SEPSIS/septic shock/SIRS Flashcards

Question

Which antibiotics are water soluble and how this affects the volume of distribution (Vd)

Answer 1

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

Answer 2

1. Enterococcus spp are resistant to TMPS because they absorb folic acid from their enviroment and TMPS act inhibitin folic acid synthesis. 2. For clindamycin: they have the ISA gene

Answer 3

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

Answer 4

It will fail to kill facultative anaerobes under anaerobe conditions. Aminoglycosides require aerobic movement across the cell wall to reach the targert site

Answer 5

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) )

Answer 6

Negative feedback, to inhibit its own release when sufficient norepi has been released into the synaptic cleft, avoiding over-stimulation.

Answer 7

1. cAMP messenger system in all receptors Alpha 2 (decrease -- Gi) medetomidine Beta 1,2,3 (increase--- Gs) norepi 2. alpha 1 activates phospholipase C pathyway (DAG or IP3) increases intracellular Ca, Ex: norepi, angiotensin II, Vasopressins (V1 receptors)

Answer 8

ALbumin is a negative acute phase protein there is an increased loss of albumin through the damage endothelium

Answer 9

1. Albumin (low) -> negative acute phase prot 2. blood glucose (high/low) -> * altered CH metabolism, increased gluconeogenesis, increased BG utilization, altered counterregulatory hormones. 3. Hepatobiliary markers increased: * cholestasis, altered hepatic perfusion, cytokine stimulation. 4. renal disease: Low GFR, and altered perfusion, increased UPC

Answer 10

Inadequate cellular energy production and/or utilization

Answer 11

10 - 12mmHg

Answer 12

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

Answer 13

In dogs 2/4 to be SIRS + HR> 120 RR> 20 T < 37.2 >39.2 WBC <6 or >16 and bands >2-3%

Answer 14

procalcitonin CRP

Answer 15

E coli Enterococcus Clostridium Staphylococcus Enterobacter Others: Streptococcus, Klebsiella, Proteus, Pastereulla

Answer 16

Serratia marcescens, Salmonella species, Clostridium perfringens, Acinetobacter baumannii, Escherichia coli, Clostridium difficile, Salmonella enterica, Klebsiella

Answer 17

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.

Answer 18

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.

Answer 19

A disease that normally exists in animals but that can infect humans.

Answer 20

o 35% by direct contact o 61% by indirect contact o 22% by vectors o 6% the transmission route is unknown.

Answer 21

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.

Answer 22

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.

Answer 23

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.

Answer 24

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.

Answer 25

o Vegetables and many fruits (tomatoes, cauliflower, berries and citrus fruits) o Organ meat (liver & kidney)

Answer 26

o L-isomer of ascorbic acid (reduced form), biologically active o D- isomer, not active

Answer 27

Heat and light

Answer 28

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.

Answer 29

1mg/100mL Maximum limits have not been identified

Answer 30

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.

Answer 31

TRUE o People with vitamin C deficiency have a higher incidence of multiple organ failure and death.

Answer 32

o Human hospitalized patients receiving full RER with enteral / parenteral nutrition had low plasma vitC, especially septic patients (90% hypovitaminosis C).

Answer 33

o Similar as critical illness itself: hypotension, excessive inflammation, capillary leakiness, microcirculatory dysfunction, oxidative organ injury and impaired immune defense and wound healing

Answer 34

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.

Answer 35

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.

Answer 36

FALSE - WBCs

Answer 37

o Facilitate chemotaxis o Support lymphocyte proliferation o Help with oxidative neutrophilic destruction of bacteria o Stimulates the reticuloendothelial system and antibody formation

Answer 38

No. It has strong bacteriostatic activity and can significantly inhibit bacterial replication.

Answer 39

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.

Answer 40

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.

Answer 41

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

Answer 42

Dogs - 60mg for a 13.6kg Cats - 12mg for 2.7kg

Answer 43

o fat-soluble seco steroids o increase

Answer 44

o Through dietary intake o Irradiation of the body in some species

Answer 45

From the plant steroid ergosterol

Answer 46

o AKA - cholecalciferol o Made from animal products via the precursor 7-dehydrocholesterol, synthesized in the body.

Answer 47

o Both are equally bioactive in domestic animals o They are the 2 most prominent forms of vitamin D

Answer 48

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.

Answer 49

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.

Answer 50

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.

Answer 51

FALSE - It is not produced in the skin of dogs and cats in sufficient amounts to prevent osteomalacia.

Answer 52

FALSE - Calcitriol is 500 times more potent than calcidiol binding VDRs

Answer 53

o Primary - intestines o Acts also through receptors in bone, kidneys, cardiovascular, hepatic, reproductive, respiratory, immune and CNS

Answer 54

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).

Answer 55

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%.

Answer 56

FALSE - Hypovitaminosis D as well as dysregulations in Ca have been identified in CI.

Answer 57

No, the abnormalities of hypovitaminosis D are acute and short-term, but prolonged deficiencies could lead to bone abnormalities.

Answer 58

o Endocrine disease o Intesintal malabsorption/maldigestion o Hepatic insufficiency o Renal disease o Drugs

Answer 59

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.

Answer 60

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?

Answer 61

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).

Answer 62

FALSE - then can lead to negative health outcomes, possibly due to a pro-inflammatory state.

Answer 63

Bacteria, fungi and plants Essential nutrient for dogs, cats and humans

Answer 64

Whole grains, legumes and some fish and meat

Answer 65

In the jejunum and ileum and it can be inhibited by folate deficiency and alcohol consumption

Answer 66

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.

Answer 67

FALSE - thiamine body stores are minimal

Answer 68

o Poor nutrition o Increased urinary excretion (diuresis) o Acute metabolic stress

Answer 69

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.

Answer 70

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)

Answer 71

o Not simple to measure, difficult in a clinical setting. o Published ranges vary considerably.

Answer 72

o History / disease process o Clinical signs o An elevated lactate without evidence of hypoperfusion o Unexplained neurological signs o +/- response to thiamine supplementation

Answer 73

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

Answer 74

Bilateral brainstem lesion

Answer 75

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.

Answer 76

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.

Answer 77

FALSE - Systemic inflammation may be triggered by products of both gram- positive and gram-negative bacteria.

Answer 78

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.

Answer 79

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.

Answer 80

Thrombin Leukocyte activation

Answer 81

TNF-α Protein C

Answer 82

TRUE Common causes of SIRS in animals include sepsis, heat stroke, pancreatitis, immune disease, neoplasia, severe polytrauma, and burns.

Answer 83

Acute-phase protein Hepatocytes TNF-α, and IL-1β

Answer 84

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.

Answer 85

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.

Answer 86

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.

Answer 87

PT PTT Antithrombin Protein C D-dimers

Answer 88

Protein C Antitrombin

Answer 89

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.

Answer 90

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.

Answer 91

Yes Cats are more likely to experience hypotension, hypoglycemia, and hyperbilirubinemia than dogs

Answer 92

"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

Answer 93

TRUE. Both processes can occur at different times in an individual.

Answer 94

TNF-α IL 1 IL6 IL8 IL12

Answer 95

TNF alpha and IL1 IL6 and IL8

Answer 96

TNF alpha Via induction of iNOS and cyclooxygenase 2 -> leading to vasodilation, increased capillary permeability, and local slowing of blood flow.

Answer 97

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.

Answer 98

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.

Answer 99

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.

Answer 100

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.

Answer 101

C3a anti-C5a antibodies

Answer 102

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.

Answer 103

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.

Answer 104

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.

Answer 105

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.

Answer 106

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.

Answer 107

FALSE - clearly contributes to the pathology of CI

Answer 108

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.

Answer 109

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.

Answer 110

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.

Answer 111

Lung Liver GI Kidney

Answer 112

They may be injured primarily (e.g., pneumonia, contusions) or secondarily by systemic inflammation generated by a process elsewhere.

Answer 113

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.

Answer 114

FALSE - Potentially reversible myocardial dysfunction in association with sepsis is well recognized in humans and is also documented in naturally occurring sepsis in dogs

Answer 115

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.

Answer 116

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.

Answer 117

As impaired gluconeogenesis and glycolysis, reduced synthetic and metabolic functions, and a coagulopathy.

Answer 118

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.

