.
o Oral - poor absorption and even more in CI
o Parenteral - IM or SQ (IV severe anaphylactic reactions and hypotension)
o Optimal dose not known
o Cat 20-300mg q12-24h, dogs 50-1250m q12-24h
o Extremely safe - dose of 100-115 ug/kg/day was found safe.
What recommendations have been made in human medicine regarding vitamin supplementation?
o All patients should have a baseline vitC level measured and treatment given if <25mmol/L
o For patients not receiving CRRT, 3-6g vitamin C should be administered daily as long as vasopressor therapy is needed (increase dose to 12g if CRRT)
o Low dose hydrocortisone (50mg q6h), thiamine (200mg q12h) and high dose vitamin C (1.5g q6h) should be given to all patients with sepsis.
Proposed criteria for the diagnosis of SIRS in dogs and cats
T/F SIRS can only be triggered with G- bacteria
FALSE - Systemic inflammation may be triggered by products of both gram- positive and gram-negative bacteria.
Factors that can trigger SIRS
o Factors known to stimulate macrophages and monocytes include lipopolysaccharide (G-), lipoteichoic acid (G+), peptidoglycan and flagellin (G+ and G-), and mannan (fungi).
o Leukocyte activation resulting from exposure to these proteins, and subsequent release of TNF-α, IL-1, IL-6, prekallikreins, bradykinin, platelet activating factor, and others in response to leukocyte activation will lead to an inflammatory response designed to protect the host.
o The proinflammatory response is accompanied by activation of antiinflammatory measures designed to counteract.
o This compensatory antiinflammatory response syndrome (CARS) is characterized by the release of antiinflammatory mediators (IL-10, transforming growth factor β [TGF-β], and IL- 13); production of soluble receptors and receptor antagonists for cytokines such as TNF-α; and reduction of B and T lymphocyte production.
T/F Excessive stimulation of the CARS may contribute to immunoparalysis and increased susceptibility to nosocomial infections seen in the late stages of sepsis.
TRUE
What can lead to the production of inflammatory mediators?
o Loss of vascular tone - suspected due to increased iNO synthase production leading to vasodilation (precursor of NO) and possibly a deficiency in ADH or cortisol.
o Disruption of endothelial permeability - direct result of cytokine production.
o Hypercoagulable state - cytokines will induce tissue factor expression on the surface of leukocytes, leading to fibrin deposition in the microvasculature and is thought to contribute to organ failure in proinflammatory states.
__________ resulting from the activation coagulation stimulates ________ _______ and further cytokine production.
Thrombin
Leukocyte activation
________. down regulates the activation of _________, which is known to have antiinflammatory properties in addition to its role as an anticoagulant
TNF-α
Protein C
T/F SIRS has been identified as an important component of sepsis, but it can occur in the absence of infection and have a clinic course resembling that of sepsis.
TRUE
Common causes of SIRS in animals include sepsis, heat stroke, pancreatitis, immune disease, neoplasia, severe polytrauma, and burns.
C reactive protein is an ___________ produced by __________ in response to inflammatory cytokine release, including ______ and ________
Acute-phase protein
Hepatocytes
TNF-α, and IL-1β
Is CRP only elevated in sepsis?
o No.
o Elevations have also been documented secondary to other inflammatory processes such as trauma, surgery, acute pancreatitis, and myocardial infarction.
o Prolonged half-life and lack of specificity, CRP is not considered the ideal marker for the diagnosis of sepsis.
Procalcitonin as a sepsis marker
o Normally produced by the thyroid gland, PCT during sepsis is thought to originate from mononuclear leukocytes after endotoxin and cytokine stimulation.
o Is released hours after endotoxin release, and peak levels persist for up to 24 hours.
o It has been shown to increase iNO synthase, increasing NO release and therefore may play a role in amplification of the inflammation.
o Studies have documented elevated PCT levels in people with bacterial infections complicated by systemic inflammation and little to no change in PCT in localized infections or in infections of viral etiology.
o In some studies, PCT levels correlate with disease severity, and they may have prognostic value in people with sepsis and septic shock.
o PCT is thought to represent a superior marker of sepsis than CRP in people.
