Benchmark questions

Small Animal Benchmark — November 2008
1) Proposed modified Duke system:
The ‘Modified Duke criteria’ were originally proposed by Li et al in 2000, to try to aid the diagnosis of infectious endocarditis in humans. These criteria have been altered for more practical relevance in the diagnosis of infectious endocarditis in canines. These criteria are described by MacDonald (in Kirks Current Veterinary Therapy XIV, 2009); Silverstein and Hopper (2009) and Sykes et al (2006) and include the following: Four major criteria: i) Positive blood culture: Two positive blood cultures, or three with a common skin contaminant New valvular insufficiency/regurgitation Oscillating valvular mass, or mass on supporting structures Vascular phenomena, major arterial emboli, septic pulmonary infarct, intracranial hemorrhage Immunological phenomena, eg polyarthritis, glomerulonephritis How a probable diagnosis is made:

To make a definitive diagnosis of infective endocarditis, either two of the
major criteria; or 1 major and two minor criteria must be met. Or there must be
histopathologic confirmation.
The make a possible diagnosis, either 1 major and 1 minor criterion; or three
minor criteria must be met. (MacDonald, 2009)
2) The four most common infectious isolates in canine patients with
endocarditis:
1) Coagulase-positive Staphylococcus spp. 2) Streptococcus spp. 3) Escherichia coli 4) Corynebacterium However, Sykes et al (2006) do mention that they believe Bartonella spp is also an important cause of canine infectious endocarditis. 3) What is meant by intermediate sensitivity?
The term intermediate sensitivity implies that the micro-organism being tested is only partially responsive to the antibiotic at the appropriate dose/rate of administration. The sensitivity is assessing the anti-microbials efficacy at the concentration of anti-microbial reached in serum/blood. It does not take into account the potential for concentration of the anti-microbial in tissues. This is an in vitro test and may not be representative of the in vivo situation. One instance in which a drug with intermediate sensitivity may be
efficacious, and why:
A drug that only has intermediate sensitivity may still be efficacious in a situation where the drug is concentrated in the particular organ/area in which the micro-organisms exist. This is because concentrations of the drug reach higher concentrations than those in serum, and therefore potentially have a greater likelihood of killing the micro-organism involved. For example, for treatment of urinary tract infections, amoxicillin is a frequently used antibiotic. Amoxicillin is concentrated in the urine, so even if the sensitivity results only read as amoxicillin having intermediate sensitivity, it may actually reach high enough concentrations in the urine to be effective in clearing the infection. 4) Mechanism of action and toxicities:

Amikacin:
Mechanism of action:
Penetrate bacteria cell -> bind to 30S ribosomal subunit ->
impairment of bacterial protein synthesis -> bacterial cell membrane permeability changes -> ↑ aminoglycoside uptake into bacterial cells -> bacterial cell disruption -> bacterial cell death. Toxicities:
1) Nephrotoxic (proximal convoluted tubules) 2) Ototoxic (cochlear and vestibular damage via destruction of sensory hair cells) – potentiated by loop diuretics +/- other diuretics. 3) Neuromuscular blockade (rare). (Inhibition of Ach release as well as Ach blockade) – especially when used at the same time as anaesthetic agents.
Enrofloxacin:
Mechanism of action:
Inhibition of DNA gyrase (bacterial topoisomerase II) and topoisomerase IV (topoisomerase enzymes). Inhibition of DNA gyrase results in inhibition of DNA supercoiling leading to inhibition of DNA replication.
Toxicities:
1) Gastro-intestinal upset (vomiting, diarrhea, nausea, abdominal 2) Cartilage damage (young dogs) 3) Cats: retinal degeneration and blindness (thought to be dose 4) Neurotoxicity – seizures, tremors, altered EEG. (Exacerbated by 5) Renal lesions (at high doses) due to crystal precipitation
Ticarcillin:
Mechanism of action:
Binds to and inhibits Penicillin binding proteins (PBP’s) -> inhibition of peptidoglycan crosslinking -> inhibition of bacterial cell wall synthesis -> bacterial cell wall damage -> cell death.
Toxicities:
1) Acute anaphylaxis; hypersensitivity reactions 2) Haemolytic anemia 3) Thrombocytopenia 4) Gastro-intestinal effects (anorexia, vomiting, diarrhea) 5) Neurotoxicity (ataxia) - dogs
Trimethoprim-Sulfa:
Mechanism of action:
Inhibits folic acid synthesis, hence inhibiting purine synthesis and
therefore also DNA synthesis.
Toxicities:
1) Hematuria, crystalluria, proteinuria 2) Anemia, thrombcytopenia, leukopenia 3) Thyroid hormone synthesis inhibition 4) Hypersensitivity reactions: fever, arthropathy, blood dyscrasias, hepatopathy, skin eruptions 5) Idiosyncratic drug reaction: polyarthropathy, KCS
Chloramphenicol:
Mechanism of action:
Binds to 50S subunit resulting in peptidyl transferase inhibition, thereby inhibiting peptide bond formation and thus protein synthesis. Toxicities:
1) Bone marrow suppression (humans: idiosyncratic/dose (Giguere et al, 2006 & Silverstein and Hopper, 2009)
5) The purpose of cilastin when combined with Imipenem
Cilastin, a dehydropeptidase inhibitor, prevents the degradation (and inactivation) of imipenem by renal dehydropeptidase that occurs when imipenem is administered on its own. 6) Minimum inhibitory concentration:
The minimum inhibitory concentration, or MIC, is the minimum concentration at which growth of a micro-organism is inhibited by a particular anti-microbial. 7) Breakpoint:
Governmental agencies or regulatory bodies set particular concentrations at which micro-organisms are deemed to be sensitive, intermediate or resistant to the anti-microbial in testing. These are known as the breakpoints. If a micro-organism is inhibited by an anti-microbial at the sensitive breakpoint, that micro-organism is deemed to be sensitive to that anti-microbial at the approved dosage and rate of administration. If the micro-organism is inhibited at the intermediate breakpoint it implies that the micro-organism will not be susceptible at the approved dosage/rate of administration, however it may be sensitive if higher concentrations are reached in the particular organ/area affected. If the micro-organism is inhibited at the resistant breakpoint, it is deemed resistant to that anti-microbial, as this is beyond the recommended therapeutic or achievable dose range (Giguere et al , 2006) 8) Difference between concentration- (dose) dependent and time dependent
antimicrobials, with examples.
Antimicrobials that rely on the concentration being above the MIC for a prolonged period of time to be effective in killing the micro-organism are known as ‘time dependant antimicrobials’. Increasing the doses of these antimicrobials does not result in increased efficacy. Examples of time dependent anti-microbials are penicillin, tetracycline, Trimethoprim sulpha. Antimicrobials that have increased efficacy at killing micro-organisms as the concentration increases above the MIC, are known at concentration dependent antimicrobials. Increasing the frequency of dosing does not increase the efficacy of these drugs. Examples of dose dependant anti-microbials include metronidazole, aminoglycosides and fluoroquinolones. (Giguere et al , 2006) 9) Four strategies used by organisms to develop antimicrobial resistance:
1) Inhibition of bacterial cell penetration. For example, Gram negative 2) Removal of antimicrobials from cells via efflux pumps. 3) Degradation/modification of antimicrobial resulting in its inactivation 4) Modification of the target of the anti-microbial resulting in inhibition 10) Two Effects by which each of 25% human albumin solution,
hydroxyethylstarch and FFP would impact on hemostasis:
25% human albumin is a large colloid that can result in a significantly expanded intravascular space after administration. This could potentially result in a dilutional coagulopathy. Can exert a “heparin-like activity on antithrombin III” as well as inhibiting platelet aggregation, resulting in anti-coagulant effects (DiBartola, 2006) Can result in decreased primary hemostasis as a result of platelet dysfunction (preventing fibrinogen binding) and inducing acquired von Willibrands disease (via decreased von Willibrand factor binding sites on platelets). (Wierenga et al, 2007 and Kudnig and Mama, 2002) Inhibition of secondary hemostasis via altered Factor VIII activity. (DiBartola, 2006) i. Provides coagulation factors therefore assisting ii. Provides anti-thrombin, thereby assisting with 11) Justification for/against correcting this patients serum albumin
concentration
It is difficult to argue for or against correcting this patient’s albumin without further information regarding this patient’s hemodynamic status and other clinical parameters. However, in the absence of this information, I would like to justify against correcting this patient’s serum albumin. Firstly, there is always a risk of both immediate and delayed reactions with the administration of human albumin. This risk would appear to be greater in ‘healthy’ dogs, speculated to be due to a greater ability to mount an immune response to the xenoprotein (Cohn, 2007). While this dog is clearly not ‘healthy’ it is not clear as to the degree of morbidity in this dog, and therefore one could argue against the administration of human albumin. Ultimately any patient is at risk of reaction and potentially fatal reaction. Secondly, we do not know whether this dog is clinically affected by the hypoalbuminemia. While albumin levels are positively correlated with colloid osmotic pressures (COP), I would like to have a COP measurement done to further assess the need to administer human albumin. Clinical parameters should also be assessed – such as presence of effusions or subcutaneous oedema. Thirdly, I would like to know the hemodynamic status prior to administration of human albumin. Human albumin is a large colloid and administration results in significant expansion of the intravascular space. Should this patient not be hypovolemic (and potentially even if he is hypovolemic), administration of human albumin could result in volume overload and hypertension. This is particularly important in this patient as his underlying disease is valvular endocarditis, therefore this patient could be particularly prone to the fluid overload and the development of pulmonary oedema, resulting in significant morbidity. 12) Why 20mL/Kg of FFP was ineffective at normalizing this patient’s serum
albumin concentration.
Fresh Frozen Plasma is often ineffective at normalizing albumin concentrations in patients as it has relatively low concentrations of albumin (only 25-30g of albumin/L (Cohn et al, 2007)) A commonly used approximate of plasma required to increase albumin is 22.5mL of plasma/Kg to increase albumin by 0.5 g/dL. Therefore in this patient, 20mL/Kg of FFP could potentially increase the albumin concentration by 0.44 g/dL (20 / 22.5 x 0.5), thereby increasing the albumin from 1.3 g/dL to 1.74 g/dL. This also does not take into account ongoing losses of albumin. 13) Amount in grams of albumin required to raise the current albumin of
1.5g/dL (15g/L) to a desired value of 2.0g/dL (20g/L). Show calculations:
Albumin defecit (g) = 10 x (target albumin (g/dL)- patient albumin (g/dL)) x body weight (Kg) x 0.3 = 10 x (2.0 - 1.5) x 15 x 0.3
= 22.5 g
(Formula obtained from DiBartola (2006) and takes into account the
intravascular and interstitial distribution of the albumin.)