Answer 119

o Glutamine is necessary to maintain gastrointestinal enterocyte health and function and deficits may increase hepatic exposure to GIT-derived bacteria or bacterial toxins. o GIT-derived catecholamines may also contribute to hepatic dysfunction because Kupffer cell adrenoceptor activation enhances production of TNF-α, IL-6, and NO.

Answer 120

o Dysfunction typically manifests as ileus, gastrointestinal ulceration, intolerance of enteral feeding, vomiting, and diarrhea. o Gastrointestinal disturbances may promote systemic inflammation and reduced mucosal barrier function, allowing bacterial translocation. o Increases in GIT wall permeability have been documented in dogs after trauma. o Endotoxemia also appears to reduce GIT motility in dogs.

Answer 121

Renal hypoperfusion o In AKI secondary to sepsis, however, injury may occur in the absence of renal hypoperfusion, with ischemic tubular damage of much lower significance. o Rather, the renal circulation may participate in the vasodilatory processes that characterize hyperdynamic postresuscitation septic shock.

Answer 122

o Azotemia results from a loss of glomerular filtration pressure associated with afferent and efferent vasodilation. o Direct nephrotoxicity from high levels of TNF-α and renal cell apoptosis. o Pulmonary failure has been found to almost universally precede AKI in burn patients with MODS -> this suggests that organ crosstalk through soluble mediators, such as Fas ligand (transmembrane protein, family of TNF alpha - binding to its receptor induces apoptosis) in plasma, may be damaging the kidney through apoptosis induction.

Answer 123

o Sepsis-associated encephalopathy is a well-recognized entity in people. To date it has not been definitively identified in small animals, although it seems probable that dogs may also suffer from CNS complications of sepsis.

Answer 124

G- infections

Answer 125

o The cerebrum is most commonly involved. o Typical lesions include leukoencephalopathy, hemorrhage, microabscessation, perivascular edema, and disruption of astrocyte foot processes. o The pathophysiology of sepsis-associated encephalopathy is poorly understood and may involve microbial toxins, inflammatory mediators, metabolic and vascular abnormalities, mitochondrial dysfunction, oxidative stress, and apoptosis.

Answer 126

A protein that provides structural support for a chromosome

Answer 127

o Extracellular histones (H3 and H4 particularly) released from necrotic cells are known to mediate MODS pathogenesis and are toxic to endothelial cells in vitro. o Activated neutrophils can also be stimulated to release neutrophil extracellular traps (NETs) that contain histones, DNA, and granule proteins. o These structures may be designed to trap and kill microorganisms, but they are also capable of inducing thrombus formation, potentially through platelet activation and polyphosphate release and by impairing protein C activation.

Answer 128

o Yes. o Endothelial activation leads to Weibel-Palade body degranulation and release of angiopoietins (Ang-) and von Willebrand factor (VWF). o The angiopoietins are epithelial growth factors, of which Ang-1 and Ang-2 are best characterized but have opposing biologic effects. o Ang-1 enhances endothelial cell survival and promotes barrier integrity, whereas Ang-2 is antagonistic to Ang-1 and promotes endothelial activation and dysfunction. o Plasma concentrations of these and other endothelial biomarkers appear to have prognostic value in sepsis.

Answer 129

o Acute Physiology and Chronic Health Evaluation score - APACHE II o Simplified Acute Physiology Score - SAPS II o Sequential Organ Failure Assessment - SOFA o Mortality Prediction Model

Answer 130

o Such scores are not designed to predict outcome in individuals because clearly it is not possible to predict 80% mortality in a single patient, in whom the outcome is binary (patients either survive or they don’t). o Scores should not be used to provide prognostic information for clients; rather, they should only be used to guide therapy as part of overall patient assessment. o Most illness severity scores are used for research purposes. o Illness severity scores may be useful to monitor therapeutic interventions and to set therapeutic targets in ICU patients.

Answer 131

o Organ failure scores for patients with MODS are typically diagnosis independent and use physiologic data to assess patient status. o Organ failure scores are designed to be used repeatedly to serially evaluate changes occurring over time in individual patients. o Although organ failure scores are primarily designed to describe the nature and extent of organ dysfunction rather than predict outcome, the number and magnitude of organ dysfunction in ICU patients is highly correlated with outcomes in people and dogs. o At least 30 organ failure assessment scores have been described in the human literature. Some have been widely used, whereas others, such as the PELOD or NEOMOD, have been developed for specific patient populations. o Although several disease-specific scores have been generated in veterinary species (e.g., for trauma, pancreatitis, and DIC), no specific veterinary MODS scoring systems have been developed to date. The application of human MODS scores to small animals is currently under investigation.

Answer 132

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.

Answer 133

o Was developed from published characteristics of organ failure using an idealized set of criteria for an organ function score. o The score was then refined using logistic regression of data from one ICU and then tested against additional patients from the same location. o As for SOFA, each of the six organ systems are equally weighted, but for MOD the first measurements of the day are used. o One potentially problematic aspect of the MOD score is the use of a composite cardiovascular variable, the product of heart rate × (central venous pressure/mean arterial pressure). o The MOD score is not designed to predict outcome but does correlate with it. As with biomarkers such as lactate, a change in MOD score over time may predict outcome more accurately.

Answer 134

o Is a hybrid score with properties of a mortality prediction index and an organ failure score. o The LODS was developed from a composite database of more than 13,000 patients from ICUs in 12 countries by multivariate logistic regression techniques. o In contrast to SOFA and the MOD score, the LODS is a weighted system in which failure of some organ systems (e.g., respiratory) contributes more to the final score than others (e.g., liver). o Although not originally intended for serial use, the LODS score has been shown to accurately chart the progression of patients during their stay in ICU.

Answer 135

o The 2001 sepsis definitions consensus conference proposed stratifying patients based on their predisposing conditions, the nature and extent of both the infection and the host response, and the degree of resulting organ dysfunction (the predisposition infection response organ [PIRO] system). o Prognostic models have since been generated based on the PIRO system. The models correlate highly with mortality rates.

Answer 136

o No one score performs perfectly. o Although there are concerns with certain parameters for each of the scoring systems, the SOFA score may be easiest to apply. o The commonly used scores (i.e., SOFA, MODS, LODS) generally have excellent discriminant ability, although in several studies the SOFA score was demonstrated to be superior.

Answer 137

o Treat the source of the physiologic insult. o Support organ function.

Answer 138

TRUE o rRnal replacement therapy is currently only recommended when AKI exists

Answer 139

that nutritional support should commence once patients are hemodynamically stable and that parenteral nutrition can be used if the enteral route is not tolerated.

Answer 140

o Current recommendations in people are that blood glucose be maintained at a level of 150mg/dl (8.33 mmol/L). o In contrast, hyperglycemia requiring insulin therapy in critically ill veterinary patients is uncommon.

Answer 141

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.

Answer 142

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

Answer 143

o In places that makes sense - bacteria are mainly extracellular o PRRs that are designed to detect bacterial PAMPs, should exist at the cell membrane as bacteria are extracellular (TLR 2,4,5). o PRRs designed to detect intracellular pathogens (bacteria - mycobacteria, mycoplasma), exist intracellularly, associated with endosomes (TL 7,8,9). o Other intracellular PRRs - RIG I receptors - sense viral DNA; NOD2 receptors - bacterial peptidoglycans but from intracellular bacteria.

Answer 144

Phagocytic cells: Macrophages Neutrophils Natural Killer cells

Answer 145

o Cytokines involved in chemotaxis o AKA chemotactic cytokines

Answer 146

Acute phase protein responsible of binding LPS and presenting it to the TLR4

Answer 147

o It is a PRR but it needs TLR4 as it does not have intracellular pathway, therefore to transmit signal, teams up with TLR4. o MD2 - protein that strengthens the complex CD14 + TLR4

Answer 148

o MyD88 dependent pathway o MyD88 independent pathway (TRIF and TRAM) Those are proteins that hang out in the cytosol and become recruited and activated when they come in contact with TLR4. o Called adaptive proteins.

Answer 149

o Through the MyD88 pathway, kinases get activated o Kinases: IRAK (IL1R associated kinase), IRAK 4, MAP kinase, IkB (I kappa B) o MAP kinase will activate a nuclear transcription factor Activated Protein-1 o Activation of IkB will result in activation of nuclear factor kB o AP1 and NFkB are the 2 main nuclear transcription factors that are activated secondary to LPS binding. They translocate into the nucleus to up regulate genes that are responsible for them.