What treatments for SIRS have been investigated in humans?
o Cytokine blockade - TNF alpha using TNF alpha antibodies - no improved survival
o Receptor antagonists to TNF, platelet activating factor and IL1 - no improved 28 day survival
o Antiinflammatory effects of ibuprofen - no survival benefit
o High dose steroids - no increased survival. In some studies, increased mortality.
o Human IVIg - increased survival in small study of people with G- sepsis
o Statins (drug to control cholesterol) - TBD
o Recombinant human activated protein C (rhAPC) recommended by PROWESS study -> DC later due to no improved survival.
T/F In both animals and humans, the criteria used for identification of SIRS may lead to overdiagnosis of this condition.
TRUE
Bradycardia has been identified in _______% of the cats with sepsis and in _____% of cats with septic peritonitis
66%
16%
In one study, when comparing dogs with and without SIRS to healthy controls, significant changes, including prolonged _______ and ______, reduced ________ and ___________ activities, and increased ___________, were seen both groups of sick dogs compared with controls.
PT
PTT
Antithrombin
Protein C
D-dimers
Several studies documented reduced activities of ______ and ________ in dogs with naturally occurring sepsis, suggesting the tendency toward hypercoagulability in this disease process.
Protein C
Antitrombin
T/F The usefulness of CRP measurements to differentiate infectious from noninfectious SIRS in animals with naturally disease has not yet been investigated.
TRUE
Proinflammatory cytokines studied and diseases in dogs and cats
o In one study of dogs with parvoviral enteritis, 7 of 17 dogs had measurable TNF activity.
o In another study, CRP was elevated in dogs with pyometra both with and without SIRS. IL-7 was significantly elevated in dogs with pyometra and SIRS compared with controls, and IL-10 was significantly elevated only in dogs with pyometra and SIRS.
Clinicopathological signs of SIRS
o Non specific, depends on underlying condition and same as sepsis
o Appetite loss, depression.
o Injected MM, short CRT, bounding peripheral pulses - hyperdynamic state
o V/D (even if not primary in origin)
o CBC - leukocytosis w/ or w/o left shift, and toxic changes in neutrophils.
o Hyper/hypoglycemia, hypoalbuminemia, increased ALT, AST and in some cases, TBIL
o Glucose - secondary to altered carbohydrate metabolism, with increased gluconeogenesis causing hyperglycemia in the early phase of infection/inflammation and hypoglycemia occurring late when glucose utilization exceeds production.
o Albumin concentration occurs secondary to reduced manufacturing by the liver in favor of production of acute- phase proteins and also to loss induced by changes in endothelial permeability.
o Liver enzyme concentrations are likely altered as a result of changes in perfusion and decreased oxygen delivery to tissues.
o Cholestasis may be the cause of elevated serum bilirubin, though it has also been suggested that immune-mediated hemolysis may play a role.
Are cats different than dogs when manifesting signs of SIRS?
Yes
Cats are more likely to experience hypotension, hypoglycemia, and hyperbilirubinemia than dogs
The 1991 American College of Chest Physicians and Society of Critical Care Medicine consensus conference on sepsis and organ failure defined MODS as
“The presence of altered organ function in an acutely ill patient such that homeostasis cannot be maintained without intervention.”
This syndrome can be primary, where organ dysfunction arises from the primary insult, or secondary, where organ dysfunction arises from systemic inflammation
Conditions that have been associated with MODS
MODS is responsible in humans for somewhere between ____ to ____ of surgical ICU deaths and is associated with a substantially greater mortality rate than that seen in patients without MODS
50-80%
T/F In dogs with SIRS or sepsis, increased organ dysfunction severity as measured by modified sequential organ failure (SOFA) score was associated with increased mortality.
TRUE
T/F Central to the pathology of MODS is immune dysregulation that results in disordered systemic inflammatory processes
TRUE
There is evidence that the initial immune dysfunction during SIRS may be augmented by ongoing inflammation in the gastrointestinal tract, the “sustained hit” theory, which can drive a patient to MODS.