14) What volume of 25% human serum albumin needs to be administered to
correct the albumin defecit?

Albumin = 22.5 g
= 22500 mg
25% solution of albumin = 250 mg/mL
Therefore amount of albumin required (mL) = 22500 mg / 250 mg/mL
= 90 mL


15) During administration of 25% human albumin, the patient develops
facial swelling, tachycardia, hypotension and tachypnea - what type of
hypersensitivity reaction is this?
This reaction is typical of a Type I hypersensitivity reaction, and presuming this dog has not been exposed to human albumin previously, is an anaphylactoid reaction. (Had this dog been previously exposed to human albumin, this reaction would be an anaphylactic reaction). Type I hypersensitivity reactions in dogs result in vasodilation and increased vascular permeability (and hence hypovolemia and shock); dermal reactions and hepatic vein congestion with portal hypertension (resulting in vomiting and diarrhea). (Silverstein and Hopper, 2009). 16) Two weeks following discharge, the patient develops azotemia, facial and
limb oedema, joint pain and proteinuria – what type of hypersensitivity
reaction is likely to be present?

This reaction is typical of ‘serum sickness’, a Type III hypersensitivity
reaction (IgG, IgM complex dependent).
This type of hypersensitivity reaction develops as the result of immune
complex (antibody-antigen complexes) deposition in the venules, particularly
in the skin, joints, kidneys and heart. There follows complement activation and
an inflammatory cascade (Francis et al, 2007 and Cohn et al, 2007).
Additional clinical signs that may be seen with Type III hypersensitivity
reactions include fever, generalized urticaria and lymphadenopathy.
17) Pentoxifylline. A) What is this agent used for? B) How may this drug help
this patient?
A) Pentoxifylline is a methylxanthine that is used
for multiple disease processes. In dogs it is used for immune mediated and other dermatological conditions, particularly those with a component of vasculitis. It is used for both its rheologic and immunodulatory effects. Its rheologic effects include increased red blood cell deformability; decreased blood viscosity; and inhibition of microvascular constriction and red blood cell and platelet aggregation. (Marks et al, 2001) Its immunomodulatory effects are thought to include “inhibition of cytokines such as interleukin-1, interleukin-6, and tumour necrosis factor-alpha (TNF-α), as well as inhibition of B- and T-cell activation” in addition to “increased leukocyte deformability and chemotaxis, decreased leukocyte adhesion; decreased neutrophil degranulation and superoxide release and decreased natural killer cell activity” (Marks et al, 2001).
B) Potentially Pentoxifylline could help this patient
with both its rheologic and immuno-modulating properties. This patient has suffered a Type III hypersensitivity reaction, resulting in inflammatory processes including vasculitis and immune complex deposition that could affect the microvascular blood flow. The immuno-modulating properties could assist in dampening down the inflammatory response and the rheologic properties assisting in improving microvascular blood flow. Ultimately this may result in increased perfusion; decreased ischemia; decreased inflammation, swelling and edema. 18) What other treatment therapies should be considered in the treatment
regime for this patient, considering the development of azotemia and
proteinuria? Give justification for the treatments.
Intravenous fluid therapy: Given that this patient has developed azotemia, intravenous fluids would certainly be warranted for diuresis. Care would need to be taken due to this patient’s underlying disease process (endocarditis) and the potential for fluid overload and congestive heart failure. Ideally, placement of a central catheter and CVP monitoring should be performed to guide the fluid therapy. The patient’s urine output should also be monitored and taken into account when calculating fluid requirements. Electrolyte and acid base monitoring and treatment if required: This patient could potentially develop both electrolyte and acid base disturbances as a result of the renal disease. These should be monitored and treated should they occur. Heparin +/- Fresh Frozen Plasma: This patient’s coagulation status should be monitored (by both coagulation screen (PT, PTT, platelets, D-dimers) and TEG). As this patient is proteinuric, presumably from glomerular disease, they could have excess loss of anti-thrombin III resulting in a hypercoagulable state. This may require treatment with heparin to reduce the formation of thrombo-emboli. Fresh frozen plasma may also be considered as a source of anti-thrombin III and also to provide clotting factors if the hypercoagulable state has resulted in consumption of clotting factors and a consumptive coagulopathy. ACE inhibitors: ACE inhibitors (ACE-I) can be used in protein losing renal disease to decrease systemic hypertension, decrease glomerular filtration pressures, improve glomerular filtration rates and decrease proteinuria. Decreasing glomerular pressures can assist in decreasing damage to the remaining renal structures. Decreased proteinuria can aid in decreased loss of anti-thrombin III, potentially decreasing the hypercoagulability of the patient. Urine protein:creatinine ratios can be obtained, to help guide treatment and assess response to treatment. Unfortunately ACE-I’s are only available in oral form, and therefore may not be able to be used in the initial phases of treatment. (Bonagura and Twedt, 2009) H2-Receptor Antagonists (eg, famotidine) +/- Proton Pump Inhibitors (eg, omeprazole): As this patient is azotemic, gastro-intestinal irritation and/or ulceration could occur. They should be treated pre-emptively. Famotidine should be dose reduced as it is renally excreted. Anti-emetics: If this patient is nauseous or vomiting, antiemetics such as metoclopramide, or dolasetron/ondansetron should be considered. Analgesia: This patient should receive analgesia for the joint pain. An opioid such as buprenorphine should be considered, or if pain is more severe a full μ agonist such as methadone. Anti-hypertensive medications such as ACE inhibitors and/or amlodipine: These may be required if this patient were to develop hypertension secondary to the glomerulonephritis. Systemic hypertension can result in further renal damage and should be treated whenever possible. Diphenhydramine: An anti-histamine that can be used to reduce ongoing histamine release and potentially help decrease the facial and limb edema present. Immuno-suppressants: In this situation I believe that immuno-suppressants would be contraindicated. Immuno-suppressants may be used in some situations with hypersensitivity reactions, to decrease ongoing immune complex formation. However in this situation the dog’s underlying disease is endocarditis. Immuno-suppressants would be contra-indicated with the presence of endocarditis. 19) List three radiographic findings that suggest to you that this patient’s
pulmonary problems are not primarily cardiogenic.
Distribution: These radiographs show a diffuse alveolar pattern throughout all lung fields. Whilst in very severe cardiogenic pulmonary edema, this distribution of pulmonary oedema could be seen, it is more common to see peri-hilar pulmonary edema in cardiac disease. Pulmonary vessel size: With cardiogenic pulmonary edema one would expect to see signs of pulmonary congestion with the pulmonic veins being larger than the pulmonic arteries. One can also look at the diameter of the pulmonary vessels on the VD view, where the pulmonary vessels cross the ninth rib. The vessels should be no greater in diameter than the width of the ninth rib. Unfortunately due to the image quality and the presence of the severe alveolar pattern, it is difficult to make out these details on the image. Cardiac silhouette: There is not obvious evidence of cardiac enlargement, which one would expect to see with congestive heart failure. On these images it is not possible to calculate a vertebral heart score, however subjectively the heart does not look to be enlarged. There does not appear to be an enlarged left atrium, with a “left atrial wedge” not being seen, nor dorsal deviation of the trachea on the lateral radiograph, nor deviation of the bronchi, or ‘cowboy legs’ seen on the VD/DV radiograph.
20) 3 pulmonary and 3 non-pulmonary causes of ARDS.
i) Pancreatitis ii) Anaphylaxis iii) SIRS/Sepsis 21) A) Starling equation for transvsacular fluid dynamics:
Jp = Kfc [(Pc-Pi) – σ (πp - πi)]
B) Define each term and describe how each component influences fluid flux.