Answer 150

Same as LPS + TLR4 -> MyD88 pathway - innate immune response is not very specific, general.

Answer 151

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.

Answer 152

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

Answer 153

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.

Answer 154

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)

Answer 155

o Yes o Pro-inflammatory cytokines bind to their receptors and increase the transcription of phospholipase A2 o Phospholipase A2 -> phospholipids -> COX / LOX

Answer 156

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

Answer 157

o iNOS induced by: LPS, TNF alpha and IL1 o iNOS will help convert L-arginine into L-citrulline, causing the release of NO o NO is the most potent endogenous vasodilator -> will act on vascular smooth muscle.

Answer 158

o On the picture it should be IL10, not ILF10 -> best well known anti-inflammatory cytokine.

Answer 159

That septic SIRS is initiated by PAMPs and non-infectious SIRS is initiated by DAMPs, but the pathways are very similar.

Answer 160

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

Answer 161

o Innate defense mechanism employed to minimize penetration of the body wall by microorganisms. AKA host-defense peptides -> on mucosal surfaces. o 3 main groups: digestive enzymes and peptides that disrupt the microbial cell membrane, peptides that bind essential elements, and peptides that act as decoys for microbial attachment. o The 2 major classes of bactericidal AMPs in the mammalian immune system are the defensins and cathelicidins. o A large number of AMPs form part of the non-oxidative killing mechanism within phagolysosomes in cells such as neutrophils and macrophages,. o Also, a growing number are thought to be actively secreted onto epithelial surfaces of the gastrointestinal, respiratory and urinary tracts, the canine testis. o Recent work has revealed that important amounts of these AMPs are secreted not only by immune cells (neutrophils and alveolar macrophages) but also by atypical defense cells such as type II pneumocytes.

Answer 162

They are not only expressed on many effector cells of the immune system (including macro- phages, neutrophils, dendritic cells, and lymphocytes) but are also found on epithelial cells, endothelial cells, and myocytes.

Answer 163

o Are produced only by microbial pathogens, not by the host (eg, peptidoglycans are produced by bacteria but not by eukaryotic cells): this confers automatic self/nonself discriminatory ability. o Generally invariant molecules shared by entire classes of microorganisms; this allows the evolutionary retention of a relatively small number of PRRs recognizing vast numbers of potential pathogens. o They are usually structures vital to the survival or pathogenicity of the microorganism (eg, lipopolysaccharide in the outer membrane of G- bacteria): this allows targeting of highly conserved molecules and obviates the need for variability in host PRRs.

Answer 164

o Toll-like receptors (TLRs) o Nucleotide-binding domain, leucine-rich repeat containing proteins (NLRs, previously known as NODs) o Retinoic acid-inducible gene-1 like receptors (RLRs)

Answer 165

1, 2, 4, 5, 6, and 11 3, 7, 8, and 9

Answer 166

Epithelial cells of the respiratory and intestinal tract flagellin

Answer 167

In the cytosolic compartment of eukaryotic cells, although some recent evidence suggests that they can also be associated with the plasma membrane.

Answer 168

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.

Answer 169

Are innate immune system receptors and sensors that regulate the activation of caspase-1 and induce inflammation in response to DAMPs and PAMPs.

Answer 170

o Caspase-1 is thought to be the executioner caspase in inflammation, important in the synthesis of active IL-1b and IL-18 and thus, pathogen defense. o However, its activity needs to be tightly controlled. Excessive caspase-1 activity and thus endotoxic shock was induced in mice given high doses of LPS, but mice deficient in caspase1

Answer 171

TRUE o NF-kB and AP-1 enter the nucleus and activate transcription sites for a variety of genes, including acute phase proteins, inducible nitric oxide synthase (iNOS), coagulation factors, and pro-inflammatory cytokines and chemokines, such as tumor necrosis factor alpha and ILs-1, 6, 8, and 12.

Answer 172

o Serum concentrations of TNF-a correlate with death in certain types of human sepsis. o Studies of sepsis in vetmed have yielded similar results, although this pattern appears not to be consistent: increased serum concentrations of TNF-a correlate with mortality in canine parvovirus and neonatal septicemia in cattle and horses, but not in septic cats

Answer 173

TRUE o TNF alpha also stimulates the expression of endothelial adhesion molecules such as E-selectin, ICAM-1, and VCAM-1. o These 3 molecules lead to the tethering of leukocytes to the endothelial wall and their transmigration into the interstitium, accompanied by fluid and plasma macromolecules. o TNF-a also induces the expression of procoagulant proteins such as tissue factor and down-regulates anti-coagulant factors such as thrombomodulin, leading to activation of the coagulation cascade.

Answer 174

FALSE o Despite the important role for TNF-a in endothelial activation, experimental evidence suggests that direct stimulation of TLRs expressed by endothelial and vascular smooth muscle cells may provide an alternative pathway for the vascular dysfunction seen in sepsis.

Answer 175

o Upregulates iNOS and COX2 production o Acts as the major endogenous pyrogen in fever o Increases corticosteroid release via hypothalamic effects.

Answer 176

o Stimulatory effects upon leukocyte activation and myeloid progenitor cell proliferation o Also triggers the acute phase response and is a powerful pyrogen. o Like TNF-a and IL-1, plasma concentrations of IL-6 are increased in sepsis and may be predictive of progression to multiple organ dysfunction and death. o Increased serum concentrations of IL-6 and IL-1b do correlate with death in reports of naturally occurring sepsis in dogs and cats.

Answer 177

o Serum concentrations of anti-inflammatory cytokines, most notably IL-10, also increase in sepsis. o Inhibit the release of TNF-a, IL-1b, and IL-6 from monocytes and macrophages o Induce the production of IL-1 receptor antagonist protein (IRAP-1) and soluble TNFR, thus reducing circulating concentrations of these cytokines. o The critical role of IL-10 in mediating the balance between pro- and anti-inflammatory processes can be seen in experimental models: IL-10 knockout mice are profoundly susceptible to sepsis, whereas IL-10 administration prevents these consequences. o In clinical situations, however, the pattern appears to be more complex, with increased serum IL-10 concentrations associated with mortality in septic foals and humans. o Increased IL 10 serum concentrations associated with a lower prevalence of feline infectious peritonitis in cats infected with feline coronavirus.

Answer 178

o Macrophage migratory inhibitory factor (MIF), produced by the anterior pituitary gland, is present at increased concentrations in SIRS and sepsis. Serum concentrations have not only correlated with mortality, but inhibition of MIF appears to be protective. o High mobility group box protein 1 (HMGB-1) is an endogenous protein involved in nuclear DNA stabilization. o However, after necrotic or apoptotic cell death, it is released into the circulation where it has direct pro-inflammatory actions -> appears to potentiate the effect of certain PAMPs and DAMPs. o HMGB-1 was initially reported as a late inflammatory mediator in sepsis, although ongoing research has highlighted a number of roles in tissue repair and angiogenesis. o Circulating concentrations of HMGB-1 appear to correlate with mortality in canine SIRS patients, but were unable to predict hospital mortality in 1 study of septic human patients.

Answer 179

o Fever, neutrophilia, activation of the coagulation, and complement cascades (classical, alternative, and mannose-binding lectin pathways) o Serum iron and zinc binding, enhanced gluconeogenesis, increased muscle catabolism, and altered lipid metabolism. o As a consequence of the up-regulation of APP production, concentrations of other plasma proteins such as albumin, protein C, protein S, and antithrombin (collectively known as negative APPs) decreases.

Answer 180

2 groups of APPs are recognized o Type I, induced by IL-1a, IL-1b, and TNF-a o Type II, induced by IL-6

Answer 181

Adiponectin Insulin-like growth factor-1

Answer 182

CRP and procalcitonin o A study of SIRS and sepsis in dogs demonstrated a correlation between decreasing serum CRP concentration and recovery from disease, suggesting its use as a prognostic biomarker in this context.