TRUE
T/F Although not diseases in themselves, both SIRS and CARS can result in MODS
TRUE. Both processes can occur at different times in an individual.
Key mediators in the proinflammatory response
TNF-α
IL 1
IL6
IL8
IL12
Which cytokines are produced first and which ones prolong the inflammatory response?
TNF alpha and IL1
IL6 and IL8
To which cytokine can many of the features of inflammation be attributed to?
TNF alpha
Via induction of iNOS and cyclooxygenase 2 -> leading to vasodilation, increased capillary permeability, and local slowing of blood flow.
Once the early inflammatory cytokines (TNF alpha and IL1) are released, what are their main effects?
o Early inflammatory cytokines induce expression of tissue factor (TF) and adhesion molecules on endothelial surfaces and prime neutrophils.
o Activated neutrophils have upregulated adhesion molecule expression and once attached to the endothelium produce enzymes that enhance endothelial permeability.
o Overall, TNF-α and IL-1 activity leads to local conditions favoring the diapedesis of circulating defense cells and the extravasation of plasma.
o Primed neutrophils have an increased capacity for generation of ROS and lipid mediators.
The inflammatory cascade will lead to cell death -> and that will lead to?
o Death of cells by necrosis, release of cytosolic and nuclear components, and degradation of proteoglycans in the extracellular matrix provide multiple new DAMPs
o These new DAMPs will accelerate innate immune system activation and resulting in the production of yet more proinflammatory cytokines/chemokines.
What is the high-mobility group box 1 (HMGB1) protein?
o It is released by active innate immune cells as well as necrotic cells and acts to promote monocyte TF expression and inhibit protein C activation.
o Such mediators then enter the circulation and travel to other organs where they exert their inflammatory influence, resulting in further cellular dysfunction and a vicious cycle of cell death and inflammation.
Does the complement get activated during MODS/SIRS/Sepsis?
o Complement activation through the classical, alternative, or lectin pathways is an important component of the innate host-defense system.
o It generates proinflammatory, biologically active peptides that, in the context of MODS, act as leukocyte chemoattractants, stimulate cytokine production, enhance adhesion molecule and TF expression, and increase vascular permeability.
o Central to these functions are the anaphylatoxins C3a and C5a.
Plasma concentrations of _____ are proportional to injury severity and mortality after trauma, and treatment with ___________ attenuates MODS in a rodent model of sepsis.
C3a
anti-C5a antibodies
T/F - The links between inflammation and coagulation pathways have been clearly established. Proinflammatory cytokines interact with the cellular regulators of thrombosis: endothelium, platelets, and leukocytes.
TRUE
How can inflammatory cytokines promote coagulation?
o The actions of TNF-α, IL-1, and IL-6 in particular lead to upregulation of reciprocal adhesion molecules on leukocytes and endothelial cells, promoting interactions designed to protect the host.
o In health, TF is concealed by the endothelium and coagulation activation is limited by various circulating proteins such as antithrombin, protein C, and tissue factor pathway inhibitor.
o Abnormal TF expression by mononuclear phagocytes and tissue parenchymal cells is induced by inflammatory cytokines, C-reactive protein, and PAMPs such as lipopolysaccharide. This triggers coagulation activation through binding of factor VII.
o In addition, proinflammatory cytokines reduce expression of antithrombotic proteins such as thrombomodulin, protein C, and the extracellular protein C receptor.
o These activities tip the balance away from anticoagulation and in favor of thrombin generation and the suppression of fibrinolysis. The combination of these phenomena impairs organ perfusion, limits reparative functions, and propagates organ dysfunction.
How can the enhanced fibrin formation during SIRS/MODS/Sepsis can be beneficial and detrimental at the same time?
o On a local level, such enhanced fibrin formation is protective because it limits hemorrhage and acts to contain pathogens.
o Activation of these processes on a systemic level, however, can lead to widespread microvascular thrombosis and endothelial injury.
What other factors play a role in the energetic deficit of critical illness, other than the inflammation/coagulation interactions?
o It has been proposed that ineffective cellular oxygen utilization in intermediate metabolic processes leads to intracellular energy deficits that contribute to MODS development -> cytopathic hypoxia.
o This cytopathic hypoxia may be due to oxidative mitochondrial damage and subsequent autophagy, which, coupled with a failure of mitochondrial synthesis, leads to depletion of mitochondrial numbers.