Jp: This is the overall fluid flux, or microvascular filtration rate that occurs across a microvascular barrier. Kfc: This is the filtration co-efficient, which takes into account the surface area of the tissue and the ease at which fluid may flow across the microvascular barrier. A large surface area and a low resistance to flow favours fluid movement (in either direction). Pc: This is the hydrostatic pressure within the capillary. A high hydrostatic pressure in the capillary favours fluid movement out of the capillary. Pi: This is the hydrostatic pressure within the interstitium. A high hydrostatic pressure in the interstitium impedes fluid flow out of the capillaries. A low hydrostatic pressure will favour fluid movement out of the capillaries into the interstitium. σ: This is the reflection coefficient and represents the permeability of the microvascular membrane. A high permeability will favour fluid movement whereas a low permeability will inhibit fluid movement. πp: This is the osmotic pressure of the plasma. A high osmotic pressure of the plasma will reduce fluid movement into the interstitium, and may even favour fluid movement into the capillary. Πi: This is the osmotic pressure of the interstitium. A low osmotic pressure pressure in the interstitium will favour fluid movement out of the capillary into the interstitium, whereas a high osmotic pressure will inhibit this movement.
(DiBartola, 2006)

C) Using the Starling variable give an argument for conservative (less
maintenance rate, with or without diuretics) fluid support.
Conservative fluid rates will result in a reduction of the hydrostatic pressure
gradient across the capillary membrane (Pc-Pi). This will decrease the movement
of fluid across the membrane therefore reducing fluid flow into the interstitium.
This would be favourable in this situation as there is already the presence of
pulmonary edema, and more fluid flow into the interstitium could result in a
worsening of this pulmonary edema (as the fluid moves from the interstitium into
the alveoli) and hence worsening this patient’s ability to oxygenate.
In this patient we presumably have the presence of vasculitis, due to the
hypersensitivity reaction. This will increase the permeability of the capillary
membrane, and therefore less hydrostatic pressure would be required to have fluid
movement across the capillary membrane into the interstitium, further favouring
the conservative fluid support approach.