Answer 183

o Is tissue factor , which initiates coagulation via the extrinsic pathway. o In health, lack of TF exposure within the vascular system and the presence of various circulating proteins (protein C, antithrombin, and tissue factor plasminogen inhibitor) modulate coagulation by the prevention of TF activation. o The expression of TF by monocytes or macrophages and tissue parenchymal cells is activated by various inflammatory cytokines, CRP, and PAMPs such as LPS (a phenomenon that has also been documented in cats and horses).

Answer 184

o Microparticles -> they are released from a variety of activated or apoptotic cells (platelets, monocytes, erythrocytes, and endothelial cells) and their interaction with endothelial cells and platelets drives the coagulation pathway. o Large numbers of TF-expressing microparticles have been identified in blood samples from septic human patients and may correlate with mortality.

Answer 185

o Whereas much research has been directed toward the inhibition of coagulation in sepsis, only activated protein C has shown any benefit in human clinical trials. o The antithrombotic and anti-inflammatory properties of recombinant human activated protein C led to recommendations for its use in severe sepsis in 2004 and 2008, but a recent meta-analysis found no evidence in support of its administration in the treatment of severe sepsis or septic shock. o Indeed, there is still debate about its mechanism of action and, as yet, little experience of its use in veterinary medicine, despite encouraging pharmacological data in experimental models.

Answer 186

Kallikrein Bradykinin o Kallikrein accelerates fibrinolysis by conversion of plasminogen to plasmin and causes additional activation of Factor XII, leading to stimulation of the classical complement pathway. o Bradykinin enhances vasodilatation and increases vascular permeability, as well as reducing platelet function.

Answer 187

o A final connection between coagulation and inflammation in sepsis has become apparent with the recent exploration of the role of ADAMTS-13. o ADAMTS-13 is a protein produced by the stellate cells of the liver and acts to cleave ultra-large von Willebrand’s Factor (vWF) multimers into smaller multimers. o These ultra-large vWF multimers are released from endothelial stores after inflammation and lead to platelet activation and aggregation; the ensuing microthrombi further compromise tissue blood flow, leading to additional propagation of the pro- inflammatory state. o Although not yet identified in clinical veterinary species, decreased plasma ADAMTS-13 activity is associated with a poor prognosis in human sepsis patients; decreased activity is attributed to both a diminution of hepatic production and an increase in breakdown by plasma proteases.

Answer 188

Rather than a sequential or compensatory change, SIRS and CARS appear to occur simultaneously, and act to balance the host’s need to maintain defense while minimizing self-induced tissue damage.

Answer 189

o The process of caspase-1-mediated programmed cell death, which is distinct from death mediated by the apoptotic caspases 3, 6, and 8. o It is characterized by rapid plasma membrane rupture and release of proinflammatory intracellular contents, some of which may act as DAMPs. o One of the targets of caspase-1 during sepsis is the glycolytic pathway.

Answer 190

A group of therapies that, when instituted together, result in better outcomes than if each individual component were to be implemented alone.

Answer 191

Lactate Samples for culture Early source control and antimicrobial administration Treat hypotension with fluids and possible vasopressors Target CVP and venous oxygen saturation

Answer 192

o Lactate production is a result of anaerobic metabolism, most commonly as a result of hypoperfusion. o High initial lactate levels are associated with poorer outcomes, particularly if the hyperlactatemia persists and if accompanied by hypotension. o Lactate clearance as it relates to traditional (e.g., blood pressure) and more recent (e.g., ScvO2) parameters remain unclear. o Lactate kinetics in the individual patient probably depends on the phase of sepsis; lactate together with ScvO2 may provide complementary information about the efficacy of resuscitation. o The Surviving Sepsis campaign guidelines (2001) recommend measuring lactate within the first 6 hours of admission and promptly initiating fluid resuscitation for patients with lactate concentrations 4 mmol/L or greater. The available veterinary literature supports this recommendation.

Answer 193

o In human health care, obtaining blood cultures in patients with sepsis or suspected sepsis is very much the standard of care and blood cultures are positive in 30% to 50% of patients with severe sepsis or septic shock. o In one study, 49% of critically ill dogs and cats had positive blood cultures. o Another study reported that 43% of dogs with gastric dilation and volvulus developed positive blood cultures. o The importance of obtaining samples for culture to aid in selection of antimicrobials cannot be over- emphasized; however, obtaining the samples should not cause a delay in initiating resuscitation nor put the patient at risk.

Answer 194

o In human patients with septic shock, elapsed time from shock recognition and qualification for early goal-directed therapy to appropriate antimicrobial therapy is a primary determinant of mortality; there is no reason to think that the same is not true in veterinary patients. o Empiric selection of appropriate antimicrobials can be challenging and should consider the location of the infection (and the ability of the antibiotic to penetrate the site), the suspected bacterial flora, community versus nosocomial source, duration of hospitalization, and previous exposure to antimicrobials. o Bactericidal better than bacteriostatic. o Septic patients require a broad-spectrum intravenous bactericidal antimicrobial regimen.

Answer 195

o Static measures to indirectly measure preload, (pulmonary artery occlusion pressure and CVP) have been used. o They can be cumbersome (PAOP) and not predictive of volume responsiveness (CVP). o Dynamic measures of fluid responsiveness may include echocardiographic evaluation of cardiac function and arterial waveform variation in ventilated patients. May also include administering serial small fluid boluses or (in people) passive leg elevation and evaluation of the hemodynamic response. o Accurate monitoring of body weight and urine output via an indwelling urinary catheter is also helpful in assessing total fluid balance as well as monitoring for oligoanuric renal failure. o However, urinary output is a result of the balance between preglomerular and postglomerular resistance. A marked increase in postglomerular resistance can induce an increase in urinary output in the presence of renal hypoperfusion.

Answer 196

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).

Answer 197

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.

Answer 198

o Venous oxygen saturation is a measure of the saturation of hemoglobin with oxygen in the venous blood; it is reflective of the difference between oxygen delivery (DO2) and oxygen consumption (VO2). o Venous oximetry is monitored intermittently via blood sampling or co-oximetry, or continuously using spectrophotometry. o Mixed venous oxygen saturation (SvO2) refers to venous blood in the pulmonary artery. Mixed venous blood is pooled blood from the entire body, including blood from the caudal half of the body and the coronary circulation. o SvO2 can be viewed as the result of the overall difference in oxygen delivery (DO2) and oxygen consumption (VO2) and therefore is a marker of global oxygen debt. o Central venous oxygen saturation (ScvO2) generally refers to the saturation of blood in the cranial vena cava, reflective of oxygen delivery and utilization in the head and upper body. In health, ScvO2 is slightly lower than SvO2 by about 2% to 3%, in part because of the high metabolic rate of the brain and cranial half of the body.

Answer 199

o Consensus and the international guidelines (2001) state that measuring ScvO2 in lieu of SvO2 (because it technically easier) can be used successfully during sepsis resuscitation. o In health much more oxygen is delivered than is extracted; however, when delivery decreases to a critical threshold, extraction decreases in concert and the patient experiences oxygen debt and lactic acidosis. o Monitoring venous oxygen saturation and using it as a therapeutic target is a recommendation in the Surviving Sepsis guidelines (2001). o The few veterinary studies that have evaluated ScvO2 as a therapeutic goal suggest its potential value in resuscitating septic and critically ill veterinary patients. o In both studies, ScvO2 was associated with prognosis. These veterinary studies mirror a large body of work in human medicine that resulted in a recommendation in the Surviving Sepsis campaign (2001) to resuscitate to an ScvO2 of 70% or greater or an SvO2 65% or greater.

Answer 200

o iIadequate cellular metabolism secondary to cardiac dysfunction when there is adequate intravascular volume.

Answer 201

o In the face of adequate intravascular volume, but reduced cardiac output from cardiac dysfunction, a patient has forward flow failure. o When this forward flow failure is sufficient to cause inadequate tissue perfusion despite an adequate intravascular volume, the patient has cardiogenic shock.

Answer 202

o Occurs secondary to elevated venous pressures, and left ventricular failure (forward flow failure) -> there is secondary reduced forward flow into the aorta and systemic circulation and blood accumulates backwards.

Answer 203

o A compensatory increase in heart rate (and systemic vascular resistance) to maintain cardiac output. o This is due to a baroreceptor-mediated sympathetic stimulation to preserve blood pressure and tissue perfusion. o In response to cardiac dysfunction–induced hypotension, neurohormonal mechanisms (RAAAS) increase the effective circulating volume.