Under normal circumstances, approximately ______% of the oxygen entering cells is converted to ROS by mitochondrial electron transport chain
1%
T/F During the inflammatory response the production of ROS by mitochondria is reduced
FALSE
o Several components of the inflammatory response disturb the normal mitochondrial activity, increasing ROS generation and resulting in deleterious effects on mitochondrial DNA and membrane integrity.
How can ROS and inflammatory cytokines affect the mitochondria?
o iNOS-generated NO can directly interfere with electron transport chain (ETC) complexes IV and V and, via peroxynitrite, also inhibits ETC complex I.
o TNF-α can directly inhibit ETC complex III.
o ROS and RNS and certain cytokines activate poly-(ADP-ribose) polymerase, reducing availability of complex I substrates.
o These effects combine to impaired ATP generation and increase oxidative stress.
o In addition to causing loss of mitochondria, the ROS/RNS-induced mitochondrial damage leads to release of cytochrome c into the cytosol, triggering apoptotic death and releasing mitochondrial DNA, which acts as a DAMP, triggering further cytokine generation via TLR-9.
T/F GIT does not contributes to the pathology of critical illness.
FALSE - clearly contributes to the pathology of CI
What is the proposed mechanism how the GIT can contribute to MODS?
In septic ICU patients, commensal bacterial overgrowth coupled with a loss of mucosal barrier function might permit bacterial translocation, thus allowing the bowel to become a pathogen reservoir that drives the generation of MODS.
T/F The GIT increased permeability however, has not been proven
FALSE
o It has been demonstrated increased GIT wall permeability in critically ill patients after splanchnic hypoperfusion, oxidative stress, and the action of inflammatory cytokines.
o It has been shown that after ischemia-reperfusion injury, the GIT can generate sufficient proinflammatory cytokines to drive systemic inflammation into MODS.
o It has also been shown that toxic GIT-derived substances entering mesenteric lymph are sufficient to cause acute respiratory distress syndrome (ARDS) and MODS (the GIT-lymph hypothesis).
o Others have argued that translocation of bacteria alone may be insufficient to generate SIRS. That such translocation may be a normal process important in creating an appropriate adaptive immune response, and that presence of bacteria in the blood may be a marker of host immunosuppression or colonization by a particularly virulent organism.
T/F Bacterial translocation may occur without GIT-derived sepsis, whereas GIT-derived sepsis can occur in the absence of bacterial translocation.
TRUE
What are the main GIT structures that play a role in MODS/SIRS/Sepsis? How is it postulated the interactions with the GIT?
o The intestinal epithelium, the mucosal immune system, and the commensal bacteria.
o Diminished GIT barrier function caused by tight junction disruption coupled with impaired local immunity may permit translocation of commensal bacteria.
o Alternatively, altered microbial flora secondary to antimicrobial administration and inadequate epithelial nutrition impairs local immunity.
o This allows for production of bacterial toxins or inflammatory mediators that are absorbed and transported in lymph to the lung (ARDS?).
o This crosstalk hypothesis posits that organ dysfunction is most likely to occur when reduced barrier function, impaired local immunity, and altered intestinal microflora all coexist, a scenario that may be a common occurrence in sickest patients.
The pattern of organ failure in human surgical patients is first ______ , then ______, ______ and _______
Lung
Liver
GI
Kidney
When can lungs be affected in patients with MODS?
They may be injured primarily (e.g., pneumonia, contusions) or secondarily by systemic inflammation generated by a process elsewhere.