D) Using the Starling equation variables give an argument for liberal fluid
support.
Liberal fluid support with a colloid will increase the osmotic pressure gradient (πp - πi) and potentially could result in decreased fluid movement out into the interstitium. However there will inevitably be an increase in the hydrostatic pressure (Pc-Pi) also, so it depends on the relative increase in osmotic pressure compared to hydrostatic pressure to ultimately determine whether there would be fluid movement into the interstitium or not.
References:
Bonagura, JD and Twedt, DC. Kir’s Current Veterinary Therapy XIV. Saunders
Elsevier, Missouri, 2009

Cohn, LA; Kerl, ME; Lenox, CE; Livingston, RS; Dodam, JR. Response of healthy
dogs to infusions of human serum albumin. American Journal of Veterinary
Research, Vol 68, No.6, June 2007, Pp657-663

DiBartola, Stephen. Fluid, electrolyte, and acid-base disorders in small animal
practice, 3rd edition. Saunders Elselvier, Missouri, 2006
Francis, AH; Martin, LG; Haldorson, GJ; Lahmers, KK; Luther TY; Alperin, SC and
Hines, SA. Adverse reactions suggestive of type III hypersensitivity insix healthy
dogs given human albumin. Journal of the American Veterinary Medical Association,
Vol 230, No.6, March 15, 2007, Pp 873-879
Kudnig, ST; Mama, K. Perioperative fluid therapy. Journal of the American
Veterinary Medical Association, Vol 221, No.8, October 15, 2002, Pp 1112-1121

Li, JS; Sexton, DJ; Mick, N; Nettles, R; Fowler, Jr, VG; Ryan, T; Bashore, T and
Corey, GR. Proposed Modifications to the Duke Criteria for the Diagnosis of
Infective Endocarditis. Clinical Infectious Diseases 2000; 30 (April), Pp 633-638

MacDonald, KA. Chapter 173: Infective Endocarditis, in Kirk’s Current Veterinary
Therapy XIV, Saunders Elselvier, Missouri, 2009
Marks, SL; Merchant, S and Foil, C. Pentoxifylline: Wonder Drug? Journal of the
American Veterinary Animal Hospital Association, Vol 37, May/June 2001
Plumb, D. Veterinary Drug Handbook, fifth edition. Blackwell Publishing
Professional, Iowa, 2005
Silverstein, DC and Hopper, K. Small Animal Critical Care Medicine. Saunders
Elselvier, Missouri, 2009
Sykes, JE; Kittleson, MD; Chomel, BB; MacDonald, KA and Pesavento, KA. Clinicopathologic findings and outcome in dogs with infective endocarditis: 71 cases (1992-2005). Journal of the American Veterinary Medical Association, Vol 228, No.11, June 1, 2006, Pp 1735-1747 Sykes, JE; Kittleson, MD; Pesavento, KA; Byrne BA; MacDonald, KA and Chomel, BB. Evaluation of the relationship between causative organisms and clinical characteristics of infective endocarditis in dogs: 71 cases (1992-2005). Journal of the American Veterinary Medical Association, Vol 228, No.11, June 1, 2006, Pp 1723-1734 Trow, AV; Rozanski, EA; deLaforcade, AM and Chan, DL. Evaulation of use of human albumin in critically ill dogs: 73 cases (2003-2006). Journal of the American Veterinary Medical Association, Vol 233, No.4, August 15, 2008 Wierenga, JA; Jandrey, KE; Haskins, SC; Tablin, F. In vitro comparison of the effects of two forms of hydroxyethyl starch solutions on platelet function in dogs. American Journal of Veterinary Research, Vol 68, No.6, June 2007, Pp 605-609

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