Answer 204

o Stroke volume is determined by preload, afterload, and contractility -> cardiogenic shock can ensue from alterations in any of these. o Compromise in either systole or diastole may result in a decreased stroke volume and cardiogenic shock.

Answer 205

o No. o Most patients deteriorate secondary to the increase in preload and subsequent congestive (backward) heart failure and pulmonary edema.

Answer 206

Dilated cardiomyopathy

Answer 207

o Will eventually lead to organ dysfunction. o Reduced coronary blood flow may result in arrhythmias or decreased contractility and will exacerbate existing cardiac dysfunction. o Inadequate renal perfusion will lead to acute kidney injury, and decreased gastrointestinal perfusion may cause mucosal sloughing and hemorrhagic diarrhea.

Answer 208

o Consistent with global hypoperfusion. o A patient with cardiogenic shock will have a change in mentation manifested as depression, unresponsiveness, or disorientation. o Peripheral extremities will be cold to the touch and the mucous membranes pale, with a prolonged capillary refill time caused by intense vasoconstriction. o If the patient has backward failure and congestive heart failure, then parenchymal (pulmonary edema) or pleural space disease may result in tachypnea, dyspnea, and cyanosis. o There may also be a compensatory respiratory alkalosis in response to a lactic acidosis.

Answer 209

o The tachycardia can be due either to an appropriate sympathetic response to hypotension or concurrent congestive heart failure or may be a malignant arrhythmia (ventricular or supraventricular tachycardia) that is not allowing adequate diastolic filling and is the primary cause of cardiogenic shock. o Correction of the malignant tachycardia in the latter case will likely improve stroke volume and cardiac output, whereas antiarrhythmic therapy for the compensatory tachycardia is contraindicated and the underlying cause should be addressed.

Answer 210

o Venous blood gas analysis often reveals a metabolic acidosis. Inadequate cellular oxygenation may result in anaerobic metabolism and a lactic acidosis. o Prerenal or renal azotemia may also contribute to the metabolic acidosis. o The patient will usually have a compensatory respiratory alkalosis. o If the patient has concurrent pulmonary edema, the alveolar-arteriolar (A-a) gradient will likely be increased on an arterial blood gas analysis.

Answer 211

o Enlarged pulmonary veins o Alveolar or interstitial pattern in the perihilar region (in dogs only; infiltrates are often patchy or diffuse in cats) o Pleural effusion. o Increased LA size

Answer 212

o Congenital or acquired structural abnormalities, along with changes in cardiac chamber size or myocardial thickness. o Pressure gradients, blood flow, and an assessment of systolic and diastolic function can be obtained. o A diagnosis of cardiogenic shock may be made if there is evidence of systolic dysfunction in the presence of adequate end-diastolic volume.

Answer 213

o A patient with cardiogenic shock will have a decreased cardiac output with an increase in the preload parameters of CVP, PAP, and PAOP. o This catheter can be helpful for obtaining a diagnosis, guiding therapy, and monitoring the response to treatment.

Answer 214

o Systolic dysfunction is the inability to pump blood out of the heart. o A decrease in cardiac contractility -> DCM, sepsis, endomyocarditis and myocardial infarction. o Decreased flow through the left ventricular outflow tract (due to a functional obstruction like aortic stenosis or hypertrophic obstructive cardiomyopathy or severe retrograde blood flow -> chordae tendinae rupture with acute, severe mitral regurgitation).

Answer 215

Dilated cardiomyopathy

Answer 216

Doberman Pinscher Boxer Great Dane Labrador Retriever American Cocker Spaniel Rarely seen in cats - except those with taurine deficiency

Answer 217

o A progressive decrease in myocardial contractility that occurs over months to years results in a gradual decrease in stroke volume and forward failure. o Activation of the RAAAS and sympathetic nervous system will stimulate renal retention of sodium and water. o The increased intravascular volume results in increased end-diastolic volume. o Eccentric hypertrophy occurs secondary to cardiac myocardial stretch. o These compensatory mechanisms will maintain CO until the myocardial failure becomes so severe that the cardiac chambers cannot sustain further enlargement. o Any further increase in intravascular volume will result in an increased end-diastolic pressure, leading to an increase in pulmonary capillary hydrostatic pressure and cardiogenic pulmonary edema (with left-sided heart failure) or ascites (with right-sided heart failure).

Answer 218

Cardiomegaly along with evidence of CHF if present.

Answer 219

o The aim of treating patients with systolic dysfunction is to maximize cardiac output by increasing stroke volume. o Preload parameters should be monitored closely and fluids given only if necessary, or diuretics administered if the dog has left-sided congestive heart failure. Positive inotropic agents such as the β1- adrenergic receptor agonist dobutamine, phosphodiesterase inhibitors such as amrinone, pimobendan, or cardiac glycosides such as digoxin can be titrated to optimize stroke volume. o Optimal positive inotropic therapy has not been determined in human or veterinary medicine, and newer agents such as the calcium-sensitizing agent levosimendan are also being investigated.

Answer 220

o Studies in both humans and dogs have documented a dysfunctional myocardium in sepsis. o Even during the hyperdynamic phase of septic shock with increased cardiac output, a decrease in ejection fraction, decreased contractility and LV dilation has been documented. o A reduction in ventricular compliance, biventricular dilation, and decrease in contractile function all contribute to the decrease in ejection fraction. o Myocardial dysfunction peaks within days of the onset of sepsis and has been shown to resolve within 7 to 10 days in patients who survive. o Low cardiac output is rare in patients with septic shock but often is due to end-stage decompensated myocardial depression.

Answer 221

o Endomyocarditis is a rare condition of cats that can occur several days after a routine procedure such as neutering. o Cats have normal myocardial function before the anesthesia and the procedure is usually uneventful, but cardiac dysfunction, hypotension, pulmonary edema, and interstitial pneumonia rapidly develop. o Although not well described, the endocardium is hyperechoic on echocardiography, and histopathology reveals neutrophilic inflammation and fibroplasia. o Supportive care is recommended, and even with positive pressure ventilation the prognosis is often poor. o Myocardial infarction is the number one cause of cardiogenic shock in humans but is rarely seen (or recognized) in dogs and cats.

Answer 222

o Cardiogenic shock resulting from mechanical failure is rare in dogs and cats. o Forward flow can be reduced by an obstruction to the left ventricular outflow tract (aortic stenosis or hypertrophic obstructive cardiomyopathy) or by severe acute retrograde blood flow as may occur with a chordae tendineae rupture. o Dogs with mitral endocardiosis and associated regurgitant flows typically have normal to increased myocardial contractility. However, chordae tendineae rupture leads to acute and extensive mitral regurgitation that commonly reduces forward flow sufficiently to result in cardiogenic shock and pulmonary edema.

Answer 223

o Inadequate ventricular filling -> inability to relax, stiff muscle. o Causes: hypovolemia, a physical restriction (cardiac tamponade), inability of the myocardium to relax (hypertrophic cardiomyopathy), or inadequate time for filling (tachycardia). o Diastolic failure will result in a decreased preload and therefore a reduced stroke volume. If the animal is unable to maintain cardiac output with an increase in heart rate, cardiogenic shock ensues. o The most common cause of a decreased preload resulting in an inadequate cardiac output is hypovolemia. This is corrected by restoration of intravascular volume and is therefore not truly cardiogenic shock.

Answer 224

Because of physical restriction secondary to fluid accumulation in the pericardium

Answer 225

Most likely a result of neoplasia but can also be secondary to a coagulopathy, trauma, an atrial tear, or an idiopathic cause.

Answer 226

o The decreased diastolic ventricular filling will lead to a decrease in stroke volume and cardiac output. o In an attempt to maintain normotension and tissue perfusion, a reflex tachycardia will ensue. o Eventually the increase in heart rate will not be sufficient to maintain an adequate cardiac output and the patient will become hypotensive. o The reduced cardiac output will result in decreased tissue perfusion and a lactic acidosis. o If the effusion is chronic, the patient may have decreased sodium and increased potassium concentrations from a reduced effective circulating volume induced pseudohypoadrenocorticism.