Describe how lung injury occurs in MODS
o Lung injury is initiated by a local or systemic proinflammatory state that promotes the sequestration of primed neutrophils.
o Inflammatory mediators and the activities of sequestered neutrophils damage basement membranes and endothelial cells and disrupt tight junctions.
o Pulmonary capillary permeability increases, promoting formation of protein-rich pulmonary edema.
o The resultant alveolar flooding and surfactant inactivation cause collapse of alveoli and terminal airways, reducing lung compliance and leading to shunting, hypoxic pulmonary vasoconstriction, and hypoxemia.
o The changes in pulmonary blood flow result in pulmonary artery hypertension and increase right ventricular workload.
o The initial exudative phase may be followed by a proliferative phase characterized by type II pneumocyte recruitment and phenotypic change and the generation of fibrous tissue by fibroblasts. This phase should be restorative but can lead to pulmonary fibrosis.
T/F Cardiac dysfunction has not been recognized in septic dogs
FALSE - Potentially reversible myocardial dysfunction in association with sepsis is well recognized in humans and is also documented in naturally occurring sepsis in dogs
Describe sepsis cardiomyopathy
o Is characterized by early contractile dysfunction leading to biventricular dilation, reduced ejection fraction and fractional shortening, as well as a reduced response to preload and catecholamines.
o In experimental sepsis in dogs, decreased ejection fraction and increased preload accompany the myocardial depression.
o In dogs with sepsis it has been identified reduced oxygen delivery compared with healthy dogs.
o However, non-septic dogs with SIRS had significantly lower cardiac output and oxygen delivery compared with both healthy dogs and septic dogs, suggesting that myocardial depression in patients with sepsis and SIRS is not uniform.
o The mechanisms of this myocardial depression remain unclear but likely involve disrupted cellular energetics, altered calcium handling, effects of circulating proinflammatory cytokines, direct and indirect effects of nitric oxide, and induction of myocyte apoptosis.
o Impaired autonomic function manifesting as inappropriate tachycardia and reduced heart rate variability has also been noted. This may reflect local effects on pacemaker cells or alterations to central nervous system function.
How can liver help prevent systemic endotoxemia and bacteremia?
o Thanks to its substantial endogenous macrophage population - Kupffer cells
o These cells can also produce cytokines in response to inflammatory signals or changes in hepatic oxygenation and secrete proteins as part of the acute-phase response.
How will liver dysfunction manifest usually?
As impaired gluconeogenesis and glycolysis, reduced synthetic and metabolic functions, and a coagulopathy.
The liver normally receives around ____% of its blood supply from the GIT and _____% coming from the hepatic arteries.
75%
25%
How can shock alter liver blood flow?
o Hypoperfusion secondary to trauma or sepsis alters the distribution of blood flow (75% from portal circulation, 25% from hepatic arteries), such that portal blood flow increases as hepatic arterial blood flow diminishes.
o Decreased hepatic perfusion during shock may cause temporary acute liver dysfunction.
o Consequently, the liver may become hypoxic, modulating the release, binding, and cytotoxicity of cytokines, including TNF-α.
o Increased hepatic and GI inflammatory cytokine production during this period predisposes postsurgical patients to liver failure, despite the increased portal blood flow.
SOFA
o The consensus-developed SOFA score is the least complex of the three commonly used systems.
o Six organ systems are evaluated (cardiovascular, respiratory, neurologic, renal, hepatic, and hematologic) and the worst value of the day is used to calculate the score.
o Each organ system is equally weighted, with values from 0 to 4, such that the total score varies from 0 to 24.
o The cardiovascular score in SOFA is based on the need for, and dose of, vasopressor agents, which may not be ideal given the variation in clinical practice between locations.
o The simplicity of the SOFA score means it is reliable and accurate across clinicians and locations.
o Recently the SOFA score with minor modifications was applied to a population of dogs with sepsis and nonseptic SIRS. Both daily and cumulative SOFA scores over the first 3 days of hospitalization were significantly correlated with outcome. An increase in SOFA score was also strongly predictive of mortality in this study.
How has the definition of sepsis changed?
How have the clinical criteria for sepsis changed over the past years?
SOFA score sepsis 3
What is the qSOFA?
o In sepsis 3 criteria they definite the quick SOFA - screening tool rather than diagnostic too
o Presence of abnormalities does not mean a patient has sepsis, but should raise index of suspicion.
Lay definition of sepsis (sepsis-3)
How has the definition of septic shock changed over the years? (sepsis-3)
What are the clinical criteria for septic shock? (sepsis-3)
Sepsis definitions vet vs human
Key components of the immune innate system
Key features of the innate immune response
What are PAMPs?
o Small molecular motifs
o Highly conserved within microbial classes
o Recognized as non-self
o Bind to pattern recognition receptors (PRRs)
o AKA microbe associated molecular patterns (MAMPs)
o Normally PAMPs are molecules that are vital for the survival of the microbe
Examples of PRRs
Phagocyte function
TLR signaling
Innate immune response effector molecules
What are cytokines
Cytokines - general properties
o Pleotropism - one mediator, like IL4, can have multiple functions (almost all inflammatory cytokines).
o Redundancy - multiple molecules that can affect the same outcome - both IL 2 and IL4 can cause cell proliferation. IL6 and TNF can act on hypothalamus to generate a fever.
o Synergy - 2 different cytokines acting on the same function and increasing the effects
o Antagonism - opposite effects - IL10 is the anti-inflammatory IL by excellence.
Cytokine receptors
o TNF receptor family
o IL1 receptor family - for IL1 and IL18
o G protein coupled receptors - for chemokine
o Type I and II cytokine receptors
What are the early pro-inflammatory cytokines?
o Principal function is to recruit leukocytes to the site of infection and activate them to kill the pathogen.
o Positive feedback loop to amplify signal.
TNF alpha functions (and cytokines overall)
Late pro-inflammatory cytokines
Procoagulant / anticoagulant pathways in sepsis
o TF is normally not exposed -> TF gets expressed and binds FVII -> initiation of coagulation by cell based model.
o Decreased anticoagulant molecules like PC and increasing concentrations of plasminogen activator inhibitor 1 (PAI1)
Does sepsis activate the AA cascade? How?
o Yes
o Pro-inflammatory cytokines bind to their receptors and increase the transcription of phospholipase A2
o Phospholipase A2 -> phospholipids -> COX / LOX
How does sepsis cause endothelial dysfunction?
o Cytokines and other inflammatory mediators actually damage cell junctions (tight junctions), that will result in interstitial edema.
o Damaging or loss of glycocalyx secondary to inflammation
Containing the inflammatory response
o On the picture it should be IL10, not ILF10 -> best well known anti-inflammatory cytokine.
What goes wrong when the activation of the innate immune system turns into SIRS/sepsis?
Sepsis pathogenesis summary
o Innate immune response is key
o Difference is PAMPs / DAMPs
o Imbalance between pro / anti-inflammatory mediators
o MODS is what makes SIRS/Sepsis lethal
o Early recognition is vital
What does activation of NLRs does?
o Recognition of the PAMP triggers the activation of a series of kinases leading to the phosphorylation of IkB, mobilization of NF-kB, and activation of MAPK signaling.
o Activation of the currently identified inflammasomes depends upon the interaction of NLR family members with their PAMP or DAMP ligands.
PRRs identified in vetmed
Septic foci in dogs and cats and pathogens involved
Bundle element: treat hypotension with fluids and possibly vasopressors (SACCM) - 2
o First line of resuscitation in septic patients is fluid therapy. Isotonic crystalloids, hypertonic crystalloid solutions, synthetic colloids, and blood component therapy may be used.
o Synthetic colloids have been a staple of fluid resuscitation in veterinary medicine; however, human studies have shown that resuscitation with these fluids in people is associated with an increased incidence of AKI and need for renal replacement therapy and, in the case of the Perner et al study, an increased risk of death at day 90.
o The current recommendation in human critical care is to avoid synthetic colloids in septic patients, especially when other fluid therapy options are available.
o Fresh frozen plasma is generally only used to prevent a further decline in albumin in severely hypoalbuminemic patients and for correction of coagulopathies and factor deficiencies.
o Coagulopathies, anemia, and thrombocytopenia may prompt the use of blood component therapy (e.g., fresh frozen plasma, packed red blood cells, fresh whole blood, respectively).