Answer 227

o Because the systemic manifestations of this condition result from the decreased preload, increasing intravascular volume with a fluid bolus is warranted. o However, emergency pericardiocentesis to allow for normal ventricular filling is also necessary to treat the cardiogenic shock. o Pericardiocentesis in patients with coagulopathies or in dogs with a pericardial effusion secondary to an atrial tear is contraindicated, although the consequences of fulminant cardiogenic shock must be weighed against the risk of exsanguination.

Answer 228

TRUE o HCM in cats.

Answer 229

Concentric hypertrophy

Answer 230

o Decreased end-diastolic ventricular volume (because of the inability of the myocardium to relax) leads to a decreased stroke volume and cardiac output. o Activation of neurohormonal mechanisms will increase the intravascular volume to protect against hypotension and decreased tissue perfusion. o Systolic function will normally remain adequate, and patients typically have backward (rather than forward) flow failure. o However, cats with CHF that receive overzealous diuretic therapy can progress easily to hypovolemic shock. o In addition, cats with end-stage hypertrophic cardiomyopathy may also have severely impaired systolic function, leading to decreased stroke volume and cardiogenic shock. Treatment of cats with hypertrophic cardiomyopathy includes the use of β-blockers or calcium channel antagonists in an attempt to enhance lusitropy and diastolic filling

Answer 231

o Inadequate ventricular filling occurs at elevated heart rates. o End- diastolic volume is largely dependent on venous return, with atrial contraction contributing little to normal preload. o When patients become severely tachycardic (HR>200bpm), there is inadequate time for diastolic filling to occur before systole. o As a result, end-diastolic volume and therefore stroke volume and cardiac output are reduced. o The most common cause of this malignant tachycardia is a supraventricular tachycardia. o This can be a result of primary cardiac disease or a cardiac manifestation of another systemic disease process. o Therapy includes vagal maneuvers, calcium channel antagonists, and β-blockers to slow the heart rate, as well as management of the underlying condition.

Answer 232

o Yes o Severe bradycardia can lead to such a decrease in cardiac output that cardiogenic shock ensues. o The most common cause of this is severe high-grade second-degree AV block or third-degree AV block. o Animals with severe sick sinus syndrome can also suffer from decreased tissue perfusion and shock.

Answer 233

o Much slower than normal o Bundle of His produces 40 to 60bpm o Ectopic beats from the bundle branches or distal Purkinje fibers produce 20 to 40bpm.

Answer 234

o Higher escape rates will be adequate for dogs at rest, but slower rates will result in a reduced cardiac output. o An increase in SV will occur secondary to an increased preload (because of the increased time for diastolic filling), but at low heart rates or during patient exertion, the cardiac output may be inadequate and cardiogenic shock will ensue.

Answer 235

FALSE - typically have a higher ventricular escape rhythm of 100 to 140 beat/min and thus less commonly present for cardiogenic shock or syncope.

Answer 236

Intravenous fluids are contraindicated until a normal heart rate has been achieved, because preload is already increased and a further increase in left ventricular filling pressures may result in congestive (backward) heart failure.

Answer 237

o Volume lost

Answer 238

Endothelial NOS (eNOS, NOS III) is mostly expressed in endothelial cells. Inducible NOS contributes to the pathophysiology of inflammatory diseases and septic shock and it is secondary to inflammatory cytokines like TNF alpha, IL1 and IL6

Answer 239

<5 pg/mL >300 pg/mL

Answer 240

Yes, after profound or prolonged stimulation

Answer 241

At a microvascular level o Tissue conditions promote offloading of O2 from Hb (shifting curve towards right -> increased temperature, CO2, 2,3-DGP or decreased pH) o Hypoxic redistribution of flow -> when there is decreased O2 -> local regulation of blood flow -> production of adenosine, PG, NO that will cause vasodilation o Capillary recruitment -> open vessels that are currently not experiencing blood flow -> shortens diffusion distance from RBCs to surrounding tissues and increases capillary surface area available for oxygen diffusion.

Answer 242

Autoregulation o Endothelial stretch -> myogenic reflex o Local metabolite control -> CO2, H+, K+, lactate, adenosine o Organs with auto regulation -> brain, heart, kidney

Answer 243

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

Answer 244

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.

Answer 245

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

Answer 246

Stressed volume -> volume of blood in the arteries, volume that produces BP by stretching elastic fibers of arterial walls. Unstressed volume -> volume of blood in the veins. Intravascular volume remaining after passive exsanguitaion.

Answer 247

Lungs and skeletal muscle

Answer 248

Heart, brain and kidneys

Answer 249

GI and liver

Answer 250

Increased glycolysis -> increased lactate production o Does not happen with norepinephrine.

Answer 251

o Diabetes mellitus o Hyperlipidemia o Surgery o Trauma o Sepsis o Bolus crystalloids

Answer 252

o Capillary leak o Edema o Progressive inflammation o PLT aggregation o Hypercoagulability o Decreased vascular tone

Answer 253

It is a strong acid that at physiologic pH is almost completely dissociated to the lactate anion and H+

Answer 254

FALSE - Increased plasma lactate concentration is termed hyperlactatemia, and may or may not be associated with a net acidemia depending on the cause of the increased lactate, concurrent acid/base disturbances, and buffer reserves.

Answer 255

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.

Answer 256

NAD+ NADH Pyruvate

Answer 257

o The TCA cycle and oxidative phosphorylation are slowed and pyruvate and NADH build up, thereby hindering ongoing glycolysis. o To allow glycolysis to continue, NAD+ is replenished and pyruvate and H+ ions are removed by conversion of pyruvate to lactate. Although glycolysis produces only 2 moles of ATP, it is very fast and so can temporarily satisfy energy demands.

Answer 258

FALSE o The metabolic acidosis associated with lactate production is due to ATP use, not lactate production. o Glycolysis produces the lactate ion, not lactic acid. o When the ATP made by glycolysis is utilized (hydrolyzed), H+ is released into the cytosol. o This proton would usually enter the mitochondrion and be used to maintain the proton gradient required for the ETC and oxidative phosphorylation. o When oxygen supplies are insufficient this cannot happen and H+ ions accumulate and are then transported out of the cell. Hence, the acidosis from increased lactate production mostly is due to reduced H+ consumption, not increased lactate production per se.

Answer 259

No Although all tissues can produce lactate, in resting conditions the majority comes from: o Muscle 25% o Skin 25% o Brain 20% o RBCs 20% o GI 10%

Answer 260

o Liver - 50-70% of lactate consumption - can metabolize markedly increased lactate loads. o Kidneys - the cortex can metabolize 25-30% of the circulating lactate o Myocardium - 15%

Answer 261

o Lactate is not excreted in the urine until its plasma concentration is high. o It is reabsorbed by the proximal convoluted tubule, and the renal threshold above which lactate will not be reabsorbed is 6 to 10mmol/L.

Answer 262

o Splachnic circulation, skin, SQ tissue and skeletal muscle. o Local disease can also affect tissue lactate production, for example, in acute lung injury the lungs increase lactate production.

Answer 263

o No. o The liver continues to extract lactate until hepatic blood flow is less than 30% of normal, but it can actually become a net lactate producer with poor perfusion, severe hypoxia, or hepatic failure.

Answer 264

o Lactate produced by tissues is exported by the cell into the interstitium, then passes into plasma. o Once in plasma it then equilibrates with the intracellular space of erythrocytes. o Whole blood lactate refers to the sum of intraerythrocytic and plasma lactate.

Answer 265

Plasma lactate

Answer 266

Hyperlactatemia with a concurrent metabolic acidosis.

Answer 267

o Type I -> increased lactate occurred without an associated metabolic acidosis o Type II -> defined as increased lactate with a concurrent metabolic acidosis. o Type II hyperlactatemia (lactic acidosis) is further classified into two categories: type A and type B. o Type A (the most common) occurs with clinical evidence of a relative or absolute tissue oxygen deficiency. o Type B occurs in the absence of clinical evidence of decreased oxygen delivery. o Type A and B may exist concurrently. o Clinical experience suggests that type B usually results in a mild to moderate increase in lactate (3 to 6 mmol/L). o Conversely, severe hyperlactatemia (>6mmol/L) usually is due to global hypoperfusion.