Bundle element: treat hypotension with fluids and possibly vasopressors (SACCM) - 3
o Hypotension that persists after restoration of intravascular volume is an indication for vasopressors or inotropic agents to support flow to tissues.
o Norepinephrine is preferred to dopamine in septic human patients, and vasopressin is also considered a reasonable first-line vasopressor.
o Although vasopressors may maintain arterial blood pressure, they can also result in excessive vasoconstriction, particularly to the splanchnic and renal circulation, thereby causing GI and renal ischemia.
o Particularly in the dog, splanchnic vasoconstriction may exacerbate the septic state by promoting loss of gut barrier function and bacterial translocation of bacteria to the bloodstream.
o Positive inotropic agents (dobutamine) are used in patients with evidence of impaired myocardial contractility (decreased fractional shortening on M-mode echocardiography, decreased cardiac output). They might also be combined with more selective vasoconstrictors such as vasopressin or phenylephrine.
Types of shock (CPBC)
Clinical shock states
Hemodynamic profiles of shock states
Hypovolemic shock - the severity of the shock depends on?
o Volume lost
Stages of hemorrhage in DO2 / VO2
Cardiogenic shock
Obstructive shock
Distributive shock
Oxygen delivery, consumption and extraction in shock states (graph)
How can we achieve an increased OER during shock states? - 2
Autoregulation
o Endothelial stretch -> myogenic reflex
o Local metabolite control -> CO2, H+, K+, lactate, adenosine
o Organs with auto regulation -> brain, heart, kidney
Compensation responses - chart
Baroreceptor reflex
o Aortic arch / carotid bodies
o Senses decreases in stretch -> increased firing from CN IX and X
o Decreased PSN -> increased HR
o Increased SNS -> increased HR, contractility, stress volume, venous return
Chemoreceptor reflex (peripheral)
o Chemoreceptors in same places as baroreceptors -> senses decreases in O2, increases in CO2, decreases in pH
o Afferent - CN IX and X
o Efferent - SNS
o Vasoconstriction, increased HR and contractility.
Chemoreceptors (central)
o Vasomotor center of medulla -> senses increased PaCO2 and decreased pH
o Excitation causes potent SNS stimulation
o CPP = MAP - ICP
o Massive vasoconstriction
o +/- reflex bradycardia
Vasopressin secretion in shock states (graph)
RAAS
Timeline of compensation responses (graph)
Stressed vs unstressed volume in shock
Consequences of glycocalyx injury
o Capillary leak
o Edema
o Progressive inflammation
o PLT aggregation
o Hypercoagulability
o Decreased vascular tone
Glycolysis and lactate production
o Glycolysis is the cytosolic process by which 1 mole of glucose is oxidized to 2 moles of pyruvate, ATP, and NADH.
o Pyruvate enters the mitochondria and is converted into acetyl CoA, which then proceeds through the tricarboxylic acid (TCA) cycle, the electron transport chain, and oxidative phosphorylation to produce 36 moles of ATP.
o Under normal aerobic conditions only a small quantity of pyruvate is converted into lactate, catalyzed by lactate dehydrogenase (LDH).
o Lactate may then be either transported out of the cell or used within the same cell.
o Ultimately lactate is either converted back into pyruvate in local or distant tissues and oxidized to produce energy or converted back into glucose by gluconeogenesis.
Causes of type A and B hyperlactatemia
Pathophysiology of sepsis associated hyperlactatemia
o The pathophysiology of sepsis-associated hyperlactatemia is complex and multifactorial.
o Suggested mechanisms include skeletal muscle Na+/K+-ATPase upregulation; mitochondrial dysfunction; increased hepatic lactate production; reduced hepatic lactate extraction; impaired tissue oxygen extraction; and capillary shunting.
o Enhanced nitric oxide production, altered neurohormonal control of endothelial smooth muscle, reduced erythrocyte flexibility, increased leukocyte activation, and pyruvate dehydrogenase (PDH) inhibition have also been implicated.
Describe Warburg’s effect
Malignant cells are known to exhibit atypical carbohydrate metabolism by preferentially utilizing glycolytic pathways for energy production despite oxygen availability.
Pathophysiology of hyperlactatemia secondary to thiamine deficiency
Suggested doses of fluids for shock resuscitation