Answer 268

30-60minutes

Answer 269

FALSE - Hyperlactatemia is most commonly associated with decreased oxygen delivery secondary to systemic hypoperfusion (i.e., hypovolemic, maldistributive, cardiogenic, or obstructive shock).

Answer 270

o Anemia-related hyperlactatemia is highly dependent on intravascular volume status and chronicity. o In experimental, acute, severe, euvolemic anemia, hyperlactatemia does not develop until the packed cell volume (PCV) drops below 15%. o Dogs and cats with chronic, euvolemic anemia may remain eulactatemic with a PCV of 10% or less.

Answer 271

o Severe - PaO2 25 to 40mmHg o Hypoxia should only rarely be considered as a sole diagnosis for increased lactate.

Answer 272

o Local hypoperfusion, such as occurs with aortic thromboembolism or organ volvulus, causes local increases in lactate concentration in the veins draining that tissue. o However, the effect on systemic plasma lactate concentration varies according to the remaining blood flow through the ischemic tissue and therefore how much lactate is washed into circulation. o If there is little washout, then systemic lactate may not increase appreciably. o Clinical experience suggests that organ torsion such as lung lobes, liver lobes, or spleens do not release much lactate and the systemic lactate concentration actually reflects the global perfusion status.

Answer 273

It has conventionally been divided into three subcategories: o Type B1 is associated with underlying disease o B2 with drugs or toxins o B3 with congenital or hereditary metabolic defects.

Answer 274

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.

Answer 275

Malignant cells are known to exhibit atypical carbohydrate metabolism by preferentially utilizing glycolytic pathways for energy production despite oxygen availability.

Answer 276

NADH / NAD+ o The severe metabolic acidosis and anion gap associated with EG toxicity is predominantly from acidic EG metabolites.

Answer 277

L-lactate D-lactate Pyruvate

Answer 278

o Catecholamines have been linked to increased Na+/K+-ATPase activity and increased glycogenolysis resulting in hyperlactatemia. o Conditions resulting in excess endogenous catecholamine release, such as pheochromocytoma, have also been associated with hyperlactatemia.

Answer 279

o Mitochondrial myopathies have been reported in the Jack Russell Terrier, German Shepherd, and Old English Sheepdog. o Pyruvate dehydrogenase deficiency has been recognized in the Clumber Spaniel and Sussex Spaniel.

Answer 280

o Cytokine or catecholamine stimulation of glycolytic rate can lead to elevated pyruvate and subsequently lactate levels, while mitochondrial function remains normal and H+ metabolism can continue. o Blood samples contaminated with sodium lactate (from lactated Ringer’s) will also show an increase in lactate with no acidosis.

Answer 281

o Lactate exists in levorotatory and dextrorotatory stereoisomeric forms: L-lactate and D-lactate. o L-Lactate is the predominant form produced by mammalian cells.

Answer 282

o In health, D-Lactate is present at 1% to 5% of the concentration of L-lactate. o Both D- and L-lactate are produced by some bacteria under anaerobic conditions. o In people, D-hyperlactatemia associated with short bowel syndrome and exocrine pancreatic disease is thought to cause encephalopathy. o D-hyperlactatemia has been reported in cats with DKA, propylene glycol intoxication, and exocrine pancreatic insufficiency with bacterial dysbioisis. o Cats with gastrointestinal disease also have significantly higher D-lactate than cats without gastrointestinal disease. o Hyperlactatemia should be considered as a rare but possible cause of a high anion gap metabolic acidosis in dogs and cats.

Answer 283

o Mild to moderate struggling seems to have minor effects on plasma lactate concentration. o Higher levels of muscle activity can significantly increase lactate (e.g., lots of struggling, trembling, tremors, marked exercise, and seizures).

Answer 284

Slightly higher Very small Irrelevant

Answer 285

0.3 - 2.5mmol/L

Answer 286

o Tissue oxygen extraction o Even a small rise is therefore very significant once other causes of hyperlactatemia have been ruled out.

Answer 287

24 to 48 hours

Answer 288

o Ill and injured dogs; systemically ill dogs; and dogs with SIRS, IMHA, GDV, severe soft tissue infections, heartworm- associated caval syndrome, babesiosis, and abdominal evisceration. o Lactate has also been demonstrated to have some limited prognostic value in cats with hypertrophic cardiomyopathy and septic peritonitis. o The APPLE (acute patient physiologic and laboratory evaluation) for dogs and cats found lactate to be one of the most significant variables associated with mortality and included lactate in both the full and fast scoring systems for both species.

Answer 289

o It can be measured on abdominal fluid and used in conjunction with glucose, pH, PO2, and PCO2. o Abdominal fluid from some severe cases of septic peritonitis may have a LOW glucose (<50 mg/dl), PO2, and pH (<7.0) and HIGH PCO2 and lactate. o Intraabdominal values for glucose, PO2, and pH will also often be lower than peripheral venous blood and PCO2 and lactate will be higher. o Increased peritoneal lactate concentration or peritoneal fluid-to-blood gradients occur with aseptic abdominal crises such as small bowel strangulation, mesenteric vascular thrombosis, or abdominal neoplasia. o The cause of high peritoneal fluid lactate concentrations with septic peritonitis is likely due to a combination of production by leukocytes, red blood cells (RBCs), and bacteria, as well as tissue anaerobiosis.

Answer 290

o Plasma lactate concentration should decrease by half every 1 to 2 hours. o If this does not occur, it raises the suspicion for another source of lactate such as ongoing hypovolemia, maldistributive shock, obstructive shock, or an internal focus of ischemia or neoplasia.

Answer 291

Lactate <6: Mortality 25% Lactate >6: Mortality 63%

Answer 292

Subcutaneous or intraperitoneal are generally not recommended for shock fluid administration because of longer absorption times.

Answer 293

o Physical examination parameters such as improvement in heart rate, pulse quality, capillary refill time, temperature of extremities, and brighter mentation. o Normalization of arterial blood pressure. o Bloodwork parameters such as lactate levels and central venous oxygen saturation, when available, can be serially monitored to ensure improvement with fluid therapy. o Evaluation of the microcirculation has been considered as a potential endpoint for resuscitation in humans, particularly in septic patients.

Answer 294

o 75% of the extracellular fluids are located in the interstitial)space -> a similar proportion of the total body sodium is in the interstitial fluids. o Exogenously administered sodium follows the same distribution -> 75% of the volume of sodium-based IV fluids is rapidly redistributed within the interstitium. o To increase plasma volume by a given amount, four times the desired volume needs to be administered to take into account the interstitial redistribution. o When administered rapidly as a bolus, isotonic crystalloids can effectively expand plasma volume -> a rapid infusion of 80 ml/kg of 0.9% saline to four healthy dogs caused a 76.4% increase in intravascular volume. o Rapid redistribution did occur, leaving a net intravascular volume increase of only 35% at 30 minutes and 18% at 4 hours post-infusion.

Answer 295

o Aggressive crystalloid-based resuscitation strategies can lead to several adverse effects, especially in patients predisposed to volume overload (e.g., patients with severe hypoproteinemia or cardiac disease). o Because these fluids redistribute into the interstitium, organ edema can occur and may be life threatening. o Pulmonary edema and acute lung injury are among the most commonly seen adverse effects of shock resuscitation, particularly in patients with increased vascular permeability secondary to systemic inflammation or sepsis.

Answer 296

o Decreased motility, increased intestinal permeability predisposing the patient to bacterial translocation, and increased risk for abdominal compartment syndrome.

Answer 297

o Increased risk of ventricular arrhythmias, disruption of cardiac contractility, and decreased cardiac output. o Starling’s myocardial performance curve; when beyond a designated point on the curve, further increases in end-diastolic volume cause a decrease in cardiac output.

Answer 298

o Coagulation disturbances can also occur as a result of dilution of coagulation factors and decreased blood viscosity. o However, these effects are significantly less than changes caused by synthetic colloids

Answer 299

o Isotonic crystalloids (particularly LRS) have been associated with alterations of the inflammatory cascade. o Many formulations of this crystalloid contain mixtures of both the L- and D-lactate. o The d-lactate has been associated with an increase in neutrophil stimulation, whereas the L-lactate is rapidly metabolized by the liver. o Administration of LRS's solution that contains only the L-isomer may even decrease inflammation in humans with pancreatitis.

Answer 300

Colloid osmotic pressure

Answer 301

o Is a synthetic colloid available as a 6% solution suspended in an isotonic crystalloid solution such as 0.9% saline (Hespan) or a lactated electrolyte solution (Hextend). o The colloid particles are composed of amylopectin molecules that vary in size from a few hundred to more than a million Daltons. o The clearance of hetastarch molecules from the intravascular space depends on the rate of their absorption by tissues (liver, spleen, kidney, and heart), uptake by the reticuloendothelial system, clearance through urine and bile, and enzymatic degradation to small particles by serum amylase. o α-Amylase-mediated hydrolysis can reduce the molecular weight of these particles to less than 72 kDA. o The degree of hydroxyl substitution in these starches is the primary determinant of how long they survive in the blood.

Answer 302

o Has particles with a slightly lower weight average molecular weight and a higher number of hydroxyl residues (lower substitution with hydroxyethyl groups) than hetastarch. o These properties are likely responsible for causing fewer effects on coagulation than hetastarch solutions. o This product has recently been approved for use in small animals (Vetstarch). o More studies in VM evaluating the effects of this particular synthetic colloid are necessary to assess its effectiveness and safety as a volume expander.

Answer 303

o Pentastarch is a low-molecular-weight derivative of hetastarch that is available as a 6% or 10% solution in isotonic saline. o Not currently approved for clinical use in the United States, it has been used in other parts of the world as an effective volume expander. o Pentastarch contains smaller but more numerous starch molecules than hetastarch and thus has a higher colloid osmotic pressure. o It is a slightly more effective volume expander than hetastarch and can increase plasma volume by up to 1.5 times the infusion volume.

Answer 304

Because colloids are retained in the vascular space longer than crystalloid solutions and can have adverse coagulation effects.

Answer 305

AKI Coagulopathy High molecular-weight starches can cause decreases in the activity of von Willebrand’s factor and its associated factor VIII and ristocetin cofactor activities, as well as some degree of platelet dysfunction.

Answer 306

o The administration of more than 20 ml/ kg/day of hetastarch in animals can cause coagulation derangements. o Because tetrastarch is purported to have fewer adverse effects on coagulation, higher doses can potentially be administered - up to 40 ml/kg/day.

Answer 307

o A hypertonic crystalloid solution is any saline solution that has an effective osmolarity exceeding that of normal plasma. o Hypertonic saline solutions are available commercially in variable concentrations of 3% to 23.4%

Answer 308

o Increase in blood volume about three times the volume of fluid administered. o Its ability to cause intravascular volume expansion in excess of the volume infused is due to the osmotic gradient generated by the sudden, dramatic increase in plasma osmolarity after administration, thus making it a good option for small-volume resuscitation.

Answer 309

o Immunomodulatory effects, such as decreased neutrophil activation and adherence, stimulation of lymphocyte proliferation, and inhibition of proinflammatory cytokine production by macrophages. o It also improves the rheologic properties of circulating blood, reduces endothelial cell swelling, and helps reduce intracranial pressure in patients with traumatic brain injury. o There is evidence to suggest that hypertonic saline administration improves myocardial function and causes coronary vasodilation, thereby improving overall cardiac function. o The clinical effect on cardiac contractility in dogs and cats requires further evaluation.

Answer 310

Because is rapidly redistributes into the interstitium within 30 minutes after administration and also causes an osmotic diuresis.

Answer 311

o The primary adverse effect of hypertonic saline is hypernatremia (usually transient). o There is a risk for hypernatremia-induced central pontine myelinolysis when administered to patients with preexisting chronic hyponatremia. o Most critical patients have frequent monitoring of electrolytes, and the risk of transient hypernatremia does not outweigh the potential benefits hypertonic saline therapy. o Hypertonic saline should be used cautiously in patients with pre- existing cardiac or pulmonary abnormalities because the increase in intravascular volume and hydrostatic pressure may lead to volume overload or pulmonary edema. o It can also cause significant interstitial (and intravascular) volume depletion, particularly in patients that are already dehydrated. Therefore hypertonic fluid administration should be followed by additional fluid therapy as indicated.

Answer 312

o Can be low especially in those patients with septic or hemorrhagic shock o Because of loss, vascular leak, third-spacing, and decreased production as a result of shifting of hepatic production toward acute-phase proteins.

Answer 313

o Maintenance of colloid osmotic pressure and endothelial integrity. o Wound healing o Metabolic and acid-base functions o Coagulation o Free radical scavenging Amongst others

Answer 314

FALSE - showed NO decrease in 28 day mortality

Answer 315

Albumin deficit (g) = 10 × (desired albumin − patient albumin) × weight (kg) × 0.3

Answer 316

2 ml/kg 25% HSA over 2 hours IV followed by 0.1 to 0.2 ml/kg/h for 10 hours for a total dose of 2 g/kg

Answer 317

o When HSA was administered to healthy dogs, adverse effects, including life- threatening anaphylactoid reactions, were observed in three of nine dogs receiving a single infusion and in two of two dogs that received a second transfusion. o A study performed in 2008 found the use of 25% HSA in critically ill dogs significantly raised serum albumin and total protein concentrations, as well colloid osmotic pressure, par- ticularly in survivors. o Although studies evaluating the use of HSA in critically ill dogs have observed increases in serum immunoglobulin G (IgG), acute type I hypersensitivity reactions have not been reported. o The use of HSA in critically ill dogs appears to be safer than in healthy dogs, but caution should be exercised and close monitoring is warranted.

Answer 318

In animals that present with signs of hemorrhagic shock secondary to trauma, nontraumatic hemoabdomen, GI, rodenticide intoxication, or other primary or secondary coagulopathies.

Answer 319

o Fresh whole blood transfusions carry the benefit of increased levels of clotting factors, fibrinogen, and platelets compared with component therapy. o Current recommendations in trauma resuscitation advocate minimizing or altogether avoiding crystalloid use in these patients. o Aggressive use of fresh frozen plasma is recommended in situations where whole blood is not easily available with FFP/pRBCs given in the ratio of 1:1.

Answer 320

o Restoration of a lower-than-normal systolic blood pressure (approximately 80 to 90 mm Hg) helps facilitate control of hemorrhage and reduces the risk of re-bleeding but at the same time ensures preserved blood flow to vital organs such as the kidney and GI tract. o A classic example in VM is the treatment of dogs with a nontraumatic hemoabdomen secondary to an actively bleeding intra-abdominal neoplasm. o In these dogs, overaggressive resuscitation is usually avoided, especially in the more stable patients, to avoid dislodging recently formed clots and helping to control active hemorrhage. o Hypotensive resuscitation is a temporary solution and is only meant to bridge the gap between presentation and definitive hemostatic control (usually via surgical intervention). o Hypotensive resuscitation should not be used as a long-term or permanent treatment approach because this puts the patient at risk for complications resulting from impairment of tissue perfusion.

Answer 321

The administration of fluids to patients that are hemodynamically unstable in order to assess their response to fluid therapy and guide further treatment decisions.

Answer 322

o Allows for subjective and objective assessment of the cardiovascular response during fluid infusion and rapid expansion of intravascular volume. o It also helps guide therapy while minimizing the risk of volume overload that can occur as a result of unnecessary fluid therapy. o Performing a fluid challenge with specific targets helps provide a more objective method of guiding fluid therapy decisions.

Answer 323

o Type of fluid: crystalloids or synthetic colloids are typically used to perform a fluid challenge. Smaller volumes with synthetic colloids (3-5mL/kg) than with crystalloids (10-20mL/kg) o Rate of fluid administration: fluid challenges are typically performed over a period of 10 to 30 minutes. o End points: identify the parameters that are abnormal and indicative of hemodynamic instability, and aim to assess changes in these parameters after a fluid challenge. For example, hypotension, weak pulse quality, prolonged capillary refill time, tachycardia, or oliguria might be identified. Assess for reversal or improvement in these abnormalities after completion of a fluid challenge with specific endpoints. Lactate and central venous oxygen saturation (ScVO2) monitoring, if available, can also be serially evaluated. o Safety of the fluid challenge: patients must be watched closely for signs of volume overload, particularly pulmonary edema, during any fluid challenge. Respiratory rate and effort, pulse oximetry, central venous pressures, and arterial blood gases should all be monitored